PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Sulfonamide and Trimethoprim Antibiotic Combinations

    DEA CLASS

    Rx

    DESCRIPTION

    Combination product of trimethoprim and sulfamethoxazole in a fixed 1:5 ratio; both are synthetic folate antagonists.

    COMMON BRAND NAMES

    Bacter-Aid DS, Bactrim, Bactrim DS, Septra, Septra DS, Sulfatrim, Sulfatrim Pediatric, Sultrex Pediatric

    HOW SUPPLIED

    Bacter-Aid DS/Bactrim/Bactrim DS/Septra/Septra DS/Sulfamethoxazole, Trimethoprim Oral Tab: 400-80mg, 800-160mg
    Septra/Sulfamethoxazole, Trimethoprim/Sulfatrim/Sulfatrim Pediatric/Sultrex Pediatric Oral Susp: 5mL, 200-40mg
    Sulfamethoxazole, Trimethoprim Intravenous Inj Sol: 1mL, 80-16mg

    DOSAGE & INDICATIONS

    For the treatment of urinary tract infection (UTI), including pyelonephritis and cystitis.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO every 12 hours. The Infectious Diseases Society of America (IDSA) recommends a 3 day treatment course for acute, uncomplicated cystitis and a 14 day treatment course for pyelonephritis in female patients. For catheter-associated UTIs, the IDSA suggests that 7 days is appropriate for patients who have prompt resolution of symptoms and 10 to 14 days is recommended for those with a delayed response. The FDA-labeled duration for UTIs in general is 10 to 14 days.

    Children and Adolescents 3 to 17 years

    8 mg/kg/day (trimethoprim component) PO divided every 12 hours (Max: 320 mg trimethoprim/1,600 mg sulfamethoxazole/day) for 10 days.

    Infants and Children 2 months to 2 years

    6 to 12 mg/kg/day (trimethoprim component) PO divided every 12 hours for 7 to 14 days is recommended by the American Academy of Pediatrics (AAP) for the treatment of initial febrile UTI in infants and young children. The FDA-approved dosing is 8 mg/kg/day (trimethoprim component) PO divided every 12 hours for 10 days.

    Intravenous dosage
    Adults

    For severe infections, the manufacturer recommends 8 to 10 mg/kg/day (trimethoprim component) IV in 2 to 4 equally divided doses for up to 14 days. The Infectious Diseases Society of America (IDSA) recommends a 14 day treatment course for pyelonephritis in female patients. For catheter-associated UTIs, the IDSA suggests that 7 days is appropriate for patients who have prompt resolution of symptoms and 10 to 14 days is recommended for those with a delayed response.

    Infants, Children, and Adolescents 2 months to 17 years

    8 to 10 mg/kg/day (trimethoprim component) IV divided every 6 to 12 hours (Max: 960 mg trimethoprim/day) for up to 14 days is recommended in FDA-approved labeling for severe infections.

    For the treatment of Pneumocystis pneumonia (PCP).
    For the treatment of PCP in HIV-infected patients.
    Oral dosage
    Adults

    15 to 20 mg/kg/day (trimethoprim component) PO divided every 6 to 8 hours (Max: 1,600 mg trimethoprim/day) or 320 mg trimethoprim/1,600 mg sulfamethoxazole PO 3 times daily for 21 days then chronic suppressive therapy.

    Adolescents

    15 to 20 mg/kg/day (trimethoprim component) PO divided every 6 to 8 hours (Max: 1,600 mg trimethoprim/day) or 320 mg trimethoprim/1,600 mg sulfamethoxazole PO 3 times daily for 21 days then chronic suppressive therapy.

    Infants and Children 2 months to 12 years

    15 to 20 mg/kg/day (trimethoprim component) PO divided every 6 hours (Max: 1,600 mg trimethoprim/day) for 21 days then chronic suppressive therapy.

    Intravenous dosage
    Adults

    15 to 20 mg/kg/day (trimethoprim component) IV divided every 6 to 8 hours (Max: 960 mg trimethoprim/day) for 21 days then chronic suppressive therapy.

    Infants, Children, and Adolescents 2 months to 17 years

    15 to 20 mg/kg/day (trimethoprim component) IV divided every 6 to 8 hours (Max: 960 mg trimethoprim/day) for 21 days then chronic suppressive therapy.

    For the treatment of PCP in solid organ transplant recipients.
    Oral dosage
    Adults

    15 to 20 mg/kg/day (trimethoprim component) PO divided every 6 to 8 hours (Max: 1,600 mg trimethoprim/day) or 320 mg trimethoprim/1,600 mg sulfamethoxazole PO 3 times daily for 14 to 21 days.  

    Adolescents

    15 to 20 mg/kg/day (trimethoprim component) PO divided every 6 to 8 hours (Max: 1,600 mg trimethoprim/day) or 320 mg trimethoprim/1,600 mg sulfamethoxazole PO 3 times daily for 14 to 21 days.  

    Infants and Children 2 months to 12 years

    15 to 20 mg/kg/day (trimethoprim component) PO divided every 6 to 8 hours (Max: 1,600 mg trimethoprim/day) for 14 to 21 days. 

    Intravenous dosage
    Adults

    15 to 20 mg/kg/day (trimethoprim component) IV divided every 6 to 8 hours (Max: 960 mg trimethoprim/day) for 14 to 21 days. May consider the addition of caspofungin for salvage therapy. 

    Infants, Children, and Adolescents 2 months to 17 years

    15 to 20 mg/kg/day (trimethoprim component) IV divided every 6 to 8 hours (Max: 960 mg trimethoprim/day) for 14 to 21 days. May consider the addition of caspofungin for salvage therapy.

    For the treatment of PCP in patients with hematological malignancies, cancer, or autoimmune/inflammatory disease.
    Oral dosage
    Adults

    15 to 20 mg/kg/day (trimethoprim component) PO divided every 6 to 8 hours (Max: 1,600 mg trimethoprim/day) for 14 to 21 days.

    Infants, Children, and Adolescents 2 months to 17 years

    15 to 20 mg/kg/day (trimethoprim component) PO divided every 6 hours (Max: 1,600 mg trimethoprim/day) for 14 to 21 days.

    Intravenous dosage
    Adults

    15 to 20 mg/kg/day (trimethoprim component) IV divided every 6 to 8 hours (Max: 960 mg trimethoprim/day) for 14 to 21 days. May consider the addition of caspofungin for salvage therapy.

    Infants, Children, and Adolescents 2 months to 17 years

    15 to 20 mg/kg/day (trimethoprim component) IV divided every 6 to 8 hours (Max: 960 mg trimethoprim/day) for 14 to 21 days. May consider the addition of caspofungin for salvage therapy.

    For Pneumocystis pneumonia (PCP) prophylaxis.
    For primary PCP prophylaxis in HIV-infected patients.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or 80 mg trimethoprim/400 mg sulfamethoxazole PO once daily. Alternatively, 160 mg trimethoprim/800 mg sulfamethoxazole PO 3 times weekly. Recommended for patients with CD4 count less than 200 cells/mm3, CD4 less than 14%, or CD4 count of 200 to 250 cells/mm3 if antiretroviral therapy (ART) initiation must be delayed and if CD4 count monitoring every 3 months is not possible. May discontinue if the CD4 count is 200 cells/mm3 or more for more than 3 months in response to ART or if the CD4 count is 100 to 200 cells/mm3 and HIV RNA remains below the limit of detection for 3 to 6 months. Restart prophylaxis if CD4 count is less than 100 cells/mm3 or CD4 count is 100 to 200 cells/mm3 and HIV RNA is above detection limit.

    Adolescents

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or 80 mg trimethoprim/400 mg sulfamethoxazole PO once daily. Alternatively, 160 mg trimethoprim/800 mg sulfamethoxazole PO 3 times weekly. Recommended for patients with CD4 count less than 200 cells/mm3, CD4 less than 14%, or CD4 count of 200 to 250 cells/mm3 if antiretroviral therapy (ART) initiation must be delayed and if CD4 count monitoring every 3 months is not possible. May discontinue if the CD4 count is 200 cells/mm3 or more for more than 3 months in response to ART or if the CD4 count is 100 to 200 cells/mm3 and HIV RNA remains below the limit of detection for 3 to 6 months. Restart prophylaxis if CD4 count is less than 100 cells/mm3 or CD4 count is 100 to 200 cells/mm3 and HIV RNA is above detection limit.

    Children 6 to 12 years

    2.5 to 5 mg/kg/dose (trimethoprim component) PO twice daily or 2 or 3 times weekly or 5 to 10 mg/kg/dose (trimethoprim component) PO once daily (Max: 320 mg trimethoprim/day). Recommended for patients with CD4 count less than 200 cells/mm3 or CD4 less than 15%. May discontinue after 6 months or more of antiretroviral therapy if the CD4 count is 200 cells/mm3 or more or CD4 is 15% or more for more than 3 consecutive months. Restart prophylaxis if CD4 count is less than 200 cells/mm3 or CD4 is less than 15%.

    Children 1 to 5 years

    2.5 to 5 mg/kg/dose (trimethoprim component) PO twice daily or 2 or 3 times weekly or 5 to 10 mg/kg/dose (trimethoprim component) PO once daily. Recommended for patients with CD4 count less than 500 cells/mm3 or CD4 less than 15%. May discontinue after 6 months or more of antiretroviral therapy if the CD4 count is 500 cells/mm3 or more or CD4 is 15% or more for more than 3 consecutive months. Restart prophylaxis if CD4 count is less than 500 cells/mm3 or CD4 is less than 15%.

    Infants 2 to 11 months

    2.5 to 5 mg/kg/dose (trimethoprim component) PO twice daily or 2 or 3 times weekly or 5 to 10 mg/kg/dose (trimethoprim component) PO once daily. Recommended for all HIV-infected or HIV-indeterminate infants younger than 12 months regardless of CD4 count or percentage. Consider prophylaxis for infants born to HIV-infected mothers beginning at 4 to 6 weeks. Discontinue prophylaxis in infants with indeterminate HIV infection status when they are determined to be definitively ore presumptively HIV-uninfected. Do not discontinue prophylaxis in HIV-infected infants younger than 12 months.

    For secondary PCP prophylaxis (i.e., long-term suppressive therapy) in HIV-infected patients.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or 80 mg trimethoprim/400 mg sulfamethoxazole PO once daily. Alternatively, 160 mg trimethoprim/800 mg sulfamethoxazole PO 3 times weekly. May discontinue if the CD4 count is more than 200 cells/mm3 for more than 3 months in response to antiretroviral therapy (ART) or if the CD4 count is 100 to 200 cells/mm3 and HIV RNA remains below the limit of detection for 3 to 6 months. Restart prophylaxis if CD4 count is less than 100 cells/mm3 or CD4 count is 100 to 200 cells/mm3 and HIV RNA is above detection limit. If PCP is diagnosed or recurs at a CD4 count of more than 200 cells/mm3, lifelong prophylaxis is necessary.[34362]

    Adolescents

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or 80 mg trimethoprim/400 mg sulfamethoxazole PO once daily. Alternatively, 160 mg trimethoprim/800 mg sulfamethoxazole PO 3 times weekly. May discontinue if the CD4 count is more than 200 cells/mm3 for more than 3 months in response to antiretroviral therapy (ART) or if the CD4 count is 100 to 200 cells/mm3 and HIV RNA remains below the limit of detection for 3 to 6 months. Restart prophylaxis if CD4 count is less than 100 cells/mm3 or CD4 count is 100 to 200 cells/mm3 and HIV RNA is above detection limit. If PCP is diagnosed or recurs at a CD4 count of more than 200 cells/mm3, lifelong prophylaxis is necessary.

    Children 6 to 12 years

    2.5 to 5 mg/kg/dose (trimethoprim component) PO twice daily or 2 or 3 times weekly or 5 to 10 mg/kg/dose (trimethoprim component) PO once daily (Max: 320 mg trimethoprim/day). May discontinue after 6 months or more of antiretroviral therapy if the CD4 count is 200 cells/mm3 or more or CD4 is 15% or more for more than 3 consecutive months. Restart prophylaxis if CD4 count is less than 200 cells/mm3 or CD4 is less than 15%.

    Children 1 to 5 years

    2.5 to 5 mg/kg/dose (trimethoprim component) PO twice daily or 2 or 3 times weekly or 5 to 10 mg/kg/dose (trimethoprim component) PO once daily. May discontinue after 6 months or more of antiretroviral therapy if the CD4 count is 500 cells/mm3 or more or CD4 is 15% or more for more than 3 consecutive months. Restart prophylaxis if CD4 count is less than 500 cells/mm3 or CD4 is less than 15%.

    Infants 2 to 11 months

    2.5 to 5 mg/kg/dose (trimethoprim component) PO twice daily or 2 or 3 times weekly or 5 to 10 mg/kg/dose (trimethoprim component) PO once daily. Do not discontinue prophylaxis in HIV-infected infants younger than 12 months.

    For primary PCP prophylaxis in hematopoietic stem cell transplantation (HSCT) recipients.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or 3 times weekly or 80 mg trimethoprim/400 mg sulfamethoxazole PO once daily starting at engraftment or 1 to 2 weeks before HSCT and continuing for at least 6 months after HSCT. Recommended for all allogenic HSCT recipients and autologous HSCT recipients with underlying hematologic malignancies, those receiving intense conditioning therapy or graft manipulation, or those who have received purine analogs. Longer-term prophylaxis is recommended for the duration of immunosuppression for all patients who are receiving immunosuppressive therapy or have chronic graft-versus-host disease.

    Adolescents

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or 3 times weekly or 80 mg trimethoprim/400 mg sulfamethoxazole PO once daily starting at engraftment or 1 to 2 weeks before HSCT and continuing for at least 6 months after HSCT. Recommended for all allogenic HSCT recipients and autologous HSCT recipients with underlying hematologic malignancies, those receiving intense conditioning therapy or graft manipulation, or those who have received purine analogs. Longer-term prophylaxis is recommended for the duration of immunosuppression for all patients who are receiving immunosuppressive therapy or have chronic graft-versus-host disease.

    Infants and Children 2 months to 12 years

    150 mg/m2/day (trimethoprim component) PO once daily on 3 consecutive days/week or divided twice daily on 3 or 7 days/week (Max: 320 mg trimethoprim/day) starting at engraftment or 1 to 2 weeks before HSCT and continuing for at least 6 months after HSCT. Recommended for all allogenic HSCT recipients and autologous HSCT recipients with underlying hematologic malignancies, those receiving intense conditioning therapy or graft manipulation, or those who have received purine analogs. Longer-term prophylaxis is recommended for the duration of immunosuppression for all patients who are receiving immunosuppressive therapy or have chronic graft-versus-host disease.

    For PCP prophylaxis in solid organ transplant recipients.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or 3 times weekly or 80 mg trimethoprim/400 mg sulfamethoxazole PO once daily for 3 to 6 months after kidney transplant, for at least 6 to 12 months after other transplants, as well as for at least 6 weeks during and after antirejection therapy in kidney transplant recipients. Lifelong prophylaxis is recommended for lung and small bowel transplant recipients, as well as patients with a history of prior PCP or chronic cytomegalovirus disease.

    Adolescents

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or 3 times weekly or 80 mg trimethoprim/400 mg sulfamethoxazole PO once daily for 3 to 6 months after kidney transplant, for at least 6 to 12 months after other transplants, as well as for at least 6 weeks during and after antirejection therapy in kidney transplant recipients. Lifelong prophylaxis is recommended for lung and small bowel transplant recipients, as well as patients with a history of prior PCP or chronic cytomegalovirus disease.

    Infants and Children 2 months to 12 years

    5 to 10 mg/kg/day (trimethoprim component) PO once daily on 7 days/week or divided twice daily on 2 or 3 days/week (Max: 320 mg trimethoprim/day) for 3 to 6 months after kidney transplant, for at least 6 to 12 months after other transplants, as well as for at least 6 weeks during and after antirejection therapy in kidney transplant recipients. Lifelong prophylaxis is recommended for lung and small bowel transplant recipients, as well as patients with a history of prior PCP or chronic cytomegalovirus disease.

    For primary PCP prophylaxis in patients with cancer-related immunosuppression and hematological malignancies.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or 3 times weekly or 80 mg trimethoprim/400 mg sulfamethoxazole PO once daily. Recommended for patients receiving alemtuzumab, fludarabine/cyclophosphamide/rituximab, corticosteroids at doses equivalent to more than 20 mg/day of prednisone for 4 weeks, nucleoside or purine analogs, radiotherapy for brain tumors/metastasis plus high-dose steroids as well as for patients with acute lymphoblastic leukemia (ALL) and lymphoma treated with R-CHOP14 or escalated BEACOPP. Duration of prophylaxis for ALL is from induction to the end of maintenance. Prophylaxis for alemtuzumab-associated treatment and fludarabine/cyclophosphamide/rituximab treatment is suggested for at least 6 months after treatment completion.

    Infants, Children, and Adolescents 2 months to 17 years

    150 mg/m2/day (trimethoprim component) PO once or twice daily, 2 or 3 times weekly, or once weekly (Max: 320 mg trimethoprim/day). Recommended for patients receiving alemtuzumab or corticosteroids at doses equivalent to more than 0.4 mg/kg/day or 16 mg/day of prednisone for 1 month or more as well as patients with acute lymphoblastic leukemia (ALL), severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome (WAS), X-linked agammaglobulinemia, human leukocyte antigen (HLA) II combined immunodeficiency, acute myeloid leukemia (AML), and solid tumors. Duration of prophylaxis for ALL is from induction to the end of maintenance. Patients receiving corticosteroids or with SCID, WAS, X-linked agammaglobulinemia, or HLA II combined immunodeficiency require lifelong prophylaxis or until restoration of the underlying defect. Prophylaxis is recommended for patients with AML and solid tumors for the duration of chemotherapy.[55864] [64855] [64857]

    For primary PCP prophylaxis in dermatology and rheumatology patients receiving corticosteroids.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or 3 times weekly or 80 mg trimethoprim/400 mg sulfamethoxazole PO once daily or 3 times weekly. Recommended for patients receiving corticosteroids at doses equivalent to 20 mg/day or more of prednisone for 4 weeks or more, particularly if an additional risk factor is present.  

