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    Monobactam Antibiotics

    DEA CLASS

    Rx

    DESCRIPTION

    Synthetic beta-lactam antibiotic; spectrum limited to aerobic gram-negative bacteria; no gram-positive or anaerobic activity; less nephrotoxic than aminoglycosides; not indicated for meningitis. Aztreonam for inhalation indicated for CF patients >= 7 years.

    COMMON BRAND NAMES

    Azactam, Cayston

    HOW SUPPLIED

    Azactam Intravenous Inj Sol: 1g, 2g, 50mL
    Azactam/Aztreonam Intramuscular Inj Pwd F/Sol: 1g, 2g
    Azactam/Aztreonam Intravenous Inj Pwd F/Sol: 1g, 2g
    Cayston Respiratory (Inhalation) Pwd F/Recon: 75mg

    DOSAGE & INDICATIONS

    For the management of pulmonary infections in patients with cystic fibrosis.
    For the improvement of respiratory symptoms in cystic fibrosis patients with Pseudomonas aeruginosa and an FEV1 between 25% to 75% predicted.
    Nebulized dosage

    NOTE: The FDA has designated aztreonam solution for inhalation as an orphan drug for control of gram-negative bacteria in the respiratory tract of patients with cystic fibrosis and for the improvement of respiratory symptoms in patients with bronchiectasis and gram-negative bacteria in the airways.

    Adults, Adolescents, and Children >= 7 years

    75 mg nebulized 3 times daily for 28 days then 28 days off aztreonam. Doses should be administered at least 4 hours apart. For patients taking multiple inhaled therapies, the recommended order of administration is bronchodilator, mucolytic