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  • CLASSES

    Carbapenems

    DEA CLASS

    Rx

    DESCRIPTION

    IV carbapenem antibiotic
    Used for complicated intraabdominal and skin and skin structure infections and bacterial meningitis
    May have a lower incidence of ADRs than imipenem

    COMMON BRAND NAMES

    Merrem

    HOW SUPPLIED

    Meropenem/Merrem Intravenous Inj Pwd F/Sol: 1g, 500mg

    DOSAGE & INDICATIONS

    For the treatment of bacterial meningitis.
    Intravenous dosage
    Adults†

    2 g IV every 8 hours is recommended by clinical practice guidelines as a treatment option for empiric or documented meningitis. The IDSA recommends meropenem as a treatment option for documented meningitis and for empiric therapy in combination with vancomycin after a penetrating trauma or postneurosurgery; meropenem may also be used in combination with vancomycin as empiric therapy for CSF shunt infections when gram negative bacilli are present on gram stain. The recommended duration of therapy is 7 days for Neisseria meningitidis and Haemophilus influenzae, 10 to 14 days for Streptococcus pneumoniae, and at least 3 weeks for gram-negative bacilli.

    Infants 3 months and older, Children, and Adolescents

    40 mg/kg/dose IV every 8 hours (Max: 2 g/dose). The IDSA recommends meropenem as a treatment option for documented meningitis and for empiric therapy in combination with vancomycin after a penetrating trauma or postneurosurgery; meropenem may also be used in combination with vancomycin as empiric therapy for CSF shunt infections when gram negative bacilli are present on gram stain. The recommended duration of therapy is 7 days for Neisseria meningitidis and Haemophilus influenzae, 10 to 14 days for Streptococcus pneumoniae, and at least 3 weeks for gram-negative bacilli.

    Term Neonates† and Infants younger than 3 months†

    40 mg/kg/dose IV every 8 hours; however, data are limited in neonates and dosing recommendations are based on pharmacokinetic data and small studies. The Infectious Diseases Society of America (IDSA) recommends 40 mg/kg/dose IV every 8 hours for infants with meningitis. Pharmacokinetic data in neonates have suggested the need for high doses (i.e., 40 mg/kg/dose IV every 8 hours), particularly for infections due to more resistant organisms, to achieve optimal pharmacodynamic targets. The recommended duration of therapy is 7 days for Neisseria meningitidis and Haemophilus influenzae, 10 to 14 days for Streptococcus pneumoniae, and at least 3 weeks for gram-negative bacilli.

    Premature Neonates†

    Limited data are available; 40 mg/kg/dose IV every 8 or 12 hours is the most commonly reported dosage. Some experts recommend 40 mg/kg/dose IV every 8 hours for all neonates with meningitis ; others recommend a dosing interval of every 12 hours for premature neonates. A dosing interval of every 12 hours for the first week of life then increase to every 8 hours has also been used. Pharmacokinetic data in neonates (including premature neonates) have suggested the need for higher doses (40 mg/kg/dose IV every 8 hours), particularly for infections due to more resistant organisms, to achieve optimal pharmacodynamic targets. The recommended duration of therapy is 7 days for Neisseria meningitidis and Haemophilus influenzae, 10 to 14 days for Streptococcus pneumoniae, and at least 3 weeks for gram-negative bacilli.

    Intravenous dosage - Extended (3 to 4 hour) infusion†
    Adults

    Based on Monte Carlo simulations and case reports, meropenem dosed at 2 g IV administered over 3 hours every 8 hours may increase the likelihood of pharmacodynamic target achievement in difficult to treat CNS infections. Monte Carlo simulation determined that there is an increased percentage of target attainment rates for a bactericidal response with a 3-hour infusion as compared to a traditional 30-minute infusion for Pseudomonas aeruginosa (84% vs. 79.9%, respectively) and Acinetobacter sp. (91.1% vs. 87.3%, respectively). In 3 case reports, patients had similar CSF and serum concentrations. Serum concentrations with the prolonged infusion demonstrated free drug concentrations were above the MIC for 100% of the dosing interval, thereby maximizing the pharmacodynamic target.

    Infants, Children, and Adolescents

    40 mg/kg/dose IV administered over 3 to 4 hours every 8 hours (Max: 2 g/dose). Extending the infusion duration to 3 to 4 hours has been shown to increase the likelihood of pharmacodynamic target achievement (%T above MIC), particularly for bacteria with higher MICs (2 mcg/mL or more), such as Pseudomonas. The IDSA recommends meropenem as a treatment option for documented meningitis and for empiric therapy in combination with vancomycin after a penetrating trauma or postneurosurgery; meropenem may also be used in combination with vancomycin as empiric therapy for CSF shunt infections when gram negative bacilli are present on gram stain. The recommended duration of therapy is 7 days for Neisseria meningitidis and Haemophilus influenzae, 10 to 14 days for Streptococcus pneumoniae, and at least 3 weeks for gram-negative bacilli.

    For the treatment of complicated skin and skin structure infections, including cellulitis, erysipelas, necrotizing infections, diabetic foot ulcer, pyomyositis, and surgical incision site infections.
    For the treatment of severe complicated skin and skin structure infections, such as cellulitis and erysipelas.
    Intravenous dosage
    Adults

    500 mg to 1 g IV every 8 hours for 5 to 14 days.

    Infants, Children, and Adolescents 3 months to 17 years

    10 to 20 mg/kg/dose (Max: 1 g/dose) IV every 8 hours for 5 to 14 days.

    Infants 1 to 2 months†

    10 to 20 mg/kg/dose IV every 8 hours for 5 to 14 days.

    Neonates 32 weeks gestation and older and 14 days and older†

    30 mg/kg/dose IV every 8 hours for 5 to 14 days.

    Neonates 32 weeks gestation and older and 0 to 13 days†

    20 mg/kg/dose IV every 8 hours for 5 to 14 days.

    Neonates less than 32 weeks gestation and 14 days and older†

    20 mg/kg/dose IV every 8 hours for 5 to 14 days.

    Neonates less than 32 weeks gestation and 0 to 13 days†

    20 mg/kg/dose IV every 12 hours for 5 to 14 days.

    For the treatment of surgical incision site infections.
    Intravenous dosage
    Adults

    1 g IV every 8 hours for incisional surgical site infections of the intestinal or genitourinary tract.

    For the treatment of necrotizing infections of the skin, fascia, and muscle.
    Intravenous dosage
    Adults

    1 g IV every 8 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours for mixed necrotizing infections.

    Infants, Children, and Adolescents 3 months to 17 years

    20 mg/kg/dose (Max: 1 g/dose) IV every 8 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours for mixed necrotizing infections.

    Infants 1 to 2 months†

    20 mg/kg/dose IV every 8 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours for mixed necrotizing infections.

    Neonates 32 weeks gestation and older and 14 days and older†

    30 mg/kg/dose IV every 8 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours for mixed necrotizing infections.

    Neonates 32 weeks gestation and older and 0 to 13 days†

    20 mg/kg/dose IV every 8 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours for mixed necrotizing infections.

    Neonates less than 32 weeks gestation and 14 days and older†

    20 mg/kg/dose IV every 8 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours for mixed necrotizing infections.

    Neonates less than 32 weeks gestation and 0 to 13 days†

    20 mg/kg/dose IV every 12 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours for mixed necrotizing infections.

    For the treatment of pyomyositis.
    Intravenous dosage
    Adults

    500 mg to 1 g IV every 8 hours for 14 to 21 days plus vancomycin in patients with underlying conditions.