    For the treatment of otitis media.
    Oral dosage
    Adults†

    160 mg trimethoprim/800 mg sulfamethoxazole PO every 12 hours.

    Infants, Children, and Adolescents 2 months to 17 years

    8 mg/kg/day (trimethoprim component) PO divided every 12 hours (Max: 320 mg trimethoprim/1,600 mg sulfamethoxazole/day) for 10 days is recommended in FDA-approved labeling. The American Academy of Pediatrics (AAP) does not recommend sulfamethoxazole; trimethoprim as a treatment option in patients with type I penicillin allergy due to the low rates of cross sensitivity between penicillin and second and third generation cephalosporins, which are the recommended alternative agents. Sulfamethoxazole; trimethoprim is also not recommended as second-line therapy for children who have failed amoxicillin therapy due to high rates of pneumococcal resistance.

    For the treatment of acute exacerbations of chronic bronchitis.
    Oral dosage
    Adults

    The manufacturer recommends 160 mg trimethoprim/800 mg sulfamethoxazole PO every 12 hours for 14 days.

    For the treatment of shigellosis.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO twice daily for 5 days. For HIV-infected patients, treat for 7 to 10 days or extend therapy to at least 14 days with bacteremia. Recurrent infection may require treating for up to 6 weeks. Shigella infections that are acquired outside of the U.S. may have high rates of trimethoprim; sulfamethoxazole resistance.

    Adolescents

    8 mg/kg/day (trimethoprim component) PO divided every 12 hours (Max: 320 mg trimethoprim/1,600 mg sulfamethoxazole/day) for 5 days.[43888] [43889] For HIV-infected patients, treat for 7 to 10 days or extend therapy to at least 14 days with bacteremia. Recurrent infection may require treating for up to 6 weeks. Shigella infections that are acquired outside of the U.S. may have high rates of trimethoprim; sulfamethoxazole resistance.[34362]

    Infants and Children 2 months to 12 years

    8 mg/kg/day (trimethoprim component) PO divided every 12 hours (Max: 320 mg trimethoprim/1,600 mg sulfamethoxazole/day) for 5 days.[43888] [43889]

    Intravenous dosage
    Adults

    8 to 10 mg/kg/day (trimethoprim component) IV divided every 6 to 12 hours for 5 days. 160 mg trimethoprim/800 mg sulfamethoxazole IV every 12 hours is recommended for HIV-infected patients. Treat for 7 to 10 days or extend therapy to at least 14 days with bacteremia. Recurrent infection may require treating for up to 6 weeks. Shigella infections that are acquired outside of the U.S. may have high rates of trimethoprim; sulfamethoxazole resistance.

    Adolescents

    8 to 10 mg/kg/day (trimethoprim component) IV divided every 6 to 12 hours for 5 days. 160 mg trimethoprim/800 mg sulfamethoxazole IV every 12 hours is recommended for HIV-infected patients. Treat for 7 to 10 days or extend therapy to at least 14 days with bacteremia. Recurrent infection may require treating for up to 6 weeks. Shigella infections that are acquired outside of the U.S. may have high rates of trimethoprim; sulfamethoxazole resistance.

    Infants and Children 2 months to 12 years

    8 to 10 mg/kg/day (trimethoprim component) IV divided every 6 to 12 hours for 5 days.

    For the treatment of traveler's diarrhea due to enterotoxigenic E. coli.
    Oral dosage
    Adults

    160 mg trimethoprim; 800 mg sulfamethoxazole PO every 12 hours for 5 days. Clinical practice guidelines do not include trimethoprim; sulfamethoxazole.

    For urinary tract infection (UTI) prophylaxis†.
    Oral dosage
    Adults

    40 to 80 mg (trimethoprim component) PO once daily each day or 3 times a week.

    Infants, Children, and Adolescents 2 months to 17 years

    2 mg/kg/dose (trimethoprim component) PO once daily in the evening or 5 mg/kg/dose (trimethoprim component) PO twice per week has been used.[31857] [39033] [41141] In a 12-month, randomized, placebo-controlled trial in pediatric patients (n = 564, median age = 14 months) with recurrent urinary tract infections, there was a 6% reduction in the absolute risk of symptomatic UTIs in predisposed children who received prophylaxis with 2 mg/kg/dose (trimethoprim component) PO daily. The pattern of recurrence suggested that the greatest benefit of prophylaxis came during the first 6 months, which was the most likely time for recurrent infection. However, the data suggest that prolonged administration resulted in changes in bacterial susceptibility patterns that increased the risk of symptomatic UTI with bacteria resistant to sulfamethoxazole; trimethoprim.[41141] Prophylaxis for UTI is only recommended in high-risk patients, which includes infants and children with recurrent febrile UTI and infants and children with reflux grade of III or higher.[51831]

    For bacterial infection prophylaxis† in HIV-infected children and infants.
    For secondary prophylaxis† in HIV-infected children with recurrent, severe bacterial infections.
    Oral dosage
    Infants and Children 2 months to 12 years

    150 mg/m2/day (trimethoprim component) PO divided every 12 hours. Secondary prophylaxis is only recommended for infants and children with more than 2 serious bacterial infections in a 1-year period who are unable to take antiretroviral therapy. Secondary prophylaxis may be discontinued for sustained (3 months or more) immune reconstitution (CD4 at least 25% if 6 years or younger; CD4 at least 20% or CD4 count more than 350 cells/mm3 if older than 6 years). Secondary prophylaxis should be restarted for more than 2 serious bacterial infections in a 1-year period despite antiretroviral therapy.

    For primary prophylaxis† to reduce opportunistic infection in HIV-infected children (regardless of CD4 count).
    Oral dosage
    Infants and Children 2 months to 12 years

    150 mg/m2/day (trimethoprim component) PO divided every 12 hours may be considered an alternative treatment to decrease the rate of serious bacterial infections in HIV-infected infants and children unable to take antiretroviral therapy; however, guidelines do not recommend routine primary prophylaxis of bacterial infections, when not indicated for PCP or MAC prophylaxis or other specific reasons. A randomized, double-blind, placebo-controlled study in Zambian children aged 1 to 14 years (n = 541) with clinical features of HIV-infection evaluated the efficacy of sulfamethoxazole; trimethoprim (SMX-TMP) in reducing opportunistic infections in an area with high levels of in vitro bacterial resistance to SMX-TMP. Children younger than 5 years received 240 mg (5 mL of suspension) PO daily and those 5 years and older received 480 mg (10 mL suspension) PO daily or matching placebo. SMX-TMP reduced mortality by 43% and hospitalization by 23% compared to placebo. It was concluded that children of all ages with clinical features of HIV infection receive SMX-TMP prophylaxis in resource-poor areas, regardless of local resistance to the antibiotic.

    For the treatment of toxoplasmic encephalitis† (TE) due to Toxoplasma gondii.
    Oral dosage
    Adults

    5 mg/kg/dose (trimethoprim component) PO every 12 hours as an alternative regimen, then chronic maintenance therapy. Treatment duration should be at least 6 weeks; however, a longer duration may be necessary if clinical or radiologic disease is extensive or if the response is incomplete at 6 weeks. Adjunctive corticosteroids may be administered when clinically indicated for the treatment of mass effect attributed to focal lesions or associated edema; however, discontinue as soon as possible. Anticonvulsants may be administered to patients with a seizure history during the acute treatment phase; however, they should not be used prophylactically.

    Adolescents

    5 mg/kg/dose (trimethoprim component) PO every 12 hours as an alternative regimen, then chronic maintenance therapy. Treatment duration should be at least 6 weeks; however, a longer duration may be necessary if clinical or radiologic disease is extensive or if the response is incomplete at 6 weeks. Adjunctive corticosteroids may be administered when clinically indicated for the treatment of mass effect attributed to focal lesions or associated edema; however, discontinue as soon as possible. Anticonvulsants may be administered to patients with a seizure history during the acute treatment phase; however, they should not be used prophylactically.

    Infants and Children 2 months to 12 years

    5 mg/kg/dose (trimethoprim component) PO every 12 hours has been used as an alternative regimen in adults; however, this regimen has not been evaluated in children.

    Intravenous dosage
    Adults

    5 mg/kg/dose (trimethoprim component) IV every 12 hours as an alternative regimen, then chronic maintenance therapy. Treatment duration should be at least 6 weeks; however, a longer duration may be necessary if clinical or radiologic disease is extensive or if the response is incomplete at 6 weeks. Adjunctive corticosteroids may be administered when clinically indicated for the treatment of mass effect attributed to focal lesions or associated edema; however, discontinue as soon as possible. Anticonvulsants may be administered to patients with a seizure history during the acute treatment phase; however, they should not be used prophylactically.

    Adolescents

    5 mg/kg/dose (trimethoprim component) IV every 12 hours as an alternative regimen, then chronic maintenance therapy. Treatment duration should be at least 6 weeks; however, a longer duration may be necessary if clinical or radiologic disease is extensive or if the response is incomplete at 6 weeks. Adjunctive corticosteroids may be administered when clinically indicated for the treatment of mass effect attributed to focal lesions or associated edema; however, discontinue as soon as possible. Anticonvulsants may be administered to patients with a seizure history during the acute treatment phase; however, they should not be used prophylactically.

    Infants and Children 2 months to 12 years

    5 mg/kg/dose (trimethoprim component) IV every 12 hours has been used as an alternative regimen in adults; however, this regimen has not been evaluated in children.

    For toxoplasmosis prophylaxis†, specifically prevention of toxoplasmic encephalitis (TE) due to Toxoplasma gondii.
    For primary prophylaxis† in HIV-infected patients.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily in patients with an IgG antibody to Toxoplasma and a CD4+ count less than 100 cells/mm3. As an alternative, may give 160 mg trimethoprim/800 mg sulfamethoxazole PO 3 times per week or 80 mg trimethoprim/400 mg sulfamethoxazole PO daily. Primary prophylaxis for TE may be discontinued in patients who have responded to highly active antiretroviral therapy with an increase in CD4 count to more than 200 cells/mm3 for at least 3 months. Prophylaxis should be reintroduced if CD4 count decreases to less than 100 to 200 cells/mm3.

    Adolescents

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily in patients with an IgG antibody to Toxoplasma and a CD4+ count less than 100 cells/mm3. As an alternative, may give 160 mg trimethoprim/800 mg sulfamethoxazole PO 3 times per week or 80 mg trimethoprim/400 mg sulfamethoxazole PO daily. Primary prophylaxis for TE may be discontinued in patients who have responded to highly active antiretroviral therapy with an increase in CD4 count to more than 200 cells/mm3 for at least 3 months. Prophylaxis should be reintroduced if CD4 count decreases to less than 100 to 200 cells/mm3.

    Infants and Children 2 months to 12 years

    150 mg/m2 trimethoprim/750 mg/m2 sulfamethoxazole PO once daily (Max: 160 mg trimethoprim/800 mg sulfamethoxazole/day) in patients with an IgG antibody to Toxoplasma and severe immunosuppression (i.e., infants and children younger than 6 years of age with a CD4 percentage less than 15% or children 6 years and older with a CD4 count less than 100 cells/mm3). Acceptable alternative regimens include 150 mg/m2 trimethoprim/750 mg/m2 sulfamethoxazole PO once daily for 3 consecutive days each week, 150 mg/m2 trimethoprim/750 mg/m2 sulfamethoxazole PO per day in 2 divided doses given every day, or 150 mg/m2 trimethoprim/750 mg/m2 sulfamethoxazole PO per day in 2 divided doses given 3 times per week on alternate days (e.g., Monday, Wednesday, Friday). Prophylaxis should not be discontinued in infants younger than 1 year of age. For children 1 to 5 years of age, primary prophylaxis may be discontinued after at least 6 months of antiretroviral therapy if CD4 percentage is at least 15% for more than 3 consecutive months. For children 6 years and older, primary prophylaxis may be discontinued after at least 6 months of antiretroviral therapy if CD4 count is more than 200 cells/mm3 for more than 3 consecutive months. Primary prophylaxis should be restarted if CD4 counts fall below these thresholds.

    For chronic maintenance therapy† (secondary prophylaxis†) after acute toxoplasmosis infection.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or twice daily is recommended as an alternative in the HIV guidelines. Once daily therapy may be associated with an increased risk of relapse; therefore, a gradual transition from acute therapy may be beneficial, utilizing the twice daily dose for 4 to 6 weeks before switching to once daily dosing. Chronic maintenance therapy may be discontinued if initial therapy is successfully completed, patient remains free of signs and symptoms of encephalitis, and has a CD4 count more than 200 cells/mm3 for more than 6 months in response to antiretroviral therapy. Restart chronic maintenance therapy if the CD4 count drops below 200 cells/mm3.

    Adolescents

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or twice daily is recommended as an alternative in the HIV guidelines. Once daily therapy may be associated with an increased risk of relapse; therefore, a gradual transition from acute therapy may be beneficial, utilizing the twice daily dose for 4 to 6 weeks before switching to once daily dosing. Chronic maintenance therapy may be discontinued if initial therapy is successfully completed, patient remains free of signs and symptoms of encephalitis, and has a CD4 count more than 200 cells/mm3 for more than 6 months in response to antiretroviral therapy. Restart chronic maintenance therapy if the CD4 count drops below 200 cells/mm3.

    Infants and Children 2 months to 12 years

    150 mg/m2 trimethoprim/750 mg/m2 sulfamethoxazole PO once daily (Max: 160 mg trimethoprim/800 mg sulfamethoxazole/day) is recommended as an alternative by guidelines. There are very limited data for alternative regimens in children and trimethoprim/sulfamethoxazole is only recommended in patients who are intolerant to other preferred regimens. Chronic maintenance therapy may be discontinued in patients who have received antiretroviral therapy for at least 6 months, have successfully completed initial therapy and remain free of signs and symptoms of encephalitis, and have a CD4 count of at least 15% (1 to 5 years of age) or more than 200 cells/mm3 (6 years and older) for more than 6 months. Restart chronic maintenance therapy if the CD4 count drops below these thresholds.

    For primary prophylaxis† in allogeneic hematopoietic stem cell transplantation (HSCT) recipients with IgG antibody to Toxoplasma.
    NOTE: Prophylaxis should be started after engraftment and given as long as the patient remains on immunosuppressant therapy (i.e., usually until 6 months after HSCT).
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily; or 80 mg trimethoprim/400 mg sulfamethoxazole PO once daily; or 160 mg trimethoprim/800 mg sulfamethoxazole PO 3 times per week.

    Adolescents

    160 mg trimethoprim/800 mg sulfamethoxazole PO once daily; or 80 mg trimethoprim/400 mg sulfamethoxazole PO once daily; or 160 mg trimethoprim/800 mg sulfamethoxazole PO 3 times per week.

    Infants and Children 2 months to 12 years

    150 mg/m2 trimethoprim/750 mg/m2 sulfamethoxazole per day PO in 1 of the following regimens: 2 divided doses 3 times weekly on consecutive days, a single dose 3 times weekly on consecutive days, 2 divided doses daily, or 2 divided doses 3 times weekly on alternate days (Max: 160 mg trimethoprim/800 mg sulfamethoxazole/day).

    For the treatment of Legionnaire's disease† caused by Legionella pneumophila.
    Intravenous dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole IV every 8 hours.

    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO every 12 hours.

    For the treatment of actinomycotic mycetoma†.
    For actinomycotic mycetoma† caused by Actinomadura pelletierii, Actinomadura madurae, Streptomyces somaliensis.
    Oral dosage
    Adults

    23 mg/kg/day PO of sulfamethoxazole and 4.6 mg/kg/day of trimethoprim PO in two divided doses in combination with streptomycin.

    For actinomycotic mycetoma† caused by Nocardia brasiliensis, Nocardia asteroides, or Nocardia otitidiscaviarum.
    Oral dosage
    Adults

    45 mg/kg/day PO of sulfamethoxazole and 9 mg/kg/day of trimethoprim PO in two divided doses in combination with dapsone or amikacin.

    For the treatment of nocardiosis† caused by Nocardia sp..
    Oral dosage
    Adults

    Uncertainty exists regarding the dose of co-trimoxazole for this condition. A retrospective review of 19 patients at Duke University who received co-trimoxazole for treatment of documented Nocardia infection revealed that patients received an average of 8.2 regular strength tablets/day for an average of 7.2 months. Resolution was achieved in 17/19 patients and in 9/19, co-trimoxazole was the only form of therapy given.

    For the treatment of pertussis (whooping cough)† caused by Bordetella pertussis or for postexposure pertussis prophylaxis†.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO every 12 hours for 14 days is recommended as an alternative to a macrolide. For postexposure prophylaxis, administer to asymptomatic close contacts within 3 weeks of exposure, especially patients at high risk for pertussis-related complications (e.g., pregnant women in third trimester). Symptomatic contacts (coughing) should be treated as if they have pertussis.

    Infants, Children, and Adolescents 2 months to 17 years

    8 mg/kg/day (trimethoprim component) PO divided every 12 hours (Max: 320 mg trimethoprim/1,600 mg sulfamethoxazole/day) for 14 days is recommended as an alternative to a macrolide. For postexposure prophylaxis, administer to asymptomatic close contacts within 3 weeks of exposure, especially patients at high risk for pertussis-related complications (e.g., infants younger than 12 months). Symptomatic contacts (coughing) should be treated as if they have pertussis.

    For the treatment of bacteremia† and catheter-associated infections†.
    Intravenous dosage
    Adults

    3 to 5 mg/kg/dose (trimethoprim component) IV every 8 hours for certain catheter-associated infections. In patients with persistent MRSA bacteremia and vancomycin treatment failures, 5 mg/kg/dose (trimethoprim component) IV every 12 hours in combination with high dose daptomycin. If there is reduced susceptibility to vancomycin and daptomycin, sulfamethoxazole; trimethoprim may be administered as a single agent or in combination with other antibiotics.

    Infants, Children, and Adolescents 2 months to 17 years

    6 to 12 mg/kg/day (trimethoprim component) IV divided every 12 hours (Max: 960 mg trimethoprim/day) for mild-to-moderate infections and 15 to 20 mg/kg/day (trimethoprim component) IV divided every 6 to 8 hours (Max: 960 mg trimethoprim/day) for certain serious catheter-associated infections.

    For prevention of bacteremia† (i.e., bacteremia prophylaxis†) or spontaneous bacterial peritonitis† (i.e., peritonitis prophylaxis†) in patients with cirrhosis and ascites.
    Oral dosage
    Adults

    Sixty patients with cirrhosis and ascites were randomly assigned to receive 1 SMX-TMP double-strength tablet PO once daily (i.e., 160 mg trimethoprim/800 mg sulfamethoxazole) for 5 consecutive days each week for 3 months or no treatment. The incidence of spontaneous bacterial peritonitis or bacteremia was significantly less in the group that received oral therapy with SMX-TMP.

    For the treatment of typhoid fever† due to Salmonella typhi.
    For acute infections.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO every 12 hours for 14 days.

    Infants, Children, and Adolescents 2 months to 17 years

    8 mg/kg/day (trimethoprim component) PO divided every 12 hours (Max: 320 mg trimethoprim/1,600 mg sulfamethoxazole/day) for 14 days.

    Intravenous dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole IV every 12 hours for 14 days.

    Infants, Children, and Adolescents 2 months to 17 years

    8 mg/kg/day (trimethoprim component) IV divided every 12 hours (Max: 320 mg trimethoprim/1,600 mg sulfamethoxazole/day) for 14 days.

    For chronic carriers.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO every 12 hours for 6 weeks.

    For the treatment of Staphylococcus aureus infections†, including endocarditis†.
    Intravenous dosage
    Adults

    In a prospective, randomized, double-blind trial, SMX-TMP dosed as 320 mg trimethoprim IV every 12 hours was compared to vancomycin in IV drug abusers with infections due to Staphylococcus aureus. Although the cure rate was significantly higher with vancomycin after roughly 3 weeks of therapy (e.g., 98% for vancomycin vs. 86% for SMX-TMP), the authors concluded that SMX-TMP could be considered an alternative in patients who cannot receive vancomycin if infection is due to methicillin-sensitive S. aureus. Clinical practice guidelines do not recommend SMX-TMP for endocarditis but acknowledge occasional use as salvage therapy.

    For the treatment of methicillin-resistant Staphylococcus aureus (MRSA) skin and skin structure infections†, including cellulitis†.
    Oral dosage
    Adults

    160 to 320 mg trimethoprim/800 to 1,600 mg sulfamethoxazole PO every 12 hours for 5 to 10 days.

    Infants, Children, and Adolescents 2 months to 17 years

    4 to 6 mg/kg/dose (trimethoprim component) PO every 12 hours (Max: 320 mg trimethoprim/1,600 mg sulfamethoxazole/dose) for 5 to 10 days.

    For the treatment of granuloma inguinale† (Donovanosis) caused by Klebsiella granulomatis.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO twice daily for a minimum of 3 weeks and until all lesions have completely healed is recommended as an alternative by the CDC. Consider the addition of an aminoglycoside, such as gentamicin, if lesions do not respond within the first few days of therapy or if the patient also has HIV infection. For pregnant and lactating patients, use erythromycin or azithromycin.

    Adolescents

    160 mg trimethoprim/800 mg sulfamethoxazole PO twice daily for a minimum of 3 weeks and until all lesions have completely healed is recommended as an alternative by the CDC. Consider the addition of an aminoglycoside, such as gentamicin, if lesions do not respond within the first few days of therapy or if the patient also has HIV infection.[59799]

    For the treatment of therapy-resistant pediculosis† capitis (head lice infestation) due to Pediculus capitis†.
    Oral dosage
    Adults

    5 mg/kg/dose (trimethoprim component) PO twice daily for 3 days, followed by another 3-day course after a 7 to 10 day interval.

    Children and Adolescents

    5 mg/kg/dose (trimethoprim component) PO every 12 hours for 10 days has been used. In 1 study, 115 children randomly received 1 of 3 treatment regimens: topical 1% permethrin alone; oral sulfamethoxazole/trimethoprim 5 mg/kg/dose (based on the trimethoprim component) PO every 12 hours for 10 days; or the combination of topical 1% permethrin and oral sulfamethoxazole/trimethoprim. At 2-week follow-up, the success rates were 79.5%, 83%, and 95%, respectively. At 4-weeks, the success rates were 72%, 78%, and 92.5%, respectively. Oral sulfamethoxazole/trimethoprim either alone or combined with topical 1% permethrin was an effective alternative; however, it was recommended that combination therapy be reserved for cases of lice resistance or multiple treatment failures.

    For the treatment of melioidosis† and for postexposure prophylaxis.
    Oral dosage
    Adults weighing more than 60 kg

    320 mg trimethoprim/1,600 mg sulfamethoxazole PO every 12 hours for 12 weeks for the oral eradication-phase of therapy after initial IV treatment and for 21 days as postexposure prophylaxis during a public health emergency. Consider adding sulfamethoxazole; trimethoprim to carbapenem therapy in setting of persistent bacteremia.

    Adults weighing 40 to 60 kg

    240 mg trimethoprim/1,200 mg sulfamethoxazole PO every 12 hours for 12 weeks for the oral eradication-phase of therapy after initial IV treatment and for 21 days as postexposure prophylaxis during a public health emergency. Consider adding sulfamethoxazole; trimethoprim to carbapenem therapy in setting of persistent bacteremia.

    Adults weighing less than 40 kg

    160 mg trimethoprim/800 mg sulfamethoxazole PO every 12 hours for 12 weeks for the oral eradication-phase of therapy after initial IV treatment and for 21 days as postexposure prophylaxis during a public health emergency. Consider adding sulfamethoxazole; trimethoprim to carbapenem therapy in setting of persistent bacteremia.

    Infants, Children, and Adolescents 2 months to 17 years

    8 mg/kg/dose (trimethoprim component) PO every 12 hours (Max: 320 mg trimethoprim/1,600 mg sulfamethoxazole/dose) for 12 weeks for the oral eradication-phase of therapy after initial IV treatment and for 21 days as postexposure prophylaxis during a public health emergency. Consider adding sulfamethoxazole; trimethoprim to carbapenem therapy in the setting of persistent bacteremia.

    For sulfonamide desensitization† in patients requiring sulfamethoxazole; trimethoprim therapy.
    Rapid sulfonamide desensitization† protocol.
    Oral dosage
    Adults

    This rapid protocol was studied in HIV infected patients who required SMX-TMP therapy. Increasing doses of SMX-TMP are given every 15 minutes for 31 doses; then, if protocol tolerated, begin sulfonamide therapy as indicated. The protocol is as follows:
    Doses 1 to 3 (10 ng/mL SMX-TMP): 1 mL, 2 mL, and 4 mL PO given 15 minutes apart for a total dose of 0.00007 mg of the SMX component.
    Doses 4 to 7 (100 ng/mL SMX-TMP): 0.5 mL, 1 mL, 2 mL, and 4 mL PO given 15 minutes apart for a total dose of 0.00075 mg of the SMX component.
    Doses 8 to 11 (1 mcg/mL SMX-TMP): 0.5 mL, 1 mL, 2 mL, and 4 mL PO given 15 minutes apart for a total dose of 0.0075 mg of the SMX component.
    Doses 12 to 15 (10 mcg/mL SMX-TMP): 0.5 mL, 1 mL, 2 mL, and 4 mL PO given 15 minutes apart for a total dose of 0.075 mg of the SMX component.
    Doses 16 to 19 (100 mcg/mL SMX-TMP): 0.5 mL, 1 mL, 2 mL, and 4 mL PO given 15 minutes apart for a total dose of 0.75 mg of the SMX component.
    Doses 20 to 23 (1 mg/mL SMX-TMP): 0.5 mL, 1 mL, 2 mL, and 4 mL PO given 15 minutes apart for a total dose of 7.5 mg of the SMX component.
    Doses 24 to 27 (10 mg/mL SMX-TMP): 0.5 mL, 1 mL, 2 mL, and 4 mL PO given 15 minutes apart for a total dose of 75 mg of the SMX component.
    Doses 28 to 30 (40 mg/mL SMX-TMP): 2 mL, 4 mL, and 8 mL PO given 15 minutes apart for a total dose of 560 mg of the SMX component.
    Dose 31: 1 double strength tablet (800 mg of the SMX component) PO.

    Infants, Children, and Adolescents 2 months to 17 years

    Data on sulfonamide desensitization protocols are lacking in pediatric patients. In 1 rapid, 4-hour oral protocol in HIV-infected children (n = 5), sulfamethoxazole; trimethoprim suspension was diluted in sterile water, and doses were given every 15 minutes at the following proportions of the final dose: 1:10,000, 1:1,000, 1:500, 1:250, 1:125, 1:62, 1:30, 1:15, 1:7.5, 1:5, 1:2.5, and full strength. After desensitization, maintenance sulfamethoxazole; trimethoprim therapy was begun at a dosage of 150 mg/m2/day PO divided twice daily. The desensitization protocol was successful in 4 of the 5 patients. Another protocol in HIV-infected patients, 4 of whom were pediatric patients, used sulfamethoxazole; trimethoprim suspension administered orally every 8 hours beginning with 1:10,000 of the desired total daily dose and progressing through serial dilutions of 1:5,000, 1:1,000, 1:500, 1:100, 1:50, and 1:10. Subsequently, the desired dosage was administered orally twice per day. The desensitization protocol was successful in 6 of the 7 patients.

    Ambulatory sulfonamide desensitization† protocol.
    Oral dosage
    Adults

    This ambulatory desensitization protocol was studied in HIV infected patients who required SMX-TMP prophylaxis. Increasing doses of SMX-TMP given PO 3 times daily were used for 8 days. On the ninth day and if protocol tolerated, the patients received 1 double-strength tablet (800 mg/160mg SMX-TMP) PO once daily.[27465] The protocol is as follows:
    Day 1 (0.00002 mg/mL SMX-TMP): 1 mL, 2 mL, and 4 mL PO given 15 minutes apart for a total dose of 0.00007 mg of the SMX component.
    Day 2 (0.0002 mg/mL SMX-TMP): 0.5 mL, 1 mL, 2 mL, and 4 mL PO given 15 minutes apart for a total dose of 0.00075 mg of the SMX component.
    Day 3 (0.002 mg/mL SMX-TMP): 0.5 mL, 1 mL, 2 mL, and 4 mL PO given 15 minutes apart for a total dose of 0.0075 mg of the SMX component.
    Day 4 (0.02 mg/mL SMX-TMP): 0.5 mL, 1 mL, 2 mL, and 4 mL PO given 15 minutes apart for a total dose of 0.075 mg of the SMX component.
    Day 5 (0.2 mg/mL SMX-TMP): 0.5 mL, 1 mL, 2 mL, and 4 mL PO given 15 minutes apart for a total dose of 0.75 mg of the SMX component.
    Day 6 (2 mg/mL SMX-TMP): 0.5 mL, 1 mL, 2 mL, and 4 mL PO given 15 minutes apart for a total dose of 7.5 mg of the SMX component.
    Day 7 (20 mg/mL SMX-TMP): 0.5 mL, 1 mL, 2 mL, and 4 mL PO given 15 minutes apart for a total dose of 75 mg of the SMX component.
    Day 8 (40 mg/mL SMX-TMP): 2 mL, 4 mL, and 8 mL PO given 15 minutes apart for a total dose of 560 mg of the SMX component.
    Day 9: Give 1 double strength tablet (800 mg of the SMX component) PO.

    Infants, Children, and Adolescents 2 months to 17 years

    Data on ambulatory sulfonamide desensitization protocols are lacking in pediatric patients. In 1 successful protocol in HIV-infected children (n = 4), 1 mL of sulfamethoxazole; trimethoprim oral suspension (8 mg/mL trimethoprim) was diluted with 19 mL of distilled water for a concentration of 0.4 mg/mL (used for Days 1 to 4 of the desensitization regimen). The following desensitization regimen was used (all doses represent trimethoprim component): Day 1: 0.4 mg; Day 2: 0.8 mg; Day 3: 1.6 mg; Day 4: 3.2 mg; Day 5: 4.8 mg; Day 6: 9.6 mg; Day 7: 20 mg; Day 8: 40 mg; Day 9: 80 mg; Days 10 to 17: 40 mg; Days 18 onward: dose increased every 3 days to 5 mg/kg/day PO.

    For the management of methicillin-resistant Staphylococcus aureus (MRSA)-associated bone and joint infections†, including osteomyelitis† and septic/infectious arthritis†, or an orthopedic device-related infection†.
    For the management of methicillin-resistant Staphylococcus aureus (MRSA)-associated osteomyelitis†.
    Oral dosage
    Adults

    The Infectious Diseases Society of America (IDSA) recommends 3.5 to 4 mg/kg/dose (trimethoprim component) PO every 8 to 12 hours plus rifampin 600 mg PO daily. A minimum duration of 8 weeks is recommended; however, an additional 1 to 3 months (or longer for chronic infection or if no debridement performed) of oral rifampin plus another MRSA agent such as sulfamethoxazole/trimethoprim, may be necessary.

    Intravenous dosage
    Adults

    The Infectious Diseases Society of America (IDSA) recommends 3.5 to 4 mg/kg/dose (trimethoprim component) IV every 8 to 12 hours plus rifampin 600 mg PO daily. A minimum duration of 8 weeks is recommended; however, an additional 1 to 3 months (or longer for chronic infection or if no debridement performed) of oral rifampin plus another MRSA agent such as sulfamethoxazole/trimethoprim, may be necessary.

    For the management of methicillin-resistant Staphylococcus aureus (MRSA)-associated septic arthritis†.
    Oral dosage
    Adults

    The Infectious Diseases Society of America (IDSA) recommends 3.5 to 4 mg/kg/dose (trimethoprim component) PO every 8 to 12 hours for 3 to 4 weeks.

    Intravenous dosage
    Adults

    The Infectious Diseases Society of America (IDSA) recommends 3.5 to 4 mg/kg/dose (trimethoprim component) IV every 8 to 12 hours for 3 to 4 weeks.

    For the management of methicillin-resistant Staphylococcus aureus (MRSA)-associated prosthetic joint infections†.
    Oral dosage
    Adults

    The Infectious Diseases Society of America (IDSA) recommends 3.5 to 4 mg/kg/dose (trimethoprim component) PO every 8 to 12 hours plus rifampin 600 mg PO daily or 300 to 450 mg PO every 12 hours for 2 weeks in patients with early-onset (less than 2 months after surgery) or acute hematogenous prosthetic joint infections involving a stable implant with short duration (3 weeks or less) of symptoms and debridement (but device retention). Additional oral therapy (rifampin plus another MRSA agent, such as sulfamethoxazole; trimethoprim) should continue for 3 months for hip infections or for 6 months for knee infections.

    Intravenous dosage
    Adults

    The Infectious Diseases Society of America (IDSA) recommends 3.5 to 4 mg/kg/dose (trimethoprim component) IV every 8 to 12 hours plus rifampin 600 mg PO daily or 300 to 450 mg PO every 12 hours for 2 weeks in patients with early-onset (less than 2 months after surgery) or acute hematogenous prosthetic joint infections involving a stable implant with short duration (3 weeks or less) of symptoms and debridement (but device retention). Additional oral therapy (rifampin plus another MRSA agent, such as sulfamethoxazole; trimethoprim) should start after the completion of IV therapy and continue for 3 months for hip infections or for 6 months for knee infections.

    For the management of methicillin-resistant Staphylococcus aureus (MRSA)-associated spinal implant infections†.
    Oral dosage
    Adults

    The Infectious Diseases Society of America (IDSA) recommends 3.5 to 4 mg/kg/dose (trimethoprim component) PO every 8 to 12 hours plus rifampin 600 mg PO daily or 300 to 450 mg PO every 12 hours in patients with early-onset spinal implant infections (30 days or less after surgery) or implants in an actively infected site. Prolonged oral therapy (rifampin plus another MRSA agent, such as sulfamethoxazole; trimethoprim) should follow parenteral therapy; however, the optimal duration of parenteral and/or oral therapy is unclear. Oral therapy should be continued until spine fusion has occurred. Long term oral suppressive therapy may be considered in select cases, especially if device removal is not possible.

    Intravenous dosage
    Adults

    The Infectious Diseases Society of America (IDSA) recommends 3.5 to 4 mg/kg/dose (trimethoprim component) IV every 8 to 12 hours plus rifampin 600 mg PO daily or 300 to 450 mg PO every 12 hours in patients with early-onset spinal implant infections (30 days or less after surgery) or implants in an actively infected site. Prolonged oral therapy (rifampin plus another MRSA agent, such as sulfamethoxazole; trimethoprim) should follow parenteral therapy; however, the optimal duration of parenteral and/or oral therapy is unclear. Oral therapy should be continued until spine fusion has occurred. Long term oral suppressive therapy may be considered in select cases, especially if device removal is not possible.

    For surgical infection prophylaxis†.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO as single dose 1 hour before transrectal biopsy of the prostate or 320 mg trimethoprim/1600 mg sulfamethoxazole PO as single dose 1 to 3 hours before transurethral resection of the prostate. No intraoperative redosing and a duration of prophylaxis less than 24 hours for most procedures are recommended by clinical practice guidelines. Clinical practice guidelines recommend sulfamethoxazole; trimethoprim for urologic procedures involving lower tract instrumentation with risk factors for infection, including transrectal prostate biopsy.