    Infants, Children, and Adolescents 3 months to 17 years

    10 to 20 mg/kg/dose (Max: 1 g/dose) IV every 8 hours for 14 to 21 days plus vancomycin in patients with underlying conditions.

    Infants 1 to 2 months†

    10 to 20 mg/kg/dose IV every 8 hours for 14 to 21 days plus vancomycin in patients with underlying conditions.

    For the treatment of diabetic foot ulcer.
    Intravenous dosage
    Adults

    500 mg to 1 g IV every 8 hours for 7 to 14 days for moderate or severe infections in patients with risk factors for resistant gram negative rods, ischemic limb/necrotizing/gas forming infections, or a macerated ulcer or in a warm climate. Continue treatment for up to 28 days if infection is improving but is extensive and resolving slower than expected or if patient has severe peripheral artery disease.

    For the treatment of complicated skin and skin structure infections due to resistant gram-negative organisms using extended infusion dosing†.
    Intravenous dosage
    Adults

    2 g administered over 3 hours IV every 8 hours.

    For the treatment of intraabdominal infections, including peritonitis, appendicitis, intraabdominal abscess, biliary tract infections (cholecystitis, cholangitis), neonatal necrotizing enterocolitis, spontaneous bacterial peritonitis†, and peritoneal dialysis-related peritonitis†.
    For the treatment of complicated community-acquired, healthcare-acquired, or hospital-acquired intraabdominal infections with adequate source control.
    Intravenous dosage
    Adults

    1 to 2 g IV every 8 hours for 3 to 7 days. Complicated infections include peritonitis and appendicitis complicated by rupture, and intraabdominal abscess.

    Infants, Children, and Adolescents

    20 mg/kg/dose (Max: 2 g/dose) IV every 8 hours for 3 to 7 days.  Higher doses (40 mg/kg/dose IV every 8 hours) have been used in patients with severe infections. Complicated infections include peritonitis and appendicitis complicated by rupture, and intraabdominal abscess.

    Neonates 32 weeks gestation and older and 14 days and older

    30 mg/kg/dose IV every 8 hours for 7 to 10 days. Meropenem is an option for necrotizing enterocolitis.

    Neonates 32 weeks gestation and older and 0 to 13 days

    20 mg/kg/dose IV every 8 hours for 7 to 10 days. Meropenem is an option for necrotizing enterocolitis.

    Neonates younger than 32 weeks gestation and 14 days and older

    20 mg/kg/dose IV every 8 hours for 7 to 10 days. Meropenem is an option for necrotizing enterocolitis.

    Neonates younger than 32 weeks gestation and 0 to 13 days

    20 mg/kg/dose IV every 12 hours for 7 to 10 days. Meropenem is an option for necrotizing enterocolitis.

    For the treatment of complicated community-acquired, healthcare-acquired, or hospital-acquired intraabdominal infections with adequate source control due to resistant gram-negative organisms using extended-infusion dosing†.
    Intravenous dosage
    Adults

    2 g administered over 3 hours IV every 8 hours for 3 to 7 days. Complicated infections include peritonitis and appendicitis complicated by rupture, and intraabdominal abscess.

    Infants, Children, and Adolescents

    20 to 40 mg/kg/dose (Max: 2 g/dose) administered over 3 to 4 hours IV every 8 hours for 3 to 7 days. Complicated infections include peritonitis and appendicitis complicated by rupture, and intraabdominal abscess.

    For the treatment of uncomplicated intraabdominal infections†.
    Intravenous dosage
    Adults

    1 to 2 g IV every 8 hours. Antibiotics should be discontinued within 24 hours. Uncomplicated infections include acute appendicitis without perforation, abscess, or local peritonitis; traumatic bowel perforations repaired within 12 hours; acute cholecystitis without perforation; and ischemic, non-perforated bowel.

    Infants, Children, and Adolescents

    20 mg/kg/dose (Max: 2 g/dose) IV every 8 hours. Antibiotics should be discontinued within 24 hours. Uncomplicated infections include acute appendicitis without perforation, abscess, or local peritonitis; traumatic bowel perforations repaired within 12 hours; acute cholecystitis without perforation; and ischemic, non-perforated bowel.

    For the treatment of spontaneous bacterial peritonitis†.
    Intravenous dosage
    Adults

    1 g IV every 8 hours for at least 5 to 7 days.

    For the treatment of peritoneal dialysis-related peritonitis†.
    Intermittent Intraperitoneal dosage†
    Adults

    1 g intraperitoneally every 24 hours for 21 to 28 days.

    For the empiric treatment of febrile neutropenia†.
    For the treatment of febrile neutropenia in adults.
    Intravenous dosage
    Adults

    1 gram IV every 8 hours has been studied for febrile neutropenia. Guidelines recommend an antipseudomonal beta-lactam, such as meropenem, as a first line therapy option with or without an aminoglycoside and/or vancomycin as a treatment option for febrile neutropenia. Alternatively, 500 mg IV every 6 hours has shown similar clinical efficacy in hospitalized patients with a variety of infections (including febrile neutropenia) and based on Monte Carlo simulations, achieves pharmacodynamic endpoints equivalent to the manufacturer's recommended dose.

    For the treatment of febrile neutropenia in pediatric patients.
    Intravenous dosage
    Infants, Children, and Adolescents

    20 mg/kg/dose (Max: 1 g/dose) IV every 8 hours. Guidelines for the management of fever and neutropenia in cancer patients recommend monotherapy with an antipseudomonal beta-lactam or a carbapenem as empiric treatment in high-risk patients; addition of a second gram-negative antimicrobial agent (i.e., aminoglycoside, aztreonam) is recommended for patients who are clinically unstable, when a resistant infection is suspected, or for centers with high rates of resistant pathogens.

    For the treatment of bacteremia†, catheter-associated infections†, and sepsis†, including infections with difficult-to-treat resistance†.
    For the treatment of unspecified bacteremia† and catheter-associated infections†.
    Intravenous dosage
    Adults

    1 g IV every 8 hours for 7 to 14 days.

    Infants, Children, and Adolescents

    20 mg/kg/dose (Max: 1 g/dose) IV every 8 hours based on limited data. Higher doses (40 mg/kg/dose IV every 8 hours) have been used in patients with severe infections.[35489] 

    Neonates 32 weeks gestation and older and 14 days and older

    30 mg/kg/dose IV every 8 hours. Some experts recommend considering the use of 40 mg/kg/dose for severe infections due to Pseudomonas sp.; pharmacokinetic data in neonates have suggested the need for the higher dose to achieve optimal pharmacodynamic targets for infections caused by more resistant organisms.[35475] [35489] [53173] Data are limited in neonates, and dosing recommendations are based on pharmacokinetic data and use of meropenem for other indications in small studies.[28347] [35475] [35489] [53170] [53173]

    Neonates 32 weeks gestation and older and 0 to 13 days

    20 mg/kg/dose IV every 8 hours. Some experts recommend considering the use of 40 mg/kg/dose for severe infections due to Pseudomonas sp.; pharmacokinetic data in neonates have suggested the need for the higher dose to achieve optimal pharmacodynamic targets for infections caused by more resistant organisms.[35475] [35489] [53173] Data are limited in neonates, and dosing recommendations are based on pharmacokinetic data and use of meropenem for other indications in small studies.[28347] [35475] [35489] [53170] [53173]

    Neonates younger than 32 weeks gestation and 14 days and older

    20 mg/kg/dose IV every 8 hours. Some experts recommend considering the use of 40 mg/kg/dose for severe infections due to Pseudomonas sp.; pharmacokinetic data in neonates have suggested the need for the higher dose to achieve optimal pharmacodynamic targets for infections caused by more resistant organisms.[35475] [35489] [53173] Data are limited in neonates, and dosing recommendations are based on pharmacokinetic data and use of meropenem for other indications in small studies.[28347] [35475] [35489] [53170] [53173]

    Neonates younger than 32 weeks gestation and 0 to 13 days

    20 mg/kg/dose IV every 12 hours. Some experts recommend considering the use of 40 mg/kg/dose for severe infections due to Pseudomonas sp.; pharmacokinetic data in neonates have suggested the need for the higher dose to achieve optimal pharmacodynamic targets for infections caused by more resistant organisms.[35475] [35489] [53173] Data are limited in neonates, and dosing recommendations are based on pharmacokinetic data and use of meropenem for other indications in small studies.[28347] [35475] [35489] [53170] [53173]

    For the treatment of bacteremia† and catheter-associated infections† due to infections with difficult-to-treat resistance using extended-infusion dosing†.
    Intravenous dosage
    Adults

    2 g IV administered over 3 hours every 8 hours for 7 to 14 days.