    For the treatment of CNS infections†, including meningitis†, brain abscess†, subdural empyema†, spinal epidural abscess†, and septic thrombosis of the cavernous or dural venous sinus†.
    Intravenous dosage
    Adults

    10 to 20 mg/kg/day (trimethoprim component) IV divided every 6 to 12 hours as an alternative therapy for bacterial meningitis caused by E. coli, L. monocytogenes, or methicillin-resistant Staphylococcus aureus (MRSA). Treat for 10 to 14 days for meningitis due to MRSA and at least 21 days for infections due to L. monocytogenes or gram-negative bacilli. For other MRSA CNS infections, including brain abscess, subdural empyema, spinal epidural abscess, and septic thrombosis of the cavernous or dural venous sinus, 5 mg/kg/dose IV every 8 to 12 hours for 4 to 6 weeks. Oral rifampin may be added.

    Infants, Children, and Adolescents 2 months to 17 years

    10 to 20 mg/kg/day (trimethoprim component) IV divided every 6 to 12 hours (Max: 960 mg trimethoprim/day) as an alternative therapy for bacterial meningitis caused by E. coli, L. monocytogenes, or methicillin-resistant Staphylococcus aureus (MRSA). Treat for 10 to 14 days for meningitis due to MRSA and at least 21 days for infections due to L. monocytogenes or gram-negative bacilli. Treat for 4 to 6 weeks for brain abscess, subdural empyema, spinal epidural abscess, or septic thrombosis of the cavernous or dural venous sinus.

    For the treatment of cholera†.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO twice daily for 3 days.

    For the treatment of cyclosporiasis†.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO twice daily for 7 to 10 days; 160 mg trimethoprim/800 mg sulfamethoxazole PO 4 times daily for 10 days, followed by 160 mg trimethoprim/800 mg sulfamethoxazole PO twice daily for 3 weeks in HIV-infected patients.

    Infants, Children, and Adolescents 2 months to 17 years

    8 to 10 mg/kg/day (trimethoprim component) PO divided every 12 hours (Max: 320 mg trimethoprim/1,600 mg sulfamethoxazole/day) for 7 to 10 days.

    For the treatment of isosporiasis† in HIV-infected patients.
    For chronic maintenance therapy (secondary prophylaxis) of isosporiasis† in HIV-infected patients.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO 3 times weekly is recommended by guidelines. Alternatively, doses of 160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or 320 mg trimethoprim/1,600 mg sulfamethoxazole PO 3 times weekly can be administered. Discontinuation of secondary prophylaxis may be considered in patients without evidence of active Isospora infection who have sustained increase in CD4 count to more than 200 cells/mm3 for longer than 6 months in response to ART.

    Adolescents

    160 mg trimethoprim/800 mg sulfamethoxazole PO 3 times weekly is recommended by guidelines. Alternatively, doses of 160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or 320 mg trimethoprim/1,600 mg sulfamethoxazole PO 3 times weekly can be administered. Discontinuation of secondary prophylaxis may be considered in patients without evidence of active Isospora infection who have sustained increase in CD4 count to more than 200 cells/mm3 for longer than 6 months in response to ART.

    Infants and Children 2 months to 12 years

    2.5 mg/kg/dose (trimethoprim component) PO 3 times weekly (Max: 80 mg trimethoprim/400 mg sulfamethoxazole/dose) is recommended by guidelines for patients with severe immunosuppression (CDC immunologic category 3). Discontinuation of secondary prophylaxis may be considered in patients without evidence of active Isospora infection who have sustained improvement in immunologic status (CDC immunologic category 1 or 2) for longer than 6 months in response to ART.

    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO 4 times daily for 10 days is recommended by guidelines. Alternatively, 160 mg trimethoprim/800 mg sulfamethoxazole PO every 12 hours for 7 to 10 days can be administered. May start with twice daily dosing and increase dose and/or duration (up to 3 to 4 weeks) if symptoms worsen or persist. After initial treatment, follow with chronic maintenance therapy (secondary prophylaxis).

    Adolescents

    160 mg trimethoprim/800 mg sulfamethoxazole PO 4 times daily for 10 days is recommended by guidelines. Alternatively, 160 mg trimethoprim/800 mg sulfamethoxazole PO every 12 hours for 7 to 10 days can be administered. May start with twice daily dosing and increase dose and/or duration (up to 3 to 4 weeks) if symptoms worsen or persist. After initial treatment, follow with chronic maintenance therapy (secondary prophylaxis).

    Infants and Children 2 months to 12 years

    5 mg/kg/dose (trimethoprim component) PO every 12 hours (Max: 160 mg trimethoprim/800 mg sulfamethoxazole/dose) for 10 days is recommended by guidelines. May increase dose to 5 mg/kg/dose (trimethoprim component) PO 3 to 4 times daily (Max: 160 mg trimethoprim/800 mg sulfamethoxazole/dose) and/or increase the duration of treatment to 3 to 4 weeks if symptoms worsen or persist. After initial treatment, follow with chronic maintenance therapy (secondary prophylaxis) in patients with severe immunosuppression (CDC immunologic category 3).

    Intravenous dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole IV 4 times daily for 10 days is recommended by guidelines. Alternatively, 160 mg trimethoprim/800 mg sulfamethoxazole IV every 12 hours for 7 to 10 days can be administered. May start with twice daily dosing and increase dose and/or duration (up to 3 to 4 weeks) if symptoms worsen or persist. After initial treatment, follow with chronic maintenance therapy (secondary prophylaxis).

    Adolescents

    160 mg trimethoprim/800 mg sulfamethoxazole IV 4 times daily for 10 days is recommended by guidelines. Alternatively, 160 mg trimethoprim/800 mg sulfamethoxazole IV every 12 hours for 7 to 10 days can be administered. May start with twice daily dosing and increase dose and/or duration (up to 3 to 4 weeks) if symptoms worsen or persist. After initial treatment, follow with chronic maintenance therapy (secondary prophylaxis).

    Infants and Children 2 months to 12 years

    5 mg/kg/dose (trimethoprim component) IV every 12 hours (Max: 160 mg trimethoprim/800 mg sulfamethoxazole/dose) for 10 days is recommended by guidelines. May increase dose to 5 mg/kg/dose (trimethoprim component) IV 3 to 4 times daily (Max: 160 mg trimethoprim/800 mg sulfamethoxazole/dose) and/or increase the duration of treatment to 3 to 4 weeks if symptoms worsen or persist. After initial treatment, follow with chronic maintenance therapy (secondary prophylaxis) in patients with severe immunosuppression (CDC immunologic category 3).

    For the treatment of salmonellosis† in HIV-infected patients.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO every 12 hours is recommended by guidelines as an alternative therapy to a fluoroquinolone. For patients with CD4 count of 200 cells/mm3 or more, the duration of therapy is 7 to 14 days for patients without bacteremia and 14 days for patients with bacteremia. A longer duration may be necessary with persistent or complicated infections. For patients with CD4 count less than 200 cells/mm3, the duration of therapy is 2 to 6 weeks with or without bacteremia. The role of long term secondary prophylaxis is not well established, but may be considered for patients with recurrent infection and in patients with CD4 count less than 200 cells/mm3 with severe diarrhea.

    Adolescents

    160 mg trimethoprim/800 mg sulfamethoxazole PO every 12 hours is recommended by guidelines as an alternative therapy to a fluoroquinolone. For patients with CD4 count of 200 cells/mm3 or more, the duration of therapy is 7 to 14 days for patients without bacteremia and 14 days for patients with bacteremia. A longer duration may be necessary with persistent or complicated infections. For patients with CD4 count less than 200 cells/mm3, the duration of therapy is 2 to 6 weeks with or without bacteremia. The role of long term secondary prophylaxis is not well established, but may be considered for patients with recurrent infection and in patients with CD4 count less than 200 cells/mm3 with severe diarrhea.

    Intravenous dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole IV every 12 hours is recommended by guidelines as an alternative therapy to a fluoroquinolone. For patients with CD4 count of 200 cells/mm3 or more, the duration of therapy is 7 to 14 days for patients without bacteremia and 14 days for patients with bacteremia. A longer duration may be necessary with persistent or complicated infections. For patients with CD4 count less than 200 cells/mm3, the duration of therapy is 2 to 6 weeks with or without bacteremia. The role of long term secondary prophylaxis is not well established, but may be considered for patients with recurrent infection and in patients with CD4 count less than 200 cells/mm3 with severe diarrhea.

    Adolescents

    160 mg trimethoprim/800 mg sulfamethoxazole IV every 12 hours is recommended by guidelines as an alternative therapy to a fluoroquinolone. For patients with CD4 count of 200 cells/mm3 or more, the duration of therapy is 7 to 14 days for patients without bacteremia and 14 days for patients with bacteremia. A longer duration may be necessary with persistent or complicated infections. For patients with CD4 count less than 200 cells/mm3, the duration of therapy is 2 to 6 weeks with or without bacteremia. The role of long term secondary prophylaxis is not well established, but may be considered for patients with recurrent infection and in patients with CD4 count less than 200 cells/mm3 with severe diarrhea.

    For the treatment of mastitis†.
    Oral dosage
    Adults

    160 to 320 mg trimethoprim/800 to 1,600 mg sulfamethoxazole PO twice daily for 10 to 14 days.

    For the treatment of exit-site and tunnel infections in CAPD-associated peritonitis†.
    Oral dosage
    Adults

    80 mg trimethoprim/400 mg sulfamethoxazole PO once daily continued until the exit site appears completely normal with a 2 week minimum duration and 3 weeks for infections due to P. aeruginosa.

    Infants, Children, and Adolescents 2 months to 17 years

    5 to 10 mg/kg/dose (trimethoprim component) PO once daily (Max: 80 mg trimethoprim/400 mg sulfamethoxazole per day). Treat for a minimum of 2 weeks and for at least 7 days after complete resolution of the infection for exit site infections. P. aeruginosa may require 3 weeks of therapy. Treat for 2 to 4 weeks for tunnel infections.

    For the treatment of brucellosis†.
    Oral dosage
    Adults

    160 mg trimethoprim/800 mg sulfamethoxazole PO every 12 hours in combination with doxycycline for 6 to 8 weeks is recommended as an alternative therapy. For serious infections or complications (i.e., endocarditis, meningitis, and osteomyelitis), the addition of streptomycin or gentamicin for the first 14 to 21 days of therapy is recommended.

    Infants, Children, and Adolescents 2 months to 17 years

    8 to 12 mg/kg/day (trimethoprim component) PO divided every 12 hours (Max: 320 mg trimethoprim/1,600 mg sulfamethoxazole/day) for 6 to 8 weeks. Give in combination with rifampin or doxycycline (pediatric patients older than 8 years) to reduce the incidence of relapse. For serious infections or complications (i.e., endocarditis, meningitis, and osteomyelitis), the addition of streptomycin or gentamicin for the first 14 to 21 days of therapy is recommended.

    For the treatment of Q fever†.
    Oral dosage
    Adults

    Doxycycline is the treatment of choice in adults; however, 160 mg trimethoprim/800 mg sulfamethoxazole PO every 12 hours throughout pregnancy is recommended for all pregnant women.

    Children and Adolescents 8 to 17 years

    Doxycycline is the treatment of choice.

    Infants and Children 2 months to 7 years

    4 mg/kg/dose (trimethoprim component) PO every 12 hours (Max: 160 mg trimethoprim/800 mg sulfamethoxazole/dose) for 14 days. Trimethoprim/sulfamethoxazole may be considered as an alternative therapy to doxycycline in children with mild or uncomplicated illness or as an option in patients who remain febrile after a 5-day course of doxycycline. Children with high-risk criteria (e.g., hospitalized or who have severe illness, children with preexisting heart valvulopathy, immunocompromised children, or children with delayed Q fever diagnosis who have experienced illness for more than 14 days without resolution of symptoms) should receive doxycycline treatment for 14 days.

    †Indicates off-label use

    MAXIMUM DOSAGE

    All doses are based on trimethoprim component.

    Adults

    20 mg/kg/day PO (Max: 1,600 mg/day); 20 mg/kg/day IV (Max: 960 mg/day).

    Geriatric

    20 mg/kg/day PO (Max: 1,600 mg/day); 20 mg/kg/day IV (Max: 960 mg/day).

    Adolescents

    20 mg/kg/day PO (Max: 1,600 mg/day); 20 mg/kg/day IV (Max: 960 mg/day).

    Children

    20 mg/kg/day PO (Max: 1,600 mg/day); 20 mg/kg/day IV (Max: 960 mg/day).

    Infants

    2 to 11 months: 20 mg/kg/day PO/IV.
    younger than 2 months: Contraindicated in infants younger than 2 months of age; however, doses up to 10 mg/kg/day PO are used off-label for PCP prophylaxis in HIV-infected/exposed infants as young as 4 weeks of age.

    Neonates

    Contraindicated in infants younger than 2 months of age; however, doses up to 10 mg/kg/day PO are used off-label for PCP prophylaxis in HIV-infected/exposed infants as young as 4 weeks of age.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Both sulfamethoxazole and trimethoprim are metabolized by the liver. Dosage adjustments may be necessary in patients with hepatic impairment; however, specific dosage adjustment guidelines are not available.

    Renal Impairment

    Adults
    General renal dosage adjustment:
    CrCl more than 30 mL/minute: No dosage adjustment needed.[28344] [42298] Alternatively, full daily dose divided every 12 hours (i.e., 8 to 12 mg/kg/day of trimethoprim component IV/PO divided every 12 hours) for 14 days, then one-half of the daily dose every 24 hours (i.e., 4 to 6 mg/kg/day of trimethoprim component IV/PO once daily).[42300] [42332]
    CrCl 15 to 30 mL/minute: Reduce dose to one-half of the usual dosage regimen.[28344] [42298] Alternatively, full daily dose divided every 12 hours (i.e., 8 to 12 mg/kg/day of trimethoprim component IV/PO divided every 12 hours) for 24 to 48 hours, then one-half of the daily dose every 24 hours (i.e., 4 to 6 mg/kg/day of trimethoprim component IV/PO once daily).[42300] [42332]
    CrCl less than 15 mL/minute: Use not recommended.[28344] [42298] Alternatively, full daily dose (i.e., 8 to 12 mg/kg/dose of trimethoprim component IV/PO) every 48 hours or one-half of the daily dose in 1 or 2 divided doses (i.e., 4 to 6 mg/kg/day of trimethoprim component IV/PO divided every 12 to 24 hours).[42300] [42332]
     
    Pneumocystis pneumonia (PCP) renal dosage adjustment:
    CrCl more than 30 mL/minute: No dosage adjustment needed.[34362] [42300] [42332]
    CrCl 15 to 30 mL/minute: For treatment, 5 mg/kg/dose of trimethoprim component IV every 12 hours or 2 double-strength tablets PO every 12 hours.[34362] Alternatively, 15 to 20 mg/kg/day of trimethoprim component IV/PO divided every 6 to 8 hours for 48 hours, then 7 to 10 mg/kg/day of trimethoprim component IV/PO divided every 12 hours. For prophylaxis, 5 mg/kg/dose of trimethoprim component IV/PO every 24 to 48 hours for 3 to 7 doses/week.[42332]
    CrCl 10 to 14 mL/minute: For treatment, 5 mg/kg/dose of trimethoprim component IV every 12 hours or 2 double-strength tablets PO every 12 hours.[34362] Alternatively, 15 to 20 mg/kg/dose of trimethoprim component IV/PO every 48 hours or 7 to 10 mg/kg/day divided every 12 to 24 hours. For prophylaxis, 5 mg/kg/dose of trimethoprim component IV/PO every 48 to 72 hours.[42332]
    CrCl less than 10 mL/minute: For treatment, 5 mg/kg/dose of trimethoprim component IV every 24 hours, 1 double-strength tablet PO every 12 hours, or 2 double-strength tablets PO every 24 hours.[34362] Alternatively, 15 to 20 mg/kg/dose of trimethoprim component IV/PO every 48 hours or 7 to 10 mg/kg/day divided every 12 to 24 hours. For prophylaxis, 5 mg/kg/dose of trimethoprim component IV/PO every 48 to 72 hours.[42332]
     
    Pediatrics
    Off-label dose adjustments
    The following dose adjustments are based on a usual recommended dose in pediatric patients of 5 to 20 mg/kg/day (trimethoprim component) divided every 6 to 12 hours [32569]:
    CrCl more than 50 mL/minute/1.73 m2: No dosage adjustment needed.
    CrCl 30 to 50 mL/minute/1.73 m2: 5 to 7.5 mg/kg/dose every 8 hours.
    CrCl 10 to 29 mL/minute/1.73 m2: 5 to 10 mg/kg/dose every 12 hours.
    CrCl less than 10 mL/minute/1.73 m2: Use not recommended; if used, 5 to 10 mg/kg/dose every 24 hours.
     
    FDA-approved dose adjustments
    CrCl more than 30 mL/minute: No dosage adjustment needed.
    CrCl 15 to 30 mL/minute: Reduce the recommended dose by 50%.
    CrCl less than 15 mL/minute: Use not recommended.[43889]
     
    Intermittent hemodialysis
    Adults
    General hemodialysis dosage adjustment:
    Use not recommended.[28344] [42298] Alternatively, full daily dose (i.e., 8 to 12 mg/kg/day of trimethoprim component IV/PO) before dialysis, then one-half of the daily dose (i.e., 4 to 6 mg/kg/day of trimethoprim component IV/PO) after dialysis.[42300] [42332] A pharmacokinetic study demonstrated that 44% of the administered trimethoprim and 57% of the administered sulfamethoxazole dose was removed during hemodialysis, suggesting that 50% of the usual dose be administered after the dialysis session.[42301]
     
    Pneumocystis pneumonia (PCP) hemodialysis dosage adjustment:
    For treatment, 5 mg/kg/day of trimethoprim component IV or 2 double-strength tablets PO after dialysis on dialysis days. Consider therapeutic drug monitoring with a target trimethoprim concentration of 5 to 8 mcg/mL.[34362] Alternatively, 15 to 20 mg/kg/dose of the trimethoprim component IV/PO before dialysis with 7 to 10 mg/kg/dose of trimethoprim component IV/PO after dialysis. For prophylaxis, 5 mg/kg/dose of trimethoprim component IV/PO after each dialysis.[42332]
     
    Pediatrics
    Generally, use is not recommended in patients receiving hemodialysis. If used, 5 to 10 mg/kg/dose of trimethoprim component every 24 hours.[32569]
     
    Peritoneal dialysis
    Adults: 160 mg trimethoprim; 800 mg sulfamethoxazole PO twice daily.[61676]
    Pediatrics: Generally, use is not recommended in patients receiving peritoneal dialysis. If used, 5 to 10 mg/kg/dose of trimethoprim component every 24 hours.[32569]
     
    Continuous renal replacement therapy
    Adults: 2.5 to 7.5 mg/kg/dose of trimethoprim component IV/PO twice daily has been recommended for CVVH, CVVHD, and CVVHDF.[42303]
    Pediatrics: 5 mg/kg/dose of trimethoprim component every 8 hours.[32569]

    ADMINISTRATION

     
    NOTE: The doses below are expressed in terms of the trimethoprim content of the fixed combination, which consists of 5 mg sulfamethoxazole: 1 mg trimethoprim.

    Oral Administration

    May be administered without regard to meals. Administer with food, water, or milk to minimize gastric irritation.

    Oral Liquid Formulations

    Suspension: Shake well before using.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Rapid or direct IV injection must be avoided.
    Dilute 5 ml of the concentrate for injection in 125 ml of D5W. For fluid-restricted patients, 75 ml of D5W may be used. Use diluted solution within 2 hours of preparation and do not refrigerate.
    If using Septra ADD-Vantage vials, dilute each 10 ml vial in ADD-Vantage diluent containers containing 250 ml of D5W.
    Infuse over a period of 60—90 minutes. Change infusion site every 48—72 hours.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion 48 hours after initial puncture of container
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Bacter-Aid DS :
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Bactrim:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Bactrim DS:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Septra:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Septra DS:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Sulfatrim:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Sulfatrim Pediatric:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Sultrex Pediatric :
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Some formulations of injectable sulfamethoxazole; trimethoprim contain propylene glycol as a solvent. When administered in high doses as for the treatment of P. jirovecii pneumonia and concomitantly with other products that contain propylene glycol, toxicity may occur. Propylene glycol toxicity may result in hyperosmolarity with anion gap metabolic acidosis, including lactic acidosis. Additionally, propylene glycol toxicity may result in acute kidney injury, CNS toxicity, and multi-organ failure. Monitor patients for the total daily intake of propylene glycol from all sources and for acid-base disturbances. Discontinue sulfamethoxazole; trimethoprim if propylene glycol toxicity is suspected.

    Carbonic anhydrase inhibitor hypersensitivity, sulfite hypersensitivity, sulfonamide hypersensitivity, sulfonylurea hypersensitivity, thiazide diuretic hypersensitivity, trimethoprim hypersensitivity

    Sulfamethoxazole; trimethoprim is contraindicated in patients with either sulfonamide hypersensitivity or trimethoprim hypersensitivity. Fatalities have been documented in patients with sulfonamide hypersensitivity who receive sulfonamides, usually secondary to Stevens-Johnson syndrome, toxic epidermal necrolysis, or hepatic necrosis. Because of structural similarity, sulfonamides should be used cautiously in patients with known allergic reactions to thiazide diuretics, oral sulfonylureas, or carbonic anhydrase inhibitors. Despite the chemical similarities between furosemide and sulfonamides and the logical conclusion that cross-sensitivity would occur, a thorough review of the published literature and direct communication with the manufacturer revealed no data supporting the conclusion that patients with sensitivity to sulfonamides also develop sensitivity to furosemide. Less is known regarding the cross-sensitivity between sulfonamides and the other agents, although some clinicians doubt that significant risk exists. Nevertheless, sulfamethoxazole; trimethoprim should be avoided in patients with furosemide hypersensitivity, thiazide diuretic hypersensitivity, sulfonylurea hypersensitivity, or carbonic anhydrase inhibitor hypersensitivity. Additionally, sulfamethoxazole; trimethoprim injection contains sodium metabisulfite and should not be used in patients with sulfite hypersensitivity; those at risk are found more frequently amongst asthmatic than non-asthmatic members of the population. Severe life-threatening anaphylactic reactions or less severe asthmatic episodes can develop in susceptible patients.

    Agranulocytosis, bone marrow suppression, folate deficiency, folate deficiency megaloblastic anemia, G6PD deficiency, hemolysis, thrombocytopenia

    Sulfamethoxazole; trimethoprim is contraindicated in patients with folate deficiency megaloblastic anemia since either component could exacerbate this condition; be use with caution in patients with mild folate deficiency. Sulfamethoxazole; trimethoprim is also contraindicated for use in patients with a history of trimethoprim and/or sulfonamide-induced immune thrombocytopenia. Thrombocytopenia may be immune-related and usually subsides within a week of treatment discontinuation; however, severe/life-threatening cases have been reported. Caution is advised when administering the drug to patients with bone marrow suppression, as sulfonamides have been associated with fatalities resulting from agranulocytosis, aplastic anemia, and other blood dyscrasias. Do not administer to patients with G6PD deficiency; hemolysis and hemolytic anemia may occur if patients with G6PD deficiency receive sulfamethoxazole; trimethoprim; this reaction is frequently dose related. Discontinue the drug at the first appearance of serious blood disorders.

    Hyperkalemia, hyponatremia, renal disease, renal failure, renal impairment

    Sulfamethoxazole; trimethoprim is contraindicated in patients with severe renal impairment, renal disease, or renal failure, defined as creatinine clearance (CrCl) less than 15 mL/minute, when renal function status cannot be monitored. It should be used cautiously in patients with moderate renal impairment (i.e., CrCl less than than 30 mL/minute); the dosage should be adjusted to avoid drug accumulation and potential toxicity. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in patients with preexisting risk factors (e.g., renal disease, elderly). Monitor serum potassium levels in patients with risk factors for developing drug-induced hyperkalemia (renal impairment, elderly, high-dose trimethoprim). In addition, use trimethoprim with caution in patients receiving drugs known to significantly increase serum potassium. Sulfamethoxazole; trimethoprim has also been associated with severe cases of hyponatremia, particularly in patients receiving treatment for pneumocystis pneumonia (PCP). Health care providers are advised to monitor for the development of hyponatremia and implement appropriate corrective measures as needed in symptomatic patients.

    Hepatic disease

    Sulfamethoxazole; trimethoprim is contraindicated in patients with marked hepatic damage or hepatic disease. Because both sulfonamides and trimethoprim are metabolized in the liver, caution should be used when these drugs are given to patients with any degree of hepatic disease. Metabolism can be decreased, and as a result, toxicity may occur. Patients who are "slow acetylators" may be more prone to idiosyncratic reactions to sulfonamides.

    Porphyria

    Sulfonamides, such as sulfamethoxazole, can cause an acute attack of porphyria, and should not be used in patients with this condition.

    Colitis, diarrhea, GI disease, inflammatory bowel disease, pseudomembranous colitis, ulcerative colitis

    Almost all antibacterial agents have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following sulfamethoxazole; trimethoprim administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over two months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

    Hypothyroidism

    As with all medications containing sulfonamides, use sulfamethoxazole; trimethoprim with caution in patients with hypothyroidism.

    Acquired immunodeficiency syndrome (AIDS)

    Caution is advised when administering sulfamethoxazole; trimethoprim to patients with acquired immunodeficiency syndrome (AIDS). Patient with AIDS may not tolerate or respond to treatment in the same manner as non-AIDS patients. Patients with AIDS may experience more drug-related side effects, including rash, fever, leukopenia, elevated hepatic enzymes, and hyperkalemia. Health care providers are encouraged to reevaluate sulfamethoxazole; trimethoprim therapy in patients who develop rash or other treatment-related adverse reactions. If treatment is continued, closely monitor potassium concentrations and ensure adequate fluid intake during therapy. Additionally, clinicians are advised to avoid coadministration of sulfamethoxazole; trimethoprim with leucovorin in HIV/AIDS patients for the treatment of pneumocystis pneumonia (PCP). During a clinical trials, HIV-positive patients with pneumocystis pneumonia who receiving these drugs in combination experienced treatment failure and excess mortality.

    Infants, neonates

    Sulfamethoxazole; trimethoprim is contraindicated in neonates and infants less than 2 months old. Sulfonamides may cause bilirubin displacement and kernicterus in this age group. Additionally, sulfamethoxazole; trimethoprim injection contains benzyl alcohol as a preservative. There have been reports of fatal gasping syndrome in neonates (less than 1 month of age) after the administration of parenteral solutions containing the preservative benzyl alcohol at dosages of 99 mg/kg/day or more. Normal sulfamethoxazole; trimethoprim doses would deliver benzyl alcohol at amounts lower than those reported with gasping syndrome; however, the minimum amount of benzyl alcohol to cause toxicity is unknown. Consider the combined daily metabolic load of benzyl alcohol from all sources if using sulfamethoxazole; trimethoprim injection in infants. Sulfamethoxazole; trimethoprim may be used as adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis or for the prophylaxis of PCP in infants (1 month and older).

    Pregnancy

    Sulfamethoxazole; trimethoprim may cause fetal harm if administered during pregnancy. Use sulfamethoxazole; trimethoprim during pregnancy only if the potential benefit justifies the potential risk to the fetus. In a nested, case-control study (n = 87,020 controls; 8,702 cases) within the Quebec Pregnancy Cohort, sulfonamide use during early pregnancy was associated with an increased risk of spontaneous abortion (adjusted odds ratio (aOR) 2.01; 95% CI: 1.36 to 2.97; 30 exposed cases); residual confounding by severity of infection may be a potential limitation of this study. Limited data have also linked first trimester exposure to sulfamethoxazole; trimethoprim to an increased risk for congenital malformations (i.e., cardiovascular malformations, neural tube defects, oral cleft, urinary tract defects, club foot). However, other studies such as the Collaborative Perinatal Project, which included 1,455 mothers with first trimester sulfonamide exposure and 5,689 with exposure anytime during pregnancy, found no evidence to suggest a relationship between sulfonamide use and fetal malformations. Sulfonamides should generally be avoided near term due to the potential for jaundice, hemolytic anemia, and kernicterus in the newborn; sulfonamides readily cross the placenta with fetal concentrations averaging 70% to 90% of maternal concentrations. If sulfamethoxazole; trimethoprim is used during pregnancy, the patient should be advised of the potential risk to the fetus and supplemental multivitamins should be administered. Use of the drug is recommended for prophylaxis of pneumocystis pneumonia (PCP) in HIV-infected pregnant women.

    Breast-feeding

    Both sulfamethoxazole and trimethoprim are excreted into human breast milk at concentrations of approximately 2% to 5% of the recommended daily dose for infants over 2 months of age. Because of the potential risk of bilirubin displacement and kernicterus, avoid breast-feeding during treatment with sulfamethoxazole; trimethoprim. However, previous American Academy of Pediatrics (AAP) recommendations considered sulfamethoxazole; trimethoprim as usually compatible with breast-feeding. An extensive review in HIV-infected women suggested that the risk of kernicterus in the breast-feeding infant is very low. In a study of 12 newborn infants of less than 3 days postnatal age receiving systemic sulfamethoxazole; trimethoprim, the authors noted that despite therapeutic serum concentrations, there was no displacement of bilirubin from albumin in the newborns. If sulfamethoxazole; trimethoprim is administered to the mother of a young infant, monitor the infant for signs of increased bilirubin and jaundice. Ciprofloxacin, amoxicillin, and nitrofurantoin (cautioned in the infant with glucose-6-phosphate dehydrogenase deficiency) may be potential alternatives to consider during breast-feeding as generally considered compatible by previous AAP recommendations.

    Antimicrobial resistance, viral infection

    Sulfamethoxazole; trimethoprim will not effectively treat an established group A beta-hemolytic streptococcal infection; therefore, its use in patients with such infections should be avoided. Additionally the drug will not treat viral infection (e.g., common cold). Prescribing this drug in the absence of a proven, or strongly suspected, susceptible bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria (antimicrobial resistance). Patients should be told to complete the full course of treatment, even if they feel better earlier. Antibiotic therapy can result in superinfection or suprainfection with nonsusceptible organisms. Patients should be monitored closely.

    Hypoglycemia, malnutrition

    Cases of hypoglycemia have been reported in non-diabetic patients receiving treatment with sulfamethoxazole; trimethoprim. These events are uncommon and usually develop after a few days of therapy. Risk factors include, renal and hepatic dysfunction, malnutrition, and those patients receiving high drug doses.

    Sunlight (UV) exposure

    Photosensitivity can occur with sulfonamide treatment, so patients should avoid or limit sunlight (UV) exposure, including sunlamps and tanning booths. Sunscreens should be employed, but may provide limited protection for this reaction. Discontinue sulfamethoxazole; trimethoprim use at the first sign of erythema.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, myocardial infarction, QT prolongation, thyroid disease

    Cases of QT prolongation resulting in ventricular tachycardia and torsade de pointes have been reported during post-marketing use of sulfamethoxazole; trimethoprim. Use sulfamethoxazole; trimethoprim with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.

    Geriatric

    Sulfamethoxazole; trimethoprim is renally eliminated and should be used cautiously in geriatric patients, who have an age-related decline in renal function. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in patients with preexisting risk factors, such as geriatric patients. Monitor serum potassium levels in geriatric patients and use sulfamethoxazole; trimethoprim with caution in geriatric patients receiving drugs known to increase serum potassium significantly.[43888] According to the Beers Criteria, use sulfamethoxazole; trimethoprim with caution in geriatric patients taking an ACE inhibitor or angiotensin receptor blocker (ARB) in the presence of renal impairment due to an increased risk of hyperkalemia. The Beers panel recommends that the dose of sulfamethoxazole; trimethoprim be reduced if the creatinine clearance is 15 to 29 mL/minute. Per the Beers panel, avoid the use of sulfamethoxazole; trimethoprim if the creatinine clearance is less than 15 mL/minute due to an increased risk of worsening renal function and hyperkalemia.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; limit the use of antibiotics to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.[60742]

    Laboratory test interference

    Laboratory test interference may occur with sulfamethoxazole; trimethoprim. Specifically, trimethoprim may interfere with serum methotrexate assays that are determined by the competitive binding protein technique (CBPA) when a bacterial dihydrofolate reductase is used as the binding protein. Methotrexate measurements by a radioimmunoassay are not affected. Sulfamethoxazole; trimethoprim may also interfere with creatinine assays that use the Jaffe alkaline picrate reaction, resulting in an overestimation of approximately 10% in the normal range of values.

    ADVERSE REACTIONS

    Severe

    erythema multiforme / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    periarteritis / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    vasculitis / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    myocarditis / Delayed / Incidence not known
    serum sickness / Delayed / Incidence not known
    megaloblastic anemia / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    erythema nodosum / Delayed / Incidence not known
    methemoglobinemia / Early / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    anuria / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    hyperkalemia / Delayed / Incidence not known
    aseptic meningitis / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    uveitis / Delayed / Incidence not known

    Moderate

    leukopenia / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    neutropenia / Delayed / Incidence not known
    hypoprothrombinemia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    dysuria / Early / Incidence not known
    crystalluria / Delayed / Incidence not known
    neuritis / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    ataxia / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    pseudomembranous colitis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    jaundice / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    phlebitis / Rapid / Incidence not known
    hyponatremia / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    metabolic acidosis / Delayed / Incidence not known