    Infants, Children, and Adolescents

    20 to 40 mg/kg/dose (Max: 2 g/dose) IV administered over 3 to 4 hours every 8 hours.[53167] [53168]

    For the treatment of unspecified sepsis†.
    Intravenous dosage
    Adults

    2 g IV every 8 hours. Start within 1 hour for septic shock or within 3 hours for possible sepsis without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for deescalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response.

    Infants, Children, and Adolescents

    20 mg/kg/dose (Max: 2 g/dose) IV every 8 hours based on limited data. Higher doses (40 mg/kg/dose IV every 8 hours) have been used in patients with severe infections.[35489]  Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for deescalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response.[64985]

    Neonates 32 weeks gestation and older and 14 days and older

    30 mg/kg/dose IV every 8 hours. Some experts recommend considering the use of 40 mg/kg/dose for severe infections due to Pseudomonas sp.; pharmacokinetic data in neonates have suggested the need for the higher dose to achieve optimal pharmacodynamic targets for infections caused by more resistant organisms.[35475] [35489] [53173] Data are limited in neonates, and dosing recommendations are based on pharmacokinetic data and use of meropenem for other indications in small studies.[28347] [35475] [35489] [53170] [53173] Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for deescalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response. Neonates younger than 37 weeks gestational age were excluded from the scope of the Surviving Sepsis Campaign guidelines.[64985]

    Neonates 32 weeks gestation and older and 0 to 13 days

    20 mg/kg/dose IV every 8 hours. Some experts recommend considering the use of 40 mg/kg/dose for severe infections due to Pseudomonas sp.; pharmacokinetic data in neonates have suggested the need for the higher dose to achieve optimal pharmacodynamic targets for infections caused by more resistant organisms.[35475] [35489] [53173] Data are limited in neonates, and dosing recommendations are based on pharmacokinetic data and use of meropenem for other indications in small studies.[28347] [35475] [35489] [53170] [53173] Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for deescalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response. Neonates younger than 37 weeks gestational age were excluded from the scope of the Surviving Sepsis Campaign guidelines.[64985]

    Neonates younger than 32 weeks gestation and 14 days and older

    20 mg/kg/dose IV every 8 hours. Some experts recommend considering the use of 40 mg/kg/dose for severe infections due to Pseudomonas sp.; pharmacokinetic data in neonates have suggested the need for the higher dose to achieve optimal pharmacodynamic targets for infections caused by more resistant organisms.[35475] [35489] [53173] Data are limited in neonates, and dosing recommendations are based on pharmacokinetic data and use of meropenem for other indications in small studies.[28347] [35475] [35489] [53170] [53173]

    Neonates younger than 32 weeks gestation and 0 to 13 days

    20 mg/kg/dose IV every 12 hours. Some experts recommend considering the use of 40 mg/kg/dose for severe infections due to Pseudomonas sp.; pharmacokinetic data in neonates have suggested the need for the higher dose to achieve optimal pharmacodynamic targets for infections caused by more resistant organisms.[35475] [35489] [53173] Data are limited in neonates, and dosing recommendations are based on pharmacokinetic data and use of meropenem for other indications in small studies.[28347] [35475] [35489] [53170] [53173]

    For the treatment of sepsis† due to infections with difficult-to-treat resistance using extended-infusion dosing†.
    Intravenous dosage
    Adults

    2 g IV administered over 3 hours every 8 hours. Start within 1 hour for septic shock or within 3 hours for possible sepsis without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for deescalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response.

    Infants, Children, and Adolescents

    20 to 40 mg/kg/dose (Max: 2 g/dose) IV administered over 3 to 4 hours every 8 hours.[53167] [53168] Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for deescalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response.[64985]

    For the treatment of systemic anthrax† infection.
    Intravenous dosage
    Adults

    2 g IV every 8 hours in combination with appropriate antimicrobial therapy. Meropenem, in combination with a fluoroquinolone and protein synthesis inhibitor (i.e., linezolid, clindamycin), is the preferred therapy for the treatment of systemic anthrax in which meningitis cannot be excluded. Meropenem, in combination with a protein synthesis inhibitor (i.e., clindamycin, linezolid, doxycycline), is an alternative therapy for systemic anthrax infection without CNS involvement. For systemic infection in which meningitis cannot be excluded, treatment should continue for at least 2 to 3 weeks or until clinical criteria for improvement are met. For systemic infection without CNS involvement, treatment should continue for at least 14 days or until clinical criteria for improvement are met. Prophylaxis to complete an antimicrobial course of up to 60 days will be required in both cases.

    Infants, Children, and Adolescents

    60 mg/kg/day IV divided every 8 hours (Max: 2 g/dose) for systemic infection without CNS involvement and 120 mg/kg/day IV divided every 8 hours (Max: 2 g/dose) for systemic infection with documented/suspected CNS involvement, in combination with appropriate antimicrobial therapy. Meropenem, in combination with a fluoroquinolone and protein synthesis inhibitor (i.e., linezolid, clindamycin), is the preferred therapy for the treatment of systemic anthrax in which meningitis cannot be excluded. Meropenem, in combination with a protein synthesis inhibitor (i.e., clindamycin, linezolid, doxycycline), is an alternative therapy for systemic anthrax infection without CNS involvement. For systemic infection in which meningitis cannot be excluded, treatment should continue for at least 2 to 3 weeks or until clinical criteria for improvement are met. For systemic infection without CNS involvement, treatment should continue for at least 14 days or until clinical criteria for improvement are met. Prophylaxis to complete an antimicrobial course of up to 60 days will be required in both cases.

    Premature Neonates 32 to 37 weeks gestational age and Term Neonates older than 7 days

    60 mg/kg/day IV divided every 8 hours for systemic infection without CNS involvement and 90 mg/kg/day IV divided every 8 hours for systemic infection with documented/suspected CNS involvement, in combination with appropriate antimicrobial therapy. Meropenem, in combination with a fluoroquinolone and protein synthesis inhibitor (i.e., linezolid, clindamycin), is the preferred therapy for the treatment of systemic anthrax in which meningitis cannot be excluded. Meropenem, in combination with a protein synthesis inhibitor (i.e., clindamycin, linezolid), is an alternative therapy for systemic anthrax infection without CNS involvement. For systemic infection in which meningitis cannot be excluded, treatment should continue for at least 2 to 3 weeks or until clinical criteria for improvement are met. For systemic infection without CNS involvement, treatment should continue for at least 14 days or until clinical criteria for improvement are met. Prophylaxis to complete an antimicrobial course of up to 60 days will be required in both cases.