    Mild

    purpura / Delayed / Incidence not known
    cough / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    fever / Early / Incidence not known
    chills / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    rash / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    headache / Early / Incidence not known
    insomnia / Early / Incidence not known
    fatigue / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    weakness / Early / Incidence not known
    myalgia / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    diarrhea / Early / Incidence not known
    nausea / Early / Incidence not known
    diuresis / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Concomitant use of sulfonamides and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use. (Moderate) Concomitant use of trimethoprim and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use.
    Acarbose: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Acetohexamide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Albiglutide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Aliskiren; Valsartan: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Alogliptin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Alogliptin; Pioglitazone: (Moderate) It is possible that an increase in the exposure of pioglitazone may occur when coadministered with other drugs that inhibit CYP2C8 such as trimethoprim. Monitor for changes in glycemic control if trimethoprim is coadministered with pioglitazone.
    Alpha-glucosidase Inhibitors: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Amantadine: (Moderate) Use caution, administration of trimethoprim may result in increased serum concentrations of amantadine. Amantadine is primarily excreted unchanged in the urine by both glomerular filtration and tubular secretion. The mechanism is not certain. Trimethoprim inhibits OCT2, but amantadine is a poor substrate of the cationic transporters OCT2 and MATE1 in vitro. Renal elimination of amantadine may be mediated in part by one or more organic cation transporters independent of OCT2. A single case of toxic delirium has been reported in the literature after coadministration of trimethoprim and amantadine. The clinical significance to a wider population is not known. Monitor for possible side effects of amantadine, including dizziness, confusion, nausea/vomiting, xerostomia, and anticholinergic effects.
    Amiloride: (Major) Trimethoprim has a potassium-sparing effect and may induce hyperkalemia, especially in patients with pre-existing risk factors for hyperkalemia (e.g., renal disease). Patients, especially those with renal dysfunction, should be carefully monitored for hyperkalemia during concomitant use of potassium-sparing diuretics and trimethoprim.
    Amiloride; Hydrochlorothiazide, HCTZ: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Major) Trimethoprim has a potassium-sparing effect and may induce hyperkalemia, especially in patients with pre-existing risk factors for hyperkalemia (e.g., renal disease). Patients, especially those with renal dysfunction, should be carefully monitored for hyperkalemia during concomitant use of potassium-sparing diuretics and trimethoprim.
    Aminosalicylate sodium, Aminosalicylic acid: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Amlodipine; Benazepril: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Amlodipine; Olmesartan: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Amlodipine; Telmisartan: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Amlodipine; Valsartan: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Amoxicillin: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Amoxicillin; Clarithromycin; Lansoprazole: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Amoxicillin; Clavulanic Acid: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Ampicillin: (Minor) Sulfonamides may compete with ampicillin for renal tubular secretion, increasing ampicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Ampicillin; Sulbactam: (Minor) Sulfonamides may compete with ampicillin for renal tubular secretion, increasing ampicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Angiotensin II receptor antagonists: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Angiotensin-converting enzyme inhibitors: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Aprepitant, Fosaprepitant: (Minor) Use caution if sulfamethoxazole and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of sulfamethoxazole. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Sulfamethoxazole is a CYP2C9 substrate and aprepitant is a CYP2C9 inducer. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant. When a 3-day regimen of aprepitant (125 mg/80 mg/80 mg) given to healthy patients on stabilized chronic warfarin therapy (another CYP2C9 substrate), a 34% decrease in S-warfarin trough concentrations was noted, accompanied by a 14% decrease in the INR at five days after completion of aprepitant.
    Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Aspirin, ASA: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Carisoprodol: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Carisoprodol; Codeine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Dipyridamole: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Omeprazole: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Oxycodone: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Pravastatin: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Atenolol; Chlorthalidone: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Atovaquone: (Moderate) Concomitant administration of atovaquone with an oral combination of trimethoprim and sulfamethoxazole lead to a minor decreases in TMP and SMX AUCs by 16% and 10%, respectively, in a small number of HIV-positive subjects. No difference was observed in atovaquone pharmacokinetics. The effect of the interaction of atovaquone with TMP-SMX is minor and unlikely to be of clinical significance. (Moderate) Concomitant administration of atovaquone with an oral combination of trimethoprim and sulfamethoxazole lead to a minor decreases in TMP and SMX AUCs in a small number of HIV-positive subjects. This may not be of any clinical significance but should be used with caution.
    Atovaquone; Proguanil: (Moderate) Concomitant administration of atovaquone with an oral combination of trimethoprim and sulfamethoxazole lead to a minor decreases in TMP and SMX AUCs by 16% and 10%, respectively, in a small number of HIV-positive subjects. No difference was observed in atovaquone pharmacokinetics. The effect of the interaction of atovaquone with TMP-SMX is minor and unlikely to be of clinical significance. (Moderate) Concomitant administration of atovaquone with an oral combination of trimethoprim and sulfamethoxazole lead to a minor decreases in TMP and SMX AUCs in a small number of HIV-positive subjects. This may not be of any clinical significance but should be used with caution.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly. (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Azathioprine: (Moderate) Azathioprine may interact with other drugs that are myelosuppressive. Drugs that may affect the production of leukocytes, including sulfamethoxazole; trimethoprim, SMX-TMP, may lead to exaggerated leukopenia, especially in patients who have received a renal transplant.
    Azilsartan: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Azilsartan; Chlorthalidone: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Benazepril: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Benazepril; Hydrochlorothiazide, HCTZ: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Bendroflumethiazide; Nadolol: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Benzocaine: (Moderate) Rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine products. Examples of other drugs that can cause methemoglobinemia include the sulfonamides. Therefore, caution is warranted when combining such medications with topical or oromucosal benzocaine products. Patients using OTC benzocaine gels and liquids should be advised to seek immediate medical attention if signs or symptoms of methemoglobinemia develop. In addition, clinicians should closely monitor patients for the development of methemoglobinemia when benzocaine sprays are used during a procedure.
    Benzocaine; Butamben; Tetracaine: (Moderate) Rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine products. Examples of other drugs that can cause methemoglobinemia include the sulfonamides. Therefore, caution is warranted when combining such medications with topical or oromucosal benzocaine products. Patients using OTC benzocaine gels and liquids should be advised to seek immediate medical attention if signs or symptoms of methemoglobinemia develop. In addition, clinicians should closely monitor patients for the development of methemoglobinemia when benzocaine sprays are used during a procedure.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly. (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Intravenous sulfamethoxazole; trimethoprim, SMX-TMP contains ethanol. A disulfiram-like reaction has occurred when metronidazole was used with IV sulfamethoxazole; trimethoprim, SMX-TMP. This reaction would not be expected to occur with oral sulfamethoxazole; trimethoprim, SMX-TMP.
    Bismuth Subsalicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Intravenous sulfamethoxazole; trimethoprim, SMX-TMP contains ethanol. A disulfiram-like reaction has occurred when metronidazole was used with IV sulfamethoxazole; trimethoprim, SMX-TMP. This reaction would not be expected to occur with oral sulfamethoxazole; trimethoprim, SMX-TMP. (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering sulfamethoxazole with boceprevir due to an increased potential for sulfamethoxazole-related adverse events. If sulfamethoxazole dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of sulfamethoxazole. Sulfamethoxazole is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated sulfamethoxazole plasma concentrations.
    Bosentan: (Moderate) Sulfamethoxazole potently inhibits CYP2C9 and may theoretically lead to elevated plasma concentrations of bosentan when coadministered. Monitor for potential adverse effects of bosentan during coadministration. Excessive bosentan dosage may result in hypotension or elevated hepatic enzymes.
    Bromocriptine: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. Bromocriptine is highly bound to serum proteins. Therefore, it may increase the unbound fraction of other highly protein-bound medications (e.g., sulfonamides), which may alter their effectiveness and risk for side effects.
    Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Lidocaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Canagliflozin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Canagliflozin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Candesartan: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Candesartan; Hydrochlorothiazide, HCTZ: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Captopril: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Captopril; Hydrochlorothiazide, HCTZ: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Carbamazepine: (Moderate) The risk for developing leukopenia and/or thrombocytopenia can be increased if other bone marrow depressants are used with sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. Megaloblastic anemia can occur when sulfamethoxazole; trimethoprim, SMX-TMP is used in patients who are taking other folate antagonists. These agents include carbamazepine. If these agents are used concomitantly, close observation of blood counts is warranted.
    Chloramphenicol: (Major) The risk for developing leukopenia and/or thrombocytopenia can be increased if other bone marrow depressants are used with sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. Megaloblastic anemia can occur when sulfamethoxazole; trimethoprim, SMX-TMP is used in patients who are taking other folate antagonists. These agents include chloramphenicol. If these agents are used concomitantly, close observation of blood counts is warranted.
    Chloroprocaine: (Major) Coadministration of chloroprocaine with sulfonamides may antagonize the effect of sulfonamides. Chloroprocaine is metabolized to para-aminobenzoic acid (PABA). PABA antagonized the effects of sulfonamides. Additionally, coadministration of chloroprocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Chlorothiazide: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Chlorpropamide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Chlorthalidone: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Chlorthalidone; Clonidine: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Choline Salicylate; Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Citric Acid; Potassium Citrate: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Citric Acid; Potassium Citrate; Sodium Citrate: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Colchicine; Probenecid: (Minor) Probenecid may inhibit the renal transport of sulfonamides. Plasma concentrations of these agents may be increased.
    Cyclosporine: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and cyclosporine. There have been reports of significant, but reversible nephrotoxicity with coadministration in renal transplant patients. In addition, there are case reports of reduced exposure to cyclosporine in patients receiving concomitant sulfonamides. Monitor renal function and cyclosporine concentrations if concomitant use is required.
    Dapagliflozin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Dapagliflozin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Dapagliflozin; Saxagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Dapsone: (Major) Agranulocytosis has been reported in the second to third month of weekly concomitant treatment with dapsone and other hemolytic agents such as folic acid antagonists (e.g., trimethoprim, sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole). These combinations increase the likelihood of adverse hematologic events. Concurrent administration of dapsone with trimethoprim increases the plasma concentrations of both drugs. The efficacy of dapsone is increased, which may provide a therapeutic advantage in the treatment of Pneumocystis pneumonia; however, an increase in the frequency and severity of dapsone toxicity (methemoglobinemia, hemolytic anemia) also has been noted. (Moderate) Coadministration of dapsone with sulfonamides may increase the risk of developing methemoglobinemia. Advise patients to discontinue treatment and seek immediate medical attention with any signs or symptoms of methemoglobinemia.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Minor) According to the manufacturer, no dosage adjustments are required when trimethoprim is administered with dasabuvir; ombitasvir; paritaprevir; ritonavir; however, use of these drugs together may result in elevated dasabuvir plasma concentrations. Trimethoprim inhibits CYP2C8, an enzyme primarily responsible for the metabolism of dasabuvir. Caution and close monitoring are advised if these drugs are administered together.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Dicloxacillin: (Minor) Sulfonamides may compete with dicloxacillin for renal tubular secretion, increasing dicloxacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Dienogest; Estradiol valerate: (Moderate) Anti-infectives that disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen-containing oral contraceptives. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Digoxin: (Major) Because both trimethoprim and digoxin undergo tubular secretion, trimethoprim can interfere with the renal tubular secretion of digoxin when administered concomitantly. The renal clearance of digoxin decreased significantly in elderly subjects receiving trimethoprim for 14 days, resulting in a 22% increase in digoxin concentrations. Similar changes were not noted in a single-dose study of young healthy volunteers. Patients receiving digoxin, especially the elderly, should be monitored carefully for digoxin toxicity if trimethoprim is added.
    Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Diphenhydramine; Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with sulfonamides, monitor patients for toxicity from either drug.
    Disulfiram: (Major) The ingestion of ethanol by patients receiving disulfiram causes an extremely unpleasant reaction that can last from 30 minutes to several hours. Intravenous sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole contains ethanol and should not be co-administered with disulfiram. This reaction would not be expected to occur with oral sulfamethoxazole; trimethoprim.
    Dofetilide: (Severe) The concurrent use of dofetilide with trimethoprim alone or in combination with sulfamethoxazole is contraindicated. Trimethoprim is an inhibitor of renal cationic secretion and decreases the renal tubular secretion of dofetilide. The combination of trimethoprim 160 mg and 800 mg sulfamethoxazole co-administered twice daily with dofetilide (500 mcg BID) for 4 days has been shown to increase dofetilide AUC by 93% and Cmax by 103%.
    Donepezil; Memantine: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as trimethoprim, may decrease memantine elimination by competing for common renal tubular transport systems. Although this interaction is theoretical, careful patient monitoring and dose adjustment of memantine and/or trimethoprim is recommended.
    Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as sulfamethoxazole, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
    Dronabinol: (Major) Use caution if coadministration of dronabinol with sulfamethoxazole is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; sulfamethoxazole is a moderate inhibitor of CYP2C9. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Drospirenone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Drospirenone; Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Drospirenone; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) L-methylfolate and trimethoprim should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with trimethoprim. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
    Dulaglutide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Elexacaftor; tezacaftor; ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as sulfamethoxazole; trimethoprim, SMX-TMP. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Eltrombopag: (Moderate) Eltrombopag is metabolized by CYP2C8. The significance of administering inhibitors of CYP2C8, such as trimethoprim, on the systemic exposure of eltrombopag has not been established. Monitor patients for signs of eltrombopag toxicity if these drugs are coadministered.
    Elvitegravir: (Moderate) Caution is warranted when elvitegravir is administered with sulfamethoxazole; trimethoprim, SMX-TMP as there is a potential for decreased sulfamethoxazole concentrations. Sulfamethoxazole is a substrate of CYP2C9, while elvitegravir is a CYP2C9 inducer.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when elvitegravir is administered with sulfamethoxazole; trimethoprim, SMX-TMP as there is a potential for decreased sulfamethoxazole concentrations. Sulfamethoxazole is a substrate of CYP2C9, while elvitegravir is a CYP2C9 inducer.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when elvitegravir is administered with sulfamethoxazole; trimethoprim, SMX-TMP as there is a potential for decreased sulfamethoxazole concentrations. Sulfamethoxazole is a substrate of CYP2C9, while elvitegravir is a CYP2C9 inducer.
    Empagliflozin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Empagliflozin; Linagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Empagliflozin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Enalapril, Enalaprilat: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Enalapril; Felodipine: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Enalapril; Hydrochlorothiazide, HCTZ: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Entecavir: (Moderate) Both entecavir and trimethoprim are secreted by active tubular secretion. In theory, coadministration of entecavir with trimethoprim may increase the serum concentrations of either drug due to competition for the drug elimination pathway.
    Eplerenone: (Major) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially with pre-existing risk factors for hyperkalemia. Trimethoprim should be used with caution with other drugs known to cause significant hyperkalemia such as eplerenone.
    Eprosartan: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Erdafitinib: (Major) Avoid coadministration of erdafitinib and sulfamethoxazole due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If sulfamethoxazole is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP2C9 substrate and sulfamethoxazole is a moderate CYP2C9 inhibitor.
    Ertugliflozin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Ertugliflozin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Ertugliflozin; Sitagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Esomeprazole; Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with sulfonamides, monitor patients for toxicity from either drug.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Anti-infectives which disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen containing oral contraceptives. Alternative or additional contraception may be advisable.
    Estradiol: (Moderate) Anti-infectives that disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen-containing oral contraceptives. (Moderate) Anti-infectives which disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen containing oral contraceptives. Alternative or additional contraception may be advisable.
    Estradiol; Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Estradiol; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Estradiol; Norgestimate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Desogestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Etonogestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) Folate antagonists, such as trimethoprim, especially when used in high doses or over a prolonged period, inhibit dihydrofolate reductase and thus may inhibit the action of folic acid, vitamin B9. (Minor) L-methylfolate and trimethoprim should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with trimethoprim. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
    Ethinyl Estradiol; Norelgestromin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norgestimate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Exenatide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as sulfamethoxazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of sulfamethoxazole during coadministration with fenofibric acid.
    Fenoprofen: (Minor) An interaction may occur between fenoprofen and sulfonamides. Fenoprofen is 99% bound to albumin. Thus, fenoprofen may displace other highly protein bound drugs from albumin or vice versa. If fenoprofen is used concurrently with sulfonamides, monitor patients for toxicity from any of the drugs.
    Fluorouracil, 5-FU: (Major) Use of other folate antagonists should be avoided during therapy with sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. Hematologic toxicity, such as leukopenia and/or thrombocytopenia, can be increased by concurrent use of fluorouracil, 5-FU or other bone marrow depressants. (Major) Use of other folate antagonists should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of fluorouracil, 5-FU.
    Fluvastatin: (Moderate) In theory, concurrent use CYP2C9 inhibitors, such as sulfonamides, and fluvastatin, a CYP2C9 substrate, may result in reduced metabolism of fluvastatin and potential for toxicity.
    Folic Acid, Vitamin B9: (Minor) Folate antagonists, such as trimethoprim, especially when used in high doses or over a prolonged period, inhibit dihydrofolate reductase and thus may inhibit the action of folic acid, vitamin B9.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with sulfamethoxazole. Sulfamethoxazole is an inhibitor of CYP2C9, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with sulfamethoxazole, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fosinopril: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Fosphenytoin: (Moderate) Concomitant use of sulfamethoxazole with fosphenytoin (which is metabolized to phenytoin) may result in increased serum concentrations of phenytoin and increase the risk for adverse reactions. Phenytoin is a substrate of hepatic isoenzyme CYP2C9; sulfamethoxazole is an inhibitor of this enzyme. Caution and close monitoring of phenytoin serum concentrations are advised if these drugs are used together; dosage adjustments may be necessary in some patients. Monitor for signs of phenytoin toxicity. (Moderate) The half-life of phenytoin may be increased when trimethoprim is given concurrently with phenytoin. It is thought that trimethoprim may interfere with phenytoin hepatic metabolism. Reduced phenytoin clearance can lead to toxicity. Phenytoin or fosphenytoin doses may need to be reduced during concomitant use of trimethoprim.
    Ganciclovir: (Moderate) Use ganciclovir and sulfamethoxazole; trimethoprim together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Glimepiride: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Glimepiride; Pioglitazone: (Moderate) It is possible that an increase in the exposure of pioglitazone may occur when coadministered with other drugs that inhibit CYP2C8 such as trimethoprim. Monitor for changes in glycemic control if trimethoprim is coadministered with pioglitazone. (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Glimepiride; Rosiglitazone: (Moderate) It is possible that an increase in the exposure of rosiglitazone may occur when coadministered with drugs that inhibit CYP2C8 such as trimethoprim. Patients should be monitored for changes in glycemic control if any CYP2C8 inhibitors are coadministered with rosiglitazone. (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Glipizide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Glipizide; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Glyburide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Glyburide; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Hetastarch; Dextrose; Electrolytes: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Hydrochlorothiazide, HCTZ: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Hydrochlorothiazide, HCTZ; Losartan: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors. (Minor) Inhibitors of the hepatic CYP2C9 isoenzyme, such as sulfonamides, have potential to inhibit the conversion of losartan to its active metabolite. Monitor therapeutic response to individualize losartan dosage.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Hydrochlorothiazide, HCTZ; Moexipril: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Hydrochlorothiazide, HCTZ; Quinapril: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Major) Trimethoprim has a potassium-sparing effect and may induce hyperkalemia, especially in patients with pre-existing risk factors for hyperkalemia (e.g., renal disease). Patients, especially those with renal dysfunction, should be carefully monitored for hyperkalemia during concomitant use of potassium-sparing diuretics and trimethoprim.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Hydrochlorothiazide, HCTZ; Triamterene: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Major) Trimethoprim has a potassium-sparing effect and may induce hyperkalemia, especially in patients with pre-existing risk factors for hyperkalemia (e.g., renal disease). Patients, especially those with renal dysfunction, should be carefully monitored for hyperkalemia during concomitant use of potassium-sparing diuretics and trimethoprim. (Major) Use of other folate antagonists should be avoided during therapy with sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. Hematologic toxicity, such as leukopenia and/or thrombocytopenia, can be increased by concurrent use of triamterene or other bone marrow depressants.
    Hydrochlorothiazide, HCTZ; Valsartan: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration. (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly. (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Ibritumomab Tiuxetan: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts. (Moderate) Use potassium phosphate cautiously with trimethoprim (especially high dose), as both drugs increase serum potassium concentrations. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Patients should have serum potassium concentration determinations at periodic intervals.
    Incretin Mimetics: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Indinavir: (Minor) Concomitant administration of indinavir and trimethoprim should be done with caution. Administration of indinavir and sulfamethoxazole; trimethoprim, SMX-TMP significantly increased the AUC of trimethoprim. There was no effect on the AUC of indinavir or sulfamethoxazole.
    Indomethacin: (Major) Avoid the concomitant use of sulfamethoxazole and indomethacin as coadministration may result in increased serum concentrations of sulfamethoxazole. Coadministration may increase the risk of sulfamethoxazole toxicity.
    Insulin Degludec; Liraglutide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Insulin Glargine; Lixisenatide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Insulins: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Iodine; Potassium Iodide, KI: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Irbesartan: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin is a potent enzyme inducer. Rifampin can increase the metabolism of sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. A pharmacokinetic effect on the combination has been reported with another rifamycin. Concomitant administration of rifabutin and sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole (double-strength) in 12 HIV-infected patients decreased the AUC of SMX-TMP by about 15 to 20%. Rifabutin decreased the AUC and Cmax of trimethoprim by 14% and 6%, respectively, when rifabutin was given with trimethoprim alone. The drugs are often given clinically together with certain patient populations, so the ultimate clinical significance of a possible pharmacokinetic interaction is not clear. Monitor for therapeutic response to therapy. (Moderate) Rifampin is a potent enzyme inducer. Rifampin can increase the metabolism of sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. A pharmacokinetic effect on the combination has been reported with another rifamycin. Concomitant administration of rifabutin and sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole (double-strength) in 12 HIV-infected patients decreased the AUC of SMX-TMP by about 15% to 20%. Rifabutin decreased the AUC and Cmax of trimethoprim by 14% and 6%, respectively, when rifabutin was given with trimethoprim alone. Additionally, sulfamethoxazole; trimethoprim may increase the serum concentration of rifampin. The drugs are often given together for certain patient populations, so the ultimate clinical significance of a possible pharmacokinetic interaction is not clear. Monitor for therapeutic response to therapy and increased rifampin toxicity
    Isoniazid, INH; Rifampin: (Moderate) Rifampin is a potent enzyme inducer. Rifampin can increase the metabolism of sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. A pharmacokinetic effect on the combination has been reported with another rifamycin. Concomitant administration of rifabutin and sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole (double-strength) in 12 HIV-infected patients decreased the AUC of SMX-TMP by about 15 to 20%. Rifabutin decreased the AUC and Cmax of trimethoprim by 14% and 6%, respectively, when rifabutin was given with trimethoprim alone. The drugs are often given clinically together with certain patient populations, so the ultimate clinical significance of a possible pharmacokinetic interaction is not clear. Monitor for therapeutic response to therapy. (Moderate) Rifampin is a potent enzyme inducer. Rifampin can increase the metabolism of sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. A pharmacokinetic effect on the combination has been reported with another rifamycin. Concomitant administration of rifabutin and sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole (double-strength) in 12 HIV-infected patients decreased the AUC of SMX-TMP by about 15% to 20%. Rifabutin decreased the AUC and Cmax of trimethoprim by 14% and 6%, respectively, when rifabutin was given with trimethoprim alone. Additionally, sulfamethoxazole; trimethoprim may increase the serum concentration of rifampin. The drugs are often given together for certain patient populations, so the ultimate clinical significance of a possible pharmacokinetic interaction is not clear. Monitor for therapeutic response to therapy and increased rifampin toxicity
    Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as sulfamethoxazole; trimethoprim, SMX-TMP. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Concomitant use of sulfonamides and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use. (Moderate) Concomitant use of trimethoprim and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use.
    Lamotrigine: (Moderate) Lamotrigine inhibits dihydrofolate reductase. Caution should be exercised when administering trimethoprim, which also inhibits this enzyme.
    Lansoprazole; Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with sulfonamides, monitor patients for toxicity from either drug.
    Lesinurad: (Moderate) Use lesinurad and sulfamethoxazole together with caution; sulfamethoxazole may increase the systemic exposure of lesinurad. Sulfamethoxazole is an inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
    Lesinurad; Allopurinol: (Moderate) Use lesinurad and sulfamethoxazole together with caution; sulfamethoxazole may increase the systemic exposure of lesinurad. Sulfamethoxazole is an inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
    Leucovorin: (Minor) Racemic leucovorin may be used to offset the toxicity of folate antagonists such as trimethoprim; however, the concomitant use of leucovorin with sulfamethoxazole; trimethoprim for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with an increased risk of treatment failure and morbidity. Levoleucovorin may result in the same effect. (Minor) The concomitant use of leucovorin with sulfamethoxazole; trimethoprim, for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with an increased risk of treatment failure and morbidity. Levoleucovorin may result in the same effect.
    Leuprolide; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Levoleucovorin: (Minor) Racemic leucovorin may be used to offset the toxicity of folate antagonists such as trimethoprim; however, the concomitant use of leucovorin with sulfamethoxazole; trimethoprim for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with an increased risk of treatment failure and morbidity. Levoleucovorin may result in the same effect. (Minor) The concomitant use of leucovorin with sulfamethoxazole; trimethoprim, for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with an increased risk of treatment failure and morbidity. Levoleucovorin may result in the same effect.
    Levomefolate: (Minor) L-methylfolate and trimethoprim should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with trimethoprim. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
    Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Linagliptin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Liraglutide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Lisinopril: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Lixisenatide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Loperamide: (Moderate) If these drugs are used together, the plasma concentrations of loperamide may increase. Loperamide is a substrate for CYP2C8. Trimethoprim has been shown in vitro and in studies of healthy human volunteers to selectively inhibit the CYP2C8 isoenzyme. Monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Loperamide; Simethicone: (Moderate) If these drugs are used together, the plasma concentrations of loperamide may increase. Loperamide is a substrate for CYP2C8. Trimethoprim has been shown in vitro and in studies of healthy human volunteers to selectively inhibit the CYP2C8 isoenzyme. Monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Losartan: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors. (Minor) Inhibitors of the hepatic CYP2C9 isoenzyme, such as sulfonamides, have potential to inhibit the conversion of losartan to its active metabolite. Monitor therapeutic response to individualize losartan dosage.
    Lumacaftor; Ivacaftor: (Minor) Concomitant use of sulfamethoxazole; trimethoprim and lumacaftor; ivacaftor may alter sulfamethoxazole; trimethoprim, SMX-TMP, Cotrimoxazole exposure. Sulfamethoxazole is a substrate of CYP2C9; in vitro data suggest it is also a substrate for the P-glycoprotein (P-gp) drug transporter. In vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C9 and P-gp. The net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism and P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Lumacaftor; Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as sulfamethoxazole; trimethoprim, SMX-TMP. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Mefenamic Acid: (Moderate) Mefenamic acid is a substrate for CYP450 2C9. Inhibitors of the 2C9 isoenzyme, such as trimethoprim, may lead to increased serum concentrations of mefenamic acid. If administered concurrently with mefenamic acid, monitor for NSAID related side effects.
    Meglitinides: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with sulfamethoxazole is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and sulfamethoxazole is a moderate CYP2C9 inhibitor.
    Memantine: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as trimethoprim, may decrease memantine elimination by competing for common renal tubular transport systems. Although this interaction is theoretical, careful patient monitoring and dose adjustment of memantine and/or trimethoprim is recommended.
    Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Mepivacaine; Levonordefrin: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Mercaptopurine, 6-MP: (Moderate) Increased bone marrow suppression may occur if mercaptopurine is coadministered with trimethoprim sulfamethoxazole. If concomitant use is necessary, monitor complete blood counts and adjust the dose of mercaptopurine if severe neutropenia or thrombocytopenia occur.
    Mestranol; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Metformin; Pioglitazone: (Moderate) It is possible that an increase in the exposure of pioglitazone may occur when coadministered with other drugs that inhibit CYP2C8 such as trimethoprim. Monitor for changes in glycemic control if trimethoprim is coadministered with pioglitazone. (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Metformin; Repaglinide: (Major) Coadministration of trimethoprim and repaglinide increases the AUC of repaglinide by 61%; if coadministration is necessary, consider a dose reduction of repaglinide and increased frequency of glucose monitoring. Trimethoprim is a CYP2C8 inhibitor and repaglinide is a CYP2C8 substrate. The possibility of an increased risk of hypoglycemia should be considered during concomitant use of trimethoprim and repaglinide. (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Metformin; Rosiglitazone: (Moderate) It is possible that an increase in the exposure of rosiglitazone may occur when coadministered with drugs that inhibit CYP2C8 such as trimethoprim. Patients should be monitored for changes in glycemic control if any CYP2C8 inhibitors are coadministered with rosiglitazone. (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Metformin; Saxagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Metformin; Sitagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Methenamine: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly.
    Methenamine; Sodium Acid Phosphate: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly.
    Methotrexate: (Major) Methotrexate is partially bound to plasma proteins, and drugs that can displace methotrexate from these proteins, such as sulfonamides could cause methotrexate-induced toxicity. Due to the potential toxicity of methotrexate, interactions with sulfonamides can be very serious even if methotrexate is administered in low doses. (Moderate) Use of other folate antagonists, such as methotrexate, should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of methotrexate.
    Methoxsalen: (Moderate) Use methoxsalen and sulfonamides together with caution; the risk of severe burns/photosensitivity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
    Methyclothiazide: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Metolazone: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Metronidazole: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Intravenous sulfamethoxazole; trimethoprim, SMX-TMP contains ethanol. A disulfiram-like reaction has occurred when metronidazole was used with IV sulfamethoxazole; trimethoprim, SMX-TMP. This reaction would not be expected to occur with oral sulfamethoxazole; trimethoprim, SMX-TMP.
    Miglitol: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Moexipril: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with sulfonamides, monitor patients for toxicity from either drug.
    Naproxen; Pseudoephedrine: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with sulfonamides, monitor patients for toxicity from either drug.
    Naproxen; Sumatriptan: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with sulfonamides, monitor patients for toxicity from either drug.
    Nebivolol; Valsartan: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Norgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Olmesartan: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Concomitant administration of rifabutin and sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole (double-strength) in 12 HIV-infected patients decreased the AUC of SMX-TMP by about 15 to 20%. Rifabutin decreased the AUC and Cmax of trimethoprim by 14% and 6%, respectively, when rifabutin was given with trimethoprim alone. sulfamethoxazole; trimethoprim, SMX-TMP did not alter the pharmacokinetics of rifabutin. (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Oritavancin: (Moderate) Sulfamethoxazole is metabolized by CYP2C9; oritavancin is a weak CYP2C9 inhibitor. Coadministration may result in elevated sulfamethoxazole plasma concentrations. If these drugs are administered concurrently, monitor for sulfamethoxazole toxicity such as diarrhea, anorexia, or nausea.
    Oxacillin: (Minor) Sulfonamides may compete with oxacillin for renal tubular secretion, increasing oxacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Paclitaxel: (Minor) Paclitaxel is a substrate of CYP2C8; in vitro, trimethoprim is a mild inhibitor of CYP2C8. If coadministration is necessary, use caution and monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy. This interaction may also be applicable to combination products containing trimethoprim, including sulfamethoxazole; trimethoprim (also known as SMX-TMP or cotrimoxazole).
    Penicillin G Benzathine: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Sulfonamides may also compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects. (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Sulfonamides may also compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Penicillin G: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Penicillin V: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Perindopril: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Perindopril; Amlodipine: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with sulfamethoxazole. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
    Phenytoin: (Moderate) Concomitant use of sulfamethoxazole with phenytoin may result in increased serum concentrations of phenytoin and increase the risk for adverse reactions. Phenytoin is a substrate of CYP2C9; sulfamethoxazole is an inhibitor of this enzyme. Caution and close monitoring of phenytoin serum concentrations are advised if these drugs are used together; dosage adjustments may be necessary in some patients. Monitor for signs of phenytoin toxicity. (Moderate) The half-life of phenytoin may be increased with trimethoprim. It is thought that trimethoprim may interfere with phenytoin hepatic metabolism. Reduced phenytoin clearance can lead to toxicity. Phenytoin doses may need to be reduced during concomitant use of trimethoprim.
    Photosensitizing agents (topical): (Moderate) Sulfonamides may cause photosensitization and may increase the photosensitizing effects of photosensitizing agents used during photodynamic therapy.
    Pioglitazone: (Moderate) It is possible that an increase in the exposure of pioglitazone may occur when coadministered with other drugs that inhibit CYP2C8 such as trimethoprim. Monitor for changes in glycemic control if trimethoprim is coadministered with pioglitazone.
    Piperacillin: (Minor) Sulfonamides may compete with piperacillin for renal tubular secretion, increasing piperacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Piperacillin; Tazobactam: (Minor) Sulfonamides may compete with piperacillin for renal tubular secretion, increasing piperacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Porfimer: (Major) Avoid coadministration of porfimer with sulfonamides due to the risk of increased photosensitivity. Porfimer is a light-activated drug used in photodynamic therapy; all patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like sulfonamides may increase the risk of a photosensitivity reaction.
    Posaconazole: (Major) Posaconazole and sulfamethoxazole should be coadministered with caution due to an increased potential for sulfamethoxazole-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of sulfamethoxazole. These drugs used in combination may result in elevated sulfamethoxazole plasma concentrations, causing an increased risk for sulfamethoxazole-related adverse events.
    Potassium Acetate: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Potassium Bicarbonate: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Potassium Chloride: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Potassium Citrate: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Potassium Gluconate: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Potassium Iodide, KI: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Potassium Phosphate: (Moderate) Use potassium phosphate cautiously with trimethoprim (especially high dose), as both drugs increase serum potassium concentrations. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Patients should have serum potassium concentration determinations at periodic intervals.
    Potassium Phosphate; Sodium Phosphate: (Moderate) Use potassium phosphate cautiously with trimethoprim (especially high dose), as both drugs increase serum potassium concentrations. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Patients should have serum potassium concentration determinations at periodic intervals.
    Potassium: (Moderate) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia. Trimethoprim should also be used with caution with other drugs known to cause significant hyperkalemia such as potassium salts.
    Potassium-sparing diuretics: (Major) Trimethoprim has a potassium-sparing effect and may induce hyperkalemia, especially in patients with pre-existing risk factors for hyperkalemia (e.g., renal disease). Patients, especially those with renal dysfunction, should be carefully monitored for hyperkalemia during concomitant use of potassium-sparing diuretics and trimethoprim.
    Pralatrexate: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as sulfamethoxazole; trimethoprim, SMX-TMP, may result in delayed clearance of pralatrexate.
    Pramlintide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Prilocaine; Epinephrine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Probenecid: (Minor) Probenecid may inhibit the renal transport of sulfonamides. Plasma concentrations of these agents may be increased.
    Procainamide: (Major) Trimethoprim and procainamide both undergo tubular secretion, and as a result, each drug can interfere with the renal clearance of the other. Although it is not necessary to avoid concomitant use of these two drugs, lower doses of procainamide may be necessary during trimethoprim administration.
    Pyrimethamine: (Major) The combination of pyrimethamine with sulfonamides can be synergistic against susceptible organisms, however, bone marrow suppression may be more likely to occur with combination therapy. CBCs should be monitored routinely in patients receiving both drugs simultaneously. Some references suggest routinely administering leucovorin during therapy with pyrimethamine even when used without any of the above drugs. (Major) Use of other folate antagonists should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of pyrimethamine.
    Pyrimethamine; Sulfadoxine: (Major) The combination of pyrimethamine with sulfonamides can be synergistic against susceptible organisms, however, bone marrow suppression may be more likely to occur with combination therapy. CBCs should be monitored routinely in patients receiving both drugs simultaneously. Some references suggest routinely administering leucovorin during therapy with pyrimethamine even when used without any of the above drugs. (Major) Use of other folate antagonists should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of pyrimethamine.
    Quinapril: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Ramelteon: (Moderate) Ramelteon should be administered with caution to patients taking CYP2C9 inhibitors, such as sulfamethoxazole. The AUC and Cmax of ramelteon have been elevated > 150% when administered with other CYP2C9 inhibitors. The patient should be monitored closely for toxicity even though ramelteon has a wide therapeutic index.
    Ramipril: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Repaglinide: (Major) Coadministration of trimethoprim and repaglinide increases the AUC of repaglinide by 61%; if coadministration is necessary, consider a dose reduction of repaglinide and increased frequency of glucose monitoring. Trimethoprim is a CYP2C8 inhibitor and repaglinide is a CYP2C8 substrate. The possibility of an increased risk of hypoglycemia should be considered during concomitant use of trimethoprim and repaglinide.
    Rifabutin: (Moderate) Concomitant administration of rifabutin and sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole (double-strength) in 12 HIV-infected patients decreased the AUC of SMX-TMP by about 15 to 20%. Rifabutin decreased the AUC and Cmax of trimethoprim by 14% and 6%, respectively, when rifabutin was given with trimethoprim alone. sulfamethoxazole; trimethoprim, SMX-TMP did not alter the pharmacokinetics of rifabutin.
    Rifampin: (Moderate) Rifampin is a potent enzyme inducer. Rifampin can increase the metabolism of sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. A pharmacokinetic effect on the combination has been reported with another rifamycin. Concomitant administration of rifabutin and sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole (double-strength) in 12 HIV-infected patients decreased the AUC of SMX-TMP by about 15 to 20%. Rifabutin decreased the AUC and Cmax of trimethoprim by 14% and 6%, respectively, when rifabutin was given with trimethoprim alone. The drugs are often given clinically together with certain patient populations, so the ultimate clinical significance of a possible pharmacokinetic interaction is not clear. Monitor for therapeutic response to therapy. (Moderate) Rifampin is a potent enzyme inducer. Rifampin can increase the metabolism of sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. A pharmacokinetic effect on the combination has been reported with another rifamycin. Concomitant administration of rifabutin and sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole (double-strength) in 12 HIV-infected patients decreased the AUC of SMX-TMP by about 15% to 20%. Rifabutin decreased the AUC and Cmax of trimethoprim by 14% and 6%, respectively, when rifabutin was given with trimethoprim alone. Additionally, sulfamethoxazole; trimethoprim may increase the serum concentration of rifampin. The drugs are often given together for certain patient populations, so the ultimate clinical significance of a possible pharmacokinetic interaction is not clear. Monitor for therapeutic response to therapy and increased rifampin toxicity
    Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and sulfamethoxazole. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Rosiglitazone: (Moderate) It is possible that an increase in the exposure of rosiglitazone may occur when coadministered with drugs that inhibit CYP2C8 such as trimethoprim. Patients should be monitored for changes in glycemic control if any CYP2C8 inhibitors are coadministered with rosiglitazone.
    Sacubitril; Valsartan: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Salicylates: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Salsalate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Sapropterin: (Moderate) Drugs that inhibit folate metabolism, such as trimethoprim, should be used with caution in patients taking sapropterin. More frequent monitoring of blood phenylalanine concentrations is warranted in patients receiving these agents concurrently. An increased dosage of sapropterin may be necessary to achieve a biochemical response. Trimethoprim may decrease the bioavailability of endogenous tetrahydrobiopterin (BH4) by inhibiting the enzyme dihydrofolate reductase. Reduction of BH4 could make management of hyperphenylalaninemia with sapropterin more difficult.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Selexipag: (Major) Consider a less frequent dosing regimen (e.g., once daily) when initiating selexipag in patients receiving trimethoprim. Reduce the selexipag dose when trimethoprim is initiated in patients already taking selexipag. Coadministration can be expected to increase exposure to selexipag and its active metabolite. Selexipag is a substrate of CYP2C8; trimethoprim is a moderate CYP2C8 inhibitor.
    Semaglutide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    SGLT2 Inhibitors: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Siponimod: (Moderate) Concomitant use of siponimod and sulfamethoxazole may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate or strong CYP3A4 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; sulfamethoxazole is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
    Sodium Iodide: (Moderate) Sulfonamides may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with trimethoprim. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Velpatasvir is a CYP2C8 substrate; trimethoprim is an inhibitor of CYP2C8.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with trimethoprim. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Velpatasvir is a CYP2C8 substrate; trimethoprim is an inhibitor of CYP2C8.
    Spironolactone: (Major) Trimethoprim has a potassium-sparing effect and may induce hyperkalemia, especially in patients with pre-existing risk factors for hyperkalemia (e.g., renal disease). Patients, especially those with renal dysfunction, should be carefully monitored for hyperkalemia during concomitant use of potassium-sparing diuretics and trimethoprim.
    Sulfinpyrazone: (Moderate) Sulfamethoxazole is roughly 60 to 70% protein-bound and can potentiate other drugs by displacing them from their binding sites. Drugs that may be affected in this manner include sulfinpyrazone.
    Sulfonylureas: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering sulfamethoxazole with telaprevir due to an increased potential for sulfamethoxazole-related adverse events. If sulfamethoxazole dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of sulfamethoxazole. Sulfamethoxazole is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated sulfamethoxazole plasma concentrations.
    Telmisartan: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering sulfamethoxazole. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9; sulfamethoxazole is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered. (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering trimethoprim. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenzymes, with major contributions coming from CYP2C8; trimethoprim is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
    Tetracaine: (Major) Coadministration of tetracaine with sulfonamides may antagonize the effect of sulfonamides. Tetracaine is metabolized to para-aminobenzoic acid (PABA). PABA antagonized the effects of sulfonamides. Additionally, coadministration of tetracaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Tezacaftor; Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as sulfamethoxazole; trimethoprim, SMX-TMP. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Thiazide diuretics: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Thiazolidinediones: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Tolazamide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Tolbutamide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. (Minor) Trimethoprim has been shown to reduce the clearance of unbound tolbutamide and prolong tolbutamide half-life. The reductions in tolbutamide clearance are relatively small. While the risk of enhanced hypoglycemic effects appears low, closely monitor blood glucose during concomitant therapy.
    Trandolapril: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Trandolapril; Verapamil: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin-converting enzyme (ACE) inhibitors and trimethoprim is necessary. Hyperkalemia may be more signficant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Triamterene: (Major) Trimethoprim has a potassium-sparing effect and may induce hyperkalemia, especially in patients with pre-existing risk factors for hyperkalemia (e.g., renal disease). Patients, especially those with renal dysfunction, should be carefully monitored for hyperkalemia during concomitant use of potassium-sparing diuretics and trimethoprim. (Major) Use of other folate antagonists should be avoided during therapy with sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. Hematologic toxicity, such as leukopenia and/or thrombocytopenia, can be increased by concurrent use of triamterene or other bone marrow depressants.
    Trimetrexate: (Major) Use of other folate antagonists should be avoided during therapy with sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. Hematologic toxicity, such as leukopenia and/or thrombocytopenia, can be increased by concurrent use of trimetrexate or other bone marrow depressants. (Major) Use of other folate antagonists should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of trimetrexate.
    Trospium: (Moderate) Both trospium and trimethoprim are eliminated by active renal tubular secretion; coadministration has the potential to increase serum concentrations of trospium or trimethoprim due to competition for the drug elimination pathway. Careful patient monitoring is recommended. For trospium, monitor for anticholinergic effects, such as dry mouth, constipation, blurred vision, urinary retention, or increased CNS effects which are not frequent when the drug is used alone. Trimethoprim dose-related side effects include nausea, vomiting, dizziness, headaches, mental depression/confusion, palpitations, and bone marrow depression. In some patients, a dosage reduction may be required.
    Typhoid Vaccine: (Major) Avoid use of sulfonamides and other antibiotics during the oral typhoid vaccination series at concurrent administration may result in a reduced immune response. In order to provided immunity, the oral typhoid vaccine requires initiation of a limited infection localized within the gastrointestinal tract. Antibiotics prevent this bacterial infection from occurring, thereby, reducing the vaccines protective immune response.
    Valganciclovir: (Moderate) Use valganciclovir and sulfamethoxazole; trimethoprim together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Valproic Acid, Divalproex Sodium: (Minor) The risk for developing leukopenia and/or thrombocytopenia can be increased if other bone marrow depressants are used with sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. Megaloblastic anemia can occur when sulfamethoxazole; trimethoprim, SMX-TMP is used in patients who are taking other folate antagonists. These agents include: valproic acid, divalproex sodium. If these agents are used concomitantly, close observation of blood counts is warranted. (Minor) Use of other folate antagonists should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of divalproex or valproic acid.
    Valsartan: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Hyperkalemia may be more significant in patients receiving IV trimethoprim. For those patients at higher risk of hyperkalemia (e.g., the elderly, patients with underlying disorders of potassium metabolism, and those with renal dysfunction), consideration of an alternate antibiotic may be warranted. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with sulfonamides is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like sulfonamides may increase the risk of a photosensitivity reaction.
    Vigabatrin: (Minor) Vigabatrin is not significantly metabolized; however, it is an inducer of CYP2C9. In theory, decreased exposure of drugs that are extensively metabolized by CYP2C9, such as sulfamethoxazole, may occur during concurrent use of vigabatrin.
    Voriconazole: (Moderate) Monitor for increased voriconazole-related adverse reactions if coadministered with sulfamethoxazole. Elevated voriconazole concentrations and, thus, adverse reactions may result. Voriconazole is a CYP2C9 substrate and sulfamethoxazole is a CYP2C9 inhibitor.
    Warfarin: (Major) Sulfonamides, including sulfamethizole, sulfamethoxazole, and sulfisoxazole, potentiate the anticoagulant effect of warfarin. Monitor for bleeding and needed warfarin dosage adjustments based on the INR. Sulfonamides are known to inhibit the hepatic metabolism of the S-warfarin and have, in some cases, doubled the hypoprothrombinemic effect of warfarin. A protein-binding interaction also may be possible, with sulfonamides displacing warfarin from protein binding sites. Most of the reported cases of an interaction between warfarin and a sulfonamide drug involved the combination of sulfamethoxazole and trimethoprim, which may be due to the additive effects of trimethoprim mediated CYP2C8 inhibition of warfarin metabolism. Among older patients receiving long-term warfarin therapy, recent sulfamethoxazole; trimethoprim use (i.e., within 14 days) was associated with an increased risk of hospitalization for upper GI bleed compared to other antibiotics commonly used for the treatment of UTI (amoxicillin, ampicillin, nitrofurantoin, and norfloxacin). Due to the potential severity of excessive anticoagulation, sulfonamides should be administered cautiously to a patient already stabilized on warfarin. Warfarin doses may need to be adjusted when sulfonamide therapy is discontinued.
    Zidovudine, ZDV: (Moderate) Concomitant use of sulfonamides and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use. (Moderate) Concomitant use of trimethoprim and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use.
    Ziprasidone: (Major) Concomitant use of ziprasidone and sulfamethoxazole; trimethoprim should be avoided if possible due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QT prolongation resulting in ventricular tachycardia and TdP has been reported during postmarketing use of sulfamethoxazole; trimethoprim.

    PREGNANCY AND LACTATION

    Pregnancy

    Sulfamethoxazole; trimethoprim may cause fetal harm if administered during pregnancy. Use sulfamethoxazole; trimethoprim during pregnancy only if the potential benefit justifies the potential risk to the fetus. In a nested, case-control study (n = 87,020 controls; 8,702 cases) within the Quebec Pregnancy Cohort, sulfonamide use during early pregnancy was associated with an increased risk of spontaneous abortion (adjusted odds ratio (aOR) 2.01; 95% CI: 1.36 to 2.97; 30 exposed cases); residual confounding by severity of infection may be a potential limitation of this study. Limited data have also linked first trimester exposure to sulfamethoxazole; trimethoprim to an increased risk for congenital malformations (i.e., cardiovascular malformations, neural tube defects, oral cleft, urinary tract defects, club foot). However, other studies such as the Collaborative Perinatal Project, which included 1,455 mothers with first trimester sulfonamide exposure and 5,689 with exposure anytime during pregnancy, found no evidence to suggest a relationship between sulfonamide use and fetal malformations. Sulfonamides should generally be avoided near term due to the potential for jaundice, hemolytic anemia, and kernicterus in the newborn; sulfonamides readily cross the placenta with fetal concentrations averaging 70% to 90% of maternal concentrations. If sulfamethoxazole; trimethoprim is used during pregnancy, the patient should be advised of the potential risk to the fetus and supplemental multivitamins should be administered. Use of the drug is recommended for prophylaxis of pneumocystis pneumonia (PCP) in HIV-infected pregnant women.

    Both sulfamethoxazole and trimethoprim are excreted into human breast milk at concentrations of approximately 2% to 5% of the recommended daily dose for infants over 2 months of age. Because of the potential risk of bilirubin displacement and kernicterus, avoid breast-feeding during treatment with sulfamethoxazole; trimethoprim. However, previous American Academy of Pediatrics (AAP) recommendations considered sulfamethoxazole; trimethoprim as usually compatible with breast-feeding. An extensive review in HIV-infected women suggested that the risk of kernicterus in the breast-feeding infant is very low. In a study of 12 newborn infants of less than 3 days postnatal age receiving systemic sulfamethoxazole; trimethoprim, the authors noted that despite therapeutic serum concentrations, there was no displacement of bilirubin from albumin in the newborns. If sulfamethoxazole; trimethoprim is administered to the mother of a young infant, monitor the infant for signs of increased bilirubin and jaundice. Ciprofloxacin, amoxicillin, and nitrofurantoin (cautioned in the infant with glucose-6-phosphate dehydrogenase deficiency) may be potential alternatives to consider during breast-feeding as generally considered compatible by previous AAP recommendations.

    MECHANISM OF ACTION

    Sulfamethoxazole; trimethoprim is usually bactericidal and acts by inhibiting sequential enzymes of the folic acid synthesis pathway. Sulfamethoxazole is a structural analog of p-aminobenzoic acid (PABA), and it inhibits the formation of dihydrofolic acid by competing with PABA for binding to bacterial dihydropteroate synthase. This action interferes with the conversion of PABA into folic acid, an essential component of bacterial development. Trimethoprim binds to and reversibly inhibits the enzyme dihydrofolate reductase, which prevents the formation of tetrahydrofolic acid from dihydrofolic acid. Tetrahydrofolic acid, or THF, is the metabolically active form of folic acid. Without THF, bacteria cannot synthesize thymidine, which leads to interference with bacterial nucleic acid and protein formation. The combination of trimethoprim with sulfamethoxazole is synergistic against some bacteria.[43890] [51808] [55864] [63994]
     
    The susceptibility interpretive criteria for sulfamethoxazole; trimethoprim are delineated by pathogen. The MICs are defined for Enterobacterales, B. cepacia complex, Acinetobacter sp., S. maltophilia, other non-Enterobacterales, and Staphylococcus sp. as susceptible at 2/38 mcg/mL or less and resistant at 4/76 mcg/mL or more. The MICs are defined for H. influenzae, H. parainfluenzae, and S. pneumoniae as susceptible at 0.5/9.5 mcg/mL or less, intermediate at 1/19 to 2/38 mcg/mL, and resistant at 4/76 mcg/mL or more. The MICs are defined for N. meningitidis as susceptible at 0.12/2.4 mcg/mL or less, intermediate at 0.25/4.75 mcg/mL, and resistant at 0.5/9.5 mcg/mL or more; sulfamethoxazole; trimethoprim may only be appropriate for prophylaxis of meningococcal case contacts.[63320] [63321]
     
    Differences in toxicity between healthy individuals and certain patient populations have been documented with sulfonamides. Sulfonamides are metabolized mainly by acetylation. Patients who are slow acetylators (50% of the US population) metabolize more sulfonamide drug by the cytochrome P450 system than fast acetylators. Metabolism via the cytochrome P450 system produces reactive metabolites, usually detoxified by scavengers, such as glutathione. Some patient populations, however, have low amounts of glutathione (i.e., AIDS patients) and toxic metabolites accumulate, leading to a higher incidence of severe toxicities such as hypersensitivity reactions.[63993] [63994]

    PHARMACOKINETICS

    Sulfamethoxazole; trimethoprim is administered orally and intravenously.
     
    Sulfamethoxazole is widely distributed throughout all body tissues and fluids, including peritoneal, synovial, pleural, and ocular fluids as well as breast milk. It also crosses the placenta. Trimethoprim is quickly and widely distributed to tissues and fluids. It also enters the bile, aqueous humor, and bone marrow. CSF concentrations are 30% to 50% of serum concentrations, and high concentrations are reached in prostatic tissue; prostatic fluid; renal, urinary, and pulmonary tissue; and vaginal fluid. It crosses the placenta and enters breast milk. Protein-binding is 44% for trimethoprim and 70% for sulfamethoxazole. In circulation, CYP2C9 metabolizes sulfamethoxazole to form the N4-hydroxy metabolite. Four other sulfamethoxazole metabolites have also been identified: N4-acetyl-, 5-methylhydroxy-, N4-acetyl-5-methylhydroxy-, and the N-glucuronide conjugate. The acetylated metabolites of sulfamethoxazole are more highly bound to protein than is the free drug. Trimethoprim is metabolized into 11 different metabolites, with the major metabolites being the 1- and 3-oxides and the 3- and 4-hydroxy derivatives. Of note, only the free forms of sulfamethoxazole and trimethoprim are considered to be therapeutically active.[43888]
     
    The kidney and liver are both important in the elimination of trimethoprim and sulfamethoxazole. Up to 80% of trimethoprim and roughly 20% of sulfamethoxazole are eliminated unchanged in the urine. Both compounds are removed by glomerular filtration, with some tubular secretion. Sulfamethoxazole is also reabsorbed, and its excretion is increased in alkaline urine. Trimethoprim's excretion is increased in acid urine and decreased in alkaline urine. In patients with normal renal function, sulfamethoxazole's half-life ranges from 6 to 12 hours and trimethoprim's half-life ranges from 8 to 10 hours. Small amounts of both trimethoprim and sulfamethoxazole are excreted in feces and bile.
     
    Affected cytochrome P450 isoenzymes and drug transporter: CYP2C9, CYP2C8, P-gp, OCT1, OCT2
    Sulfamethoxazole is a substrate and inhibitor of CYP2C9. In vitro data suggest trimethoprim is a substrate for the drug transporters P-glycoprotein (P-gp), OCT1, and OCT2. Trimethoprim also inhibits both OCT2 and the hepatic isoenzyme CYP2C8.[43888]

    Oral Route

    Sulfamethoxazole; trimethoprim is rapidly and well absorbed (90% to 100%) from the GI tract. Peak serum concentrations of 1 to 2 mcg/mL and 40 to 60 mcg/mL are achieved 1 to 4 hours after a single oral dose of 160 mg trimethoprim and 800 mg sulfamethoxazole, respectively. At steady state, the serum ratio of trimethoprim to sulfamethoxazole is 1:20. [51809]

    Intravenous Route

    After IV infusion of 160 mg trimethoprim and 800 mg sulfamethoxazole, peak steady-state serum concentrations are roughly 9 mcg/mL and 105 mcg/mL, and troughs are 6 mcg/mL and 70 mcg/mL, respectively.