    Premature Neonates 34 to 37 weeks gestational age and Term Neonates 0 to 7 days

    60 mg/kg/day IV divided every 8 hours for systemic infection with or without CNS involvement, in combination with appropriate antimicrobial therapy. Meropenem, in combination with a fluoroquinolone and protein synthesis inhibitor (i.e., linezolid, clindamycin), is the preferred therapy for the treatment of systemic anthrax in which meningitis cannot be excluded. Meropenem, in combination with a protein synthesis inhibitor (i.e., clindamycin, linezolid), is an alternative therapy for systemic anthrax infection without CNS involvement. For systemic infection in which meningitis cannot be excluded, treatment should continue for at least 2 to 3 weeks or until clinical criteria for improvement are met. For systemic infection without CNS involvement, treatment should continue for at least 14 days or until clinical criteria for improvement are met. Prophylaxis to complete an antimicrobial course of up to 60 days will be required in both cases.

    Premature Neonates 32 to 34 weeks gestational age and 0 to 7 days

    40 mg/kg/day IV divided every 8 hours for systemic infection without CNS involvement and 60 mg/kg/day IV divided every 8 hours for systemic infection with documented/suspected CNS involvement, in combination with appropriate antimicrobial therapy. Meropenem, in combination with a fluoroquinolone and protein synthesis inhibitor (i.e., linezolid, clindamycin), is the preferred therapy for the treatment of systemic anthrax in which meningitis cannot be excluded. Meropenem, in combination with a protein synthesis inhibitor (i.e., clindamycin, linezolid), is an alternative therapy for systemic anthrax infection without CNS involvement. For systemic infection in which meningitis cannot be excluded, treatment should continue for at least 2 to 3 weeks or until clinical criteria for improvement are met. For systemic infection without CNS involvement, treatment should continue for at least 14 days or until clinical criteria for improvement are met. Prophylaxis to complete an antimicrobial course of up to 60 days will be required in both cases.

    For the treatment of pneumonia†, including community-acquired pneumonia (CAP)† and nosocomial pneumonia†.
    For the treatment of pneumonia, including infections due to resistant gram-negative organisms, using extended-infusion dosing†.
    Intravenous dosage
    Adults

    2 g administered over 3 hours IV every 8 hours for at least 7 days.

    Infants, Children, and Adolescents

    20 to 40 mg/kg/dose (Max: 2 g/dose) administered over 3 to 4 hours IV every 8 hours.[53167] [53168]

    For the treatment of community-acquired pneumonia (CAP)†.
    Intravenous dosage
    Adults

    1 g IV every 8 hours for at least 7 days.[34362] [64669]

    Adolescents

    20 mg/kg/dose (Max: 2 g/dose) IV every 8 hours for 5 to 7 days based on limited data. Higher doses (40 mg/kg/dose IV every 8 hours) have been used in patients with severe infections.[34362] [35489]

    For the treatment of nosocomial pneumonia†.
    Intravenous dosage
    Adults

    1 g IV every 8 hours for 7 days.[61215]

    Infants, Children, and Adolescents

    20 mg/kg/dose IV every 8 hours (Max: 2 g/dose) based on limited data. Higher doses (40 mg/kg/dose IV every 8 hours) have been used in patients with severe infections.[35489] A trial of 47 patients with a mean age of 2 years (range, 4 days to 20 years) examined meropenem 20 mg/kg/dose (or up to 40 mg/kg/dose for CNS or critical infections) IV every 8 hours for a variety of infections. Hospital-associated pneumonia cases (n = 21) had the worst response, with 43% of cases unchanged or worsened despite meropenem therapy.[35489]

    Neonates 32 weeks gestation and older and 14 days and older

    30 mg/kg/dose IV every 8 hours. Some experts recommend considering 40 mg/kg/dose IV every 8 hours for severe infections due to P. aeruginosa; pharmacokinetic data in neonates have suggested the need for the higher dose to achieve optimal pharmacodynamic targets for infections caused by more resistant organisms.[35475] [35489] [53173] Data are limited in neonates, and dosing recommendations are based on pharmacokinetic data and use of meropenem for other indications in small studies.[28347] [35475] [35489] [53170] [53173]

    Neonates 32 weeks gestation and older and 0 to 13 days

    20 mg/kg/dose IV every 8 hours. Some experts recommend considering 40 mg/kg/dose IV every 8 hours for severe infections due to P. aeruginosa; pharmacokinetic data in neonates have suggested the need for the higher dose to achieve optimal pharmacodynamic targets for infections caused by more resistant organisms.[35475] [35489] [53173] Data are limited in neonates, and dosing recommendations are based on pharmacokinetic data and use of meropenem for other indications in small studies.[28347] [35475] [35489] [53170] [53173]

    Neonates younger than 32 weeks gestation and 14 days and older

    20 mg/kg/dose IV every 8 hours. Some experts recommend considering 40 mg/kg/dose IV every 8 hours for severe infections due to P. aeruginosa; pharmacokinetic data in neonates have suggested the need for the higher dose to achieve optimal pharmacodynamic targets for infections caused by more resistant organisms.[35475] [35489] [53173] Data are limited in neonates, and dosing recommendations are based on pharmacokinetic data and use of meropenem for other indications in small studies.[28347] [35475] [35489] [53170] [53173]

    Neonates younger than 32 weeks gestation and 0 to 13 days

    20 mg/kg/dose IV every 12 hours. Some experts recommend considering 40 mg/kg/dose IV every 12 hours for severe infections due to P. aeruginosa; pharmacokinetic data in neonates have suggested the need for the higher dose to achieve optimal pharmacodynamic targets for infections caused by more resistant organisms.[35475] [35489] [53173] Data are limited in neonates, and dosing recommendations are based on pharmacokinetic data and use of meropenem for other indications in small studies.[28347] [35475] [35489] [53170] [53173]

    For the treatment of drug-resistant tuberculosis infection† paired with clavulanic acid as part of combination therapy.
    Intravenous dosage
    Adults

    1 g IV every 8 hours.

    Infants, Children, and Adolescents

    20 to 40 mg/kg/dose (Max: 1 g/dose) IV every 8 hours.

    For the treatment of severe or complicated extensively drug-resistant typhoid fever†.
    Intravenous dosage
    Adults

    1 g IV every 8 hours for 10 to 14 days. Consider adding azithromycin for patients who do not improve.

    Infants, Children, and Adolescents

    60 mg/kg/day divided every 8 hours (Max: 1 g/dose) for 10 to 14 days. Consider adding azithromycin for patients who do not improve.

    For the treatment of bone and joint infections†, including native vertebral osteomyelitis†, orthopedic device-related infection† (e.g., prosthetic joint infection), and infections with difficult-to-treat resistance.
    For the treatment of native vertebral osteomyelitis†.
    Intravenous dosage
    Adults

    1 g IV every 8 hours for 6 weeks as first-line therapy for infections due to P. aeruginosa. May consider double coverage (i.e., beta-lactam and ciprofloxacin or aminoglycoside).

    For the treatment of prosthetic joint infection†.
    Intravenous dosage
    Adults

    1 g IV every 8 hours for 4 to 6 weeks as first-line therapy for infections due to P. aeruginosa or Enterobacterales, which may be followed by chronic oral suppressive therapy. May consider addition of an aminoglycoside for P. aeruginosa infections; if aminoglycoside is in spacer and organism is aminoglycoside-susceptible, then double coverage is provided with IV or oral monotherapy.

    For the treatment of bone and joint infections with difficult-to-treat resistance using extended infusion dosing†.
    Intravenous dosage
    Adults

    2 g administered over 3 hours IV every 8 hours.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    1 gm IV every 8 hours; doses of 2 g IV every 8 hours have been used for meningitis.

    Geriatric

    1 gm IV every 8 hours; doses of 2 g IV every 8 hours have been used for meningitis.

    Adolescents

    40 mg/kg/dose, not to exceed 2 g IV every 8 hours.

    Children

    40 mg/kg/dose, not to exceed 2 g IV every 8 hours.

    Infants

    3 months and older: 40 mg/kg/dose IV every 8 hours.
    Younger than 3 months: 30 mg/kg/dose IV every 8 hours is FDA-approved maximum dosage for complicated intra-abdominal infections; however, doses up to 40 mg/kg/dose IV every 8 hours have been used off-label for the treatment of meningitis.

    Neonates

    Neonates 32 weeks gestational age and older and 14 days postnatal age and older: 30 mg/kg/dose IV every 8 hours is FDA-approved maximum dosage for complicated intra-abdominal infections; however, doses up to 40 mg/kg/dose IV every 8 hours have been used off-label for the treatment of meningitis.
    Neonates 32 weeks gestational age and older and younger than 14 days postnatal age: 20 mg/kg/dose IV every 8 hours is FDA-approved maximum dosage for complicated intra-abdominal infections; however, doses up to 40 mg/kg/dose IV every 8 hours have been used off-label for the treatment of meningitis.
    Premature neonates younger than 32 weeks gestational age and 14 days postnatal age and older: 20 mg/kg/dose IV every 8 hours is FDA-approved maximum dosage for complicated intra-abdominal infections; however, doses up to 40 mg/kg/dose IV every 8 hours have been used off-label for the treatment of meningitis.
    Premature neonates younger than 32 weeks gestational age and younger than 14 days postnatal age: 20 mg/kg/dose IV every 12 hours is FDA-approved maximum dosage for complicated intra-abdominal infections; however, doses up to 40 mg/kg/dose IV every 8 hours have been used off-label for the treatment of meningitis.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is needed.

    Renal Impairment

    The following is for dosage adjustment in adults with renal impairment; there is no experience with this drug in children with renal impairment.
    CrCl > 50 ml/min: no dose adjustment needed.
    CrCl 26—50 ml/min: give the recommended dose every 12 hours.
    CrCl 10—25 ml/min: give one-half the recommended dose every 12 hours.
    CrCl < 10 ml/min: give one-half the recommended dose every 24 hours.
     
    Intermittent hemodialysis
    Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis. Supplemental doses should be given after hemodialysis sessions.
     
    Continuous hemodialysis (CVVHD, CVVHDF)
    Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis. Effective dosing regimens for patients receiving continuous hemodialysis vary from 500 mg IV every 12 hours to 1 g IV every 8 hours. Conflicting data exist regarding the most appropriate meropenem dosing regimen for patients receiving continuous hemodialysis. Differing operational characteristics of continuous hemodialysis (e.g., dialysate flow rate, membrane or filter type) at various centers involved in the studies and whether the goal of the study was to treat infections caused by susceptible or intermediate microorganisms may explain the variable dosing recommendations for continuous hemodialysis.

    ADMINISTRATION

     
    Tuberculosis patients†
    Directly observed therapy (DOT) is recommended for all children as well as adolescents and adults living with HIV.[34361] [34362] [61094]

    Injectable Administration

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

    Intravenous Administration

    Intermittent Intravenous (IV) Infusion
    Powder Vials for Injection
    Reconstitution
    Reconstitute 500 mg or 1 g vials with 10 or 20 mL of Sterile Water for Injection, respectively, for a resultant concentration of approximately 50 mg/mL. Shake to dissolve and let stand until clear.
    Alternatively, vials may be directly reconstituted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration ranging from 1 to 20 mg/mL.
    Storage: Storage requirements for reconstituted solutions are dependent on the diluent used. Do not freeze.
    Sterile Water for Injection: Stable up to 3 hours at controlled room temperature 25 degrees C (77 degrees F) or up to 13 hours at 5 degrees C (41 degrees F).
    0.9% Sodium Chloride Injection: Stable up to 1 hour at controlled room temperature 25 degrees C (77 degrees F) or up to 15 hours at 5 degrees C (41 degrees F).
    5% Dextrose Injection: Use immediately.[28347]
     
    Dilution
    If reconstituted with Sterile Water for Injection, further dilute the reconstituted solution 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration ranging from 1 to 20 mg/mL.
    Storage: Storage requirements for reconstituted solutions are dependent on the diluent used. Do not freeze.
    0.9% Sodium Chloride Injection: Stable up to 1 hour at controlled room temperature 25 degrees C (77 degrees F) or up to 15 hours at 5 degrees C (41 degrees F).
    5% Dextrose Injection: Use immediately.[28347]
     
    Duplex Drug Delivery System
    For administration in patients who require the entire 500 mg or 1 g dose and not any fraction of the dose.
    Use only if container and seals are intact.
    To inspect the drug powder for foreign matter or discoloration, peel the foil strip from the drug chamber. Protect from light after removal of foil strip.
    Allow the product to reach room temperature before patient use.
    Unfold Duplex container and point the set port downward. Starting at the hanger tab end, fold the Duplex container just below the diluent meniscus trapping all air above the fold.
    To activate, squeeze the folded diluent chamber until the seal between the diluent and powder opens, releasing diluent into the drug powder chamber.
    Agitate the liquid-powder mixture until the drug powder completely dissolves.
    Storage: If the foil strip is removed and the container will not be used immediately, refold container and latch the side tab until ready to activate; use within 7 days at room temperature. After reconstitution (activation), use within 1 hour if stored at room temperature or within 15 hours if stored under refrigeration.[62808]
     
    Intermittent IV Infusion
    Infuse IV over 15 to 30 minutes.
    Do not use in series connections.[28347] [62808]
     
    Intermittent Extended IV Infusion†
    NOTE: Administration by extended infusion is not FDA-approved.[28347]
    Administering as an extended infusion (3- to 4-hour infusion) may increase the likelihood of pharmacodynamic target achievement in difficult to treat infections.[35478] [35479] [35480] [35481] [35482]
     
    Intravenous (IV) Push
    Powder Vials for Injection
    Reconstitution
    Reconstitute 500 mg or 1 g vials with 10 or 20 mL of Sterile Water for Injection, respectively, for a resultant concentration of approximately 50 mg/mL.
    Shake to dissolve and let stand until clear.
    Storage: Stable for up to 3 hours at controlled room temperature 25 degrees C (77 degrees F) or up to 13 hours at 5 degrees C (41 degrees F).[28347]
     
    Intermittent IV Push
    Inject doses up to 1 g (Max concentration: 50 mg/mL) IV over 3 to 5 minutes.[28347]
     
    Continuous Intravenous (IV) Infusion†
    NOTE: Meropenem is not FDA-approved for administration as a continuous intravenous infusion.[28347]
    Powder Vials for Injection
    Reconstitution
    Reconstitute 1 g vials with 20 mL of Sterile Water for Injection, respectively, for a resultant concentration of approximately 50 mg/mL. Shake to dissolve and let stand until clear.[28347]
     
    Dilution
    3 g/day continuous IV infusion: Further dilute in 50 mL or 250 mL of 0.9% Sodium Chloride Injection and administer over 8 hours. For continuous infusion, administer a new infusion bag every 8 hours.[35484] [35485]
    4 g/day continuous IV infusion: Further dilute in 100 mL of 0.9% Sodium Chloride Injection and administer over 6 hours. For continuous infusion, administer a new infusion bag every 6 hours.[35483]
    3 g/day IV continuous infusion in ambulatory infusion pump with freezer packs: Reconstitute 1 g vial according to manufacturer recommendations by adding 20 mL of 0.9% Sodium Chloride Injection to each vial. Add 3 g (60 mL) to a 100 mL medication cassette reservoir and bring the final volume to 100 mL (final concentration, 30 mg/mL). Administer over 24 hours.[35488]
     
    Stability of Continuous IV Infusion Solutions
    Although specific stability studies were not completed, clinical studies comparing continuous infusion to intermittent infusions of meropenem suggest similar serum concentrations between the 2 groups and possibly more therapeutic benefit.[35484] [35485]
    A stability study of meropenem diluted to 1 mg/mL and 20 mg/mL with Sterile Water for Injection or 0.9% Sodium Chloride Injection found that concentrations did not decrease below the allowable concentrations (95% of initial concentration) when stored at room temperature in polyvinyl chloride bags, but did fall below 95% of initial concentrations by 8 hours. However, when these same solutions were stored at 4 to 5 degrees C, the concentration was more than 95% of initial at 24 hours. When stored at room temperature at a concentration of 2.5 mg/mL in 0.9% Sodium Chloride Injection in glass vials, more than 95% of the initial concentration was remaining at 8 hours; however, when mixed in Sterile Water for Injection or 5% Dextrose Injection in glass vials, more than 95% of the concentration was NOT remaining after 4 hours and 3 hours, respectively. When diluted in 0.9% Sodium Chloride Injection and stored in the Baxter Minibag Plus system at room temperature, more than 95% of the initial concentration remained at 4 hours. When stored at 4 to 5 degrees C, however, more than 95% of the initial concentration remained after 24 hours (20 mg/mL concentration). When diluted in 5% Dextrose Injection and stored in the Baxter Minibag Plus system at 4 to 5 degrees C, more than 95% of the initial concentration remained after 8 hours (2.5 mg/mL concentration only).[35487]
    Continuous ambulatory infusion pump with freezer packs: An open-label, multidose study in 7 cystic fibrosis patients analyzed the stability of meropenem administered via a continuous ambulatory infusion pump stored between 2 freezer packs designed to maintain a refrigerated temperature of 5 degrees C or less. Current manufacturer recommendations state that meropenem is stable in 0.9% Sodium Chloride Injection at 4 degrees C for 24 hours. The mean recovery of meropenem 30 mg/mL (starting concentration) at 12 to 16 hours was 102.9% with no cassette having a concentration of less than 90% of the original concentration. At 24 to 28 hours, the mean recovery of meropenem was 103.3%, but 1 cassette had a concentration of 86.3% of the initial concentration. The temperature of meropenem was not measured.[35488]

    STORAGE

    Merrem:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze reconstituted product
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store diluted product in accordance with package insert instructions

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Positive Coombs' tests have been reported in patients receiving meropenem. In patients receiving meropenem and undergoing hematologic testing, a positive Coombs' test should be considered as possibly being caused by the antibiotic.
     
    A false-positive reaction for glucose in the urine has been observed in patients receiving beta-lactam antibiotics, including carbapenems, and using copper-reduction tests (e.g., Benedict's solution, Fehling's solution, and Clinitest tablets). This reaction, however, has not been observed with glucose oxidase tests (e.g., Tes-tape, Clinistix, Diastix).

    Carbapenem hypersensitivity, cephalosporin hypersensitivity, penicillin hypersensitivity

    Meropenem is contraindicated in patients with known meropenem hypersensitivity, a history of carbapenem hypersensitivity, or a previous anaphylactic reaction to beta-lactams. Because of the potential for cross-sensitivity, caution is advised in patients with cephalosporin hypersensitivity, penicillin hypersensitivity, or hypersensitivity to any beta-lactam antibiotic. Serious and occasionally fatal hypersensitivity reactions have been reported in patients receiving therapy with beta-lactams and are more likely to occur in persons with a history of sensitivity to multiple allergens.

    Head trauma, neurological disease, seizure disorder, seizures

    Use meropenem cautiously in patients with brain lesions, a history of seizure disorder, or other neurological disease or condition that may lower the seizure threshold, such as head trauma or bacterial meningitis. Seizures have been reported with meropenem use and have occurred most commonly in patients with these types of conditions; however, the risk of seizures appears to be low and is thought to be less than the risk associated with imipenem; cilastatin. The risk of seizures increases in patients given meropenem doses higher than recommended (e.g., patients with compromised renal function) or patients receiving concomitant medications with seizure potential.

    Renal failure, renal impairment

    Use meropenem cautiously in patients with renal impairment or renal failure because the drug is primarily eliminated by the kidneys. These patients are at higher risk for developing seizures while receiving meropenem. Thrombocytopenia has also been reported in patients with renal function impairment, although clinical bleeding has not been reported. Dosage adjustments are required in patients with renal impairment.

    C. difficile-associated diarrhea, diarrhea, pseudomembranous colitis

    Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including meropenem, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

    Pregnancy

    There are insufficient data to establish whether there is a drug-associated risk of major birth defects or miscarriages with meropenem use in human pregnancy. No teratogenic effects have been demonstrated in animals given meropenem intravenously at doses up to 3.2 times the maximum recommended human dose (MRHD) based on body surface area comparison.[28347] [62808]

    Breast-feeding

    Meropenem is excreted in human breast milk; however, no information is available on the effects of meropenem on the breast-fed child or on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for meropenem and any potential adverse effects on the breast-fed child from meropenem or the underlying maternal condition. In case reports in which meropenem was used during breast-feeding, no adverse events were reported in the infants.

    Driving or operating machinery

    Neuromotor impairment, including seizures, delirium, headache, and/or paresthesias may occur in patients receiving meropenem. Patients should avoid driving or operating machinery until drug tolerability has been established.

    Geriatric

    No overall differences in safety or effectiveness of meropenem were observed between geriatric subjects and younger adult subjects in clinical trials; spontaneous reports and other reported clinical experience have not identified differences in responses. Meropenem is substantially excreted by the kidney and the risk of adverse reactions may be greater in those with renal impairment. Because geriatric patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). According to OBRA, use of antibiotics should be limited 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.

    Heart failure, sodium restriction

    Avoid sodium-containing meropenem formulations in patients who are particularly sensitive to sodium intake (e.g., elderly, patients with heart failure) or who may require sodium restriction.

    ADVERSE REACTIONS

    Severe

    apnea / Delayed / 1.3-1.3
    GI obstruction / Delayed / 0-1.0
    ileus / Delayed / 0-1.0
    hepatic failure / Delayed / 0-1.0
    heart failure / Delayed / 0-1.0
    cardiac arrest / Early / 0-1.0
    myocardial infarction / Delayed / 0-1.0
    bradycardia / Rapid / 0-1.0
    pulmonary edema / Early / 0-1.0
    pulmonary embolism / Delayed / 0-1.0
    pleural effusion / Delayed / 0-1.0
    renal failure (unspecified) / Delayed / 0-1.0
    seizures / Delayed / 0.7-0.7
    GI bleeding / Delayed / 0.5-0.5
    azotemia / Delayed / 0.2
    hemolytic anemia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    C. difficile-associated diarrhea / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 1.4-7.0
    anemia / Delayed / 0.1-5.5
    hyperbilirubinemia / Delayed / 0-5.0
    candidiasis / Delayed / 0-3.1
    delirium / Early / 0-1.0
    hallucinations / Early / 0-1.0
    confusion / Early / 0-1.0
    depression / Delayed / 0-1.0
    skin ulcer / Delayed / 0-1.0
    jaundice / Delayed / 0-1.0
    cholestasis / Delayed / 0-1.0
    chest pain (unspecified) / Early / 0-1.0
    peripheral edema / Delayed / 0-1.0
    hypervolemia / Delayed / 0-1.0
    hypertension / Early / 0-1.0
    sinus tachycardia / Rapid / 0-1.0
    hypotension / Rapid / 0-1.0
    dyspnea / Early / 0-1.0
    dysuria / Early / 0-1.0
    urinary incontinence / Early / 0-1.0
    glossitis / Early / 1.0-1.0
    hypokalemia / Delayed / 0-1.0
    phlebitis / Rapid / 0.8-0.8
    melena / Delayed / 0.3-0.3
    eosinophilia / Delayed / 0.2
    elevated hepatic enzymes / Delayed / 0.2
    hypoglycemia / Early / 1.0
    leukopenia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    thrombocytosis / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    hypoxia / Early / Incidence not known
    superinfection / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known

    Mild

    nausea / Early / 0.8-7.8
    headache / Early / 2.3-7.8
    diarrhea / Early / 3.5-7.0
    rash / Early / 1.6-6.0
    vomiting / Early / 0.8-3.6
    injection site reaction / Rapid / 0.2-2.4
    pruritus / Rapid / 1.2-1.2
    anorexia / Delayed / 0-1.0
    dyspepsia / Early / 0-1.0
    abdominal pain / Early / 0-1.0
    flatulence / Early / 0-1.0
    asthenia / Delayed / 0-1.0
    anxiety / Delayed / 0-1.0
    agitation / Early / 0-1.0
    drowsiness / Early / 0-1.0
    dizziness / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    insomnia / Early / 0-1.0
    urticaria / Rapid / 0-1.0
    syncope / Early / 0-1.0
    cough / Delayed / 0-1.0
    fever / Early / 0-1.0
    chills / Rapid / 0-1.0
    pelvic pain / Delayed / 0-1.0
    back pain / Delayed / 0-1.0
    epistaxis / Delayed / 0.2-0.2
    leukocytosis / Delayed / 0.2
    infection / Delayed / 1.0
    pharyngitis / Delayed / 1.0
    diaper dermatitis / Delayed / Incidence not known

    DRUG INTERACTIONS

    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.
    Probenecid: (Moderate) Concurrent administration of meropenem with probenecid is not recommended as probenecid inhibits the renal excretion of meropenem by competing for active tubular secretion. After administration of probenecid with meropenem, the mean systemic exposure of meropenem increased by 56% and the half-life increased by 38%. Meropenem is a substrate of OAT1 and OAT3 transporters in the proximal tubule of the kidney, and probenecid is an inhibitor of these drug transporters.
    Probenecid; Colchicine: (Moderate) Concurrent administration of meropenem with probenecid is not recommended as probenecid inhibits the renal excretion of meropenem by competing for active tubular secretion. After administration of probenecid with meropenem, the mean systemic exposure of meropenem increased by 56% and the half-life increased by 38%. Meropenem is a substrate of OAT1 and OAT3 transporters in the proximal tubule of the kidney, and probenecid is an inhibitor of these drug transporters.
    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.
    Valproic Acid, Divalproex Sodium: (Major) Avoid concomitant carbapenem and valproic acid use. Consider alternative antibacterial therapies other than carbapenems to treat infections in patients whose seizures are well controlled with valproic acid or divalproex sodium. If coadministered, monitor valproic acid concentrations. Coadministration of carbapenems with valproic acid or divalproex sodium may reduce the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. Carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing valproic acid serum concentrations.
    Warfarin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including carbapenems, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.

    PREGNANCY AND LACTATION

    Pregnancy

    There are insufficient data to establish whether there is a drug-associated risk of major birth defects or miscarriages with meropenem use in human pregnancy. No teratogenic effects have been demonstrated in animals given meropenem intravenously at doses up to 3.2 times the maximum recommended human dose (MRHD) based on body surface area comparison.[28347] [62808]

    Meropenem is excreted in human breast milk; however, no information is available on the effects of meropenem on the breast-fed child or on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for meropenem and any potential adverse effects on the breast-fed child from meropenem or the underlying maternal condition. In case reports in which meropenem was used during breast-feeding, no adverse events were reported in the infants.

    MECHANISM OF ACTION

    Meropenem, a carbapenem beta-lactam antibiotic, is mainly bactericidal. It inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall.[28347] PBPs are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. PBPs vary among different bacterial species. Meropenem readily penetrates the outer membrane of bacteria cells. After penetrating the bacterial cell wall, it binds to several PBPs. Meropenem has a high affinity for PBP-2, PBP-3, and PBP-4 of E. coli and P. aeruginosa and PBP-1, PBP-2, and PBP-4 of S. aureus.[28347] [35440] The rapid bactericidal activity of the carbapenems against gram-negative bacteria is associated with their great affinity for PBP-1a, PBP-1b, and PBP-2, rather than PBP-3 (the primary target for other beta-lactams).[35441] There are differences in preferential binding sites between the carbapenems. Imipenem preferentially binds to PBP-2, then PBP-1a and PBP-1b, with a weak affinity for PBP-3. Meropenem and ertapenem preferentially bind to PBP-2, then PBP-3, but also have a strong affinity for PBP-1a and PBP-1b. Doripenem has a strong affinity for PBP-3 in P. aeruginosa, PBP-1, PBP-2, and PBP-4 in S. aureus, and PBP-2 in E. coli.[35441] Cell lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor. Prevention of the autolysin response to beta-lactam antibiotic exposure through loss of autolytic activity (mutation) or inactivation of autolysin (low-medium pH) by the microorganism can lead to tolerance to the beta-lactam antibiotic resulting in bacteriostatic activity.[51465]
     
    Beta-lactams, including meropenem, exhibit concentration-independent or time-dependent killing. In vitro and in vivo animal studies have demonstrated that the major pharmacodynamic parameter that determines efficacy for beta-lactams is the amount of time free (non-protein bound) drug concentrations exceed the minimum inhibitory concentration (MIC) of the organism.[34145] [34143] [35436] [35437] [35438] [35439] This microbiological killing pattern is due to the mechanism of action, which is acylation of PBPs. There is a maximum proportion of PBPs that can be acylated; therefore, once maximum acylation has occurred, killing rates cannot increase.[35439] Free beta-lactam concentrations do not have to remain above the MIC for the entire dosing interval. The percentage of time required for both bacteriostatic and maximal bactericidal activity is different for the various classes of beta-lactams. Carbapenems require free drug concentrations to exceed the MIC for 20% of the dosing interval for bacteriostatic activity and 40% of the dosing interval for maximal bactericidal activity.[35436] [35437] [35438] Carbapenems also are reported to have a post-antibiotic effect (PAE). PAE is defined as the suppression of bacterial growth that continues after the antibiotic concentration falls below the bacterial MIC. PAE has been reported to be 1.3 to 4 hours with imipenem, 4 to 5 hours with meropenem, and 1.5 hours with ertapenem.[35441]
     
    The susceptibility interpretive criteria for meropenem are delineated by pathogen. Breakpoints for Enterobacterales and P. aeruginosa are based on a dosage regimen of 1 g IV every 8 hours while breakpoints for Acinetobacter sp. are based on a dosage regimen of 1 g IV every 8 hours or 500 mg IV every 6 hours. The MICs are defined for Enterobacterales as susceptible at 1 mcg/mL or less, intermediate at 2 mcg/mL, and resistant at 4 mcg/mL or more. The MICs are defined for Acinetobacter sp. and P. aeruginosa as susceptible at 2 mcg/mL or less, intermediate at 4 mcg/mL, and resistant at 8 mcg/mL or more. The MICs are defined for B. cepacia complex, other non-Enterobacterales, and anaerobes as susceptible at 4 mcg/mL or less, intermediate at 8 mcg/mL, and resistant at 16 mcg/mL or more. The MICs are defined for H. influenzae, H. parainfluenzae, beta-hemolytic streptococci, and S. viridans group as susceptible at 0.5 mcg/mL or less. The MICs are defined for S. pneumoniae as susceptible at 0.25 mcg/mL or less, intermediate at 0.5 mcg/mL, and resistant at 1 mcg/mL or more. The MICs are defined for N. meningitidis as susceptible at 0.25 mcg/mL or less. Oxacillin-susceptible staphylococci may be considered susceptible to meropenem.[63320] [63321]
     
    There are 4 general mechanisms of carbapenem resistance including decreased permeability of the outer membrane of gram-negative organisms due to decreased porin channel production, decreased affinity for the target PBPs, over-expression of efflux pumps, and enzymatic degradation.[28347] Generally, carbapenems show stability to the majority of beta-lactamases, including AmpC beta-lactamases and extended-spectrum beta-lactamases (ESBLs). However, specific intrinsic or acquired beta-lactamases, generally called carbapenemases, can hydrolyze the carbapenems. These include some class A enzymes, several class D (OXA) enzymes, and the class B metallo-beta-lactamases.[28347] [35440] [35441] A deficiency in the outer membrane porin protein (Opr) D2 is associated with decreased carbapenem susceptibility in gram-negative bacteria. However, it is theorized that a combination of resistance mechanisms is required for significant carbapenem resistance. Decreased porin OprD in combination with activity of a chromosomal AmpC beta-lactamase is associated with imipenem, doripenem, and to a lesser extent meropenem resistance. Doripenem and meropenem may also require over-expression of efflux pumps for resistance to emerge; imipenem is not subject to efflux. Theoretically, efflux activity plus loss of membrane permeability is less likely to happen in vivo than AmpC beta-lactamase expression and loss of membrane permeability.[35440] [35441]

    PHARMACOKINETICS

    Meropenem is administered intravenously. Plasma protein binding is approximately 2%. After administration, it is distributed into most body fluids and tissues including cerebrospinal fluid (CSF). Higher CSF concentrations have been noted with increasing CSF white blood cells suggesting better penetration in the presence of meningeal inflammation. Meropenem is minimally metabolized to 1 microbiologically inactive metabolite. Approximately 70% (50% to 75%) of the dose is excreted unchanged in the urine over 12 hours and 28% excreted as the inactive metabolite; fecal elimination is minimal (2%). Urinary concentrations more than 10 mcg/mL are maintained for up to 5 hours in adults after a 500 mg dose. In adult patients with normal renal function, the elimination half-life is approximately 1 hour.
     
    Affected cytochrome P450 isoenzymes and/or drug transporters: OAT1, OAT3
    Meropenem is a substrate of OAT1 and OAT3 transporters in the proximal tubule of the kidney. Carbapenems have not shown the potential for CYP450 inhibition or induction.

    Intravenous Route

    IV Push (over 5 minutes)
    In healthy adults, the mean peak plasma concentration after a 500 mg dose is 45 mcg/mL (range, 18 to 65 mcg/mL) and after a 1 g dose is 112 mcg/mL (range, 83 to 140 mcg/mL).
     
    Short Infusion (over 30 minutes)
    In healthy adults, the mean peak plasma concentration after a 500 mg dose is 23 mcg/mL (range, 14 to 26 mcg/mL) and after a 1 g dose is 49 mcg/mL (range, 39 to 58 mcg/mL). Peak CSF concentrations in adult patients with uninflamed meninges have been reported to be 0.2 mcg/mL (range, 0.1 to 0.3 mcg/mL) 2 hours after a 1 g dose (data based on 4 samples). In pediatric patients (1 month to 15 years of age) with inflamed meninges who received meropenem 40 mg/kg IV, the mean peak CSF concentration was 3.3 mcg/mL (range, 0.9 to 6.5 mcg/mL) 3 hours after the dose.
     
    Extended Infusion (over 3 to 4 hours)
    Based on Monte Carlo simulations and population pharmacokinetic studies in adults, an extended infusion (3 to 4 hours) may increase the likelihood of pharmacodynamic target achievement (amount of time free drug concentrations exceed the minimum inhibitory concentration (MIC) of the organism [%T more than the MIC]), particularly for bacteria with higher MICs (2 mcg/mL or greater), such as Pseudomonas. In 1 study, the 3-hour infusion achieved the pharmacodynamic target 99% of the time for bacteriostatic exposure and 93% of the time for bactericidal exposure. Additionally, this regimen had a higher probability of achieving the pharmacodynamic target than traditionally infused meropenem for intermediately resistant pathogens with an MIC of 8 mcg/mL (62% vs. less than 40%). Another study demonstrated that 2 g IV administered over 3 hours every 8 hours in combination with an aminoglycoside was able to suppress resistance and achieve the bacteriocidal pharmacodynamic parameter 79% of the time.
     
    Based on Monte Carlo simulations and population pharmacokinetic studies in children, an extended infusion (3 to 4 hours) may increase the likelihood of pharmacodynamic target achievement (amount of time free drug concentrations exceed the minimum inhibitory concentration (MIC) of the organism [%T more than the MIC]), particularly for bacteria with higher MICs (2 mcg/mL or greater), such as Pseudomonas. In 1 study using population pharmacokinetic modeling based on data from 50 children, the probability of target attainment (PTA; 50% T more than the MIC) against Pseudomonas was increased from 60.7% with a 30-minute infusion to 89.9% with a 4-hour infusion (40 mg/kg/dose every 8 hours). In another study using a Monte Carlo simulation, a 3-hour meropenem infusion was necessary to obtain bactericidal PTAs for organisms at the susceptibility breakpoint. PTA (40% T more than the MIC) for Pseudomonas aeruginosa isolates at the susceptibility breakpoint increased from 33% with a 30-minute infusion to 97% with a 3-hour infusion.
     
    Peak concentrations are achieved at the end of infusion for extended infusion administration. In a pharmacokinetic trial in neonates, a lower Cmax and longer time to Cmax were observed with extended infusions compared to shorter infusions; all other pharmacokinetic parameters were similar between the 2 infusion methods. Unlike in older populations studied, meropenem infusions over 30 minutes are optimal for achieving a 40% T more than the MIC in the majority of very low birth weight neonates.
     
    Continuous Infusion
    To maximize the likelihood of pharmacodynamic target achievement, several studies, including population pharmacokinetic studies, and Monte Carlo simulations have reviewed meropenem as a continuous intravenous infusion (CI). A retrospective cohort study of 89 patients compared intermittent meropenem dosing (1 g IV every 6 hours) to CI dosing (4 g/day IV, given as four 1 g infusions, each over 6 hours). The CI group had a greater clinical cure rate (90.47% vs. 59.7%, p less than 0.001). In a randomized study of 10 patients, CI meropenem (500 mg IV load over 3 minutes, then 3 g/day IV, given as three 1 g infusions, each over 8 hours) achieved higher median trough concentrations than intermittent dosing (1.5 g IV load, then 1 g IV every 8 hours). Another prospective crossover study of 15 patients determined CI meropenem (2 g IV load, then 3 g/day IV, given as three 1 g infusions, each over 8 hours) was equivalent to intermittent dosing (2 g IV every 8 hours), but required a smaller total daily dose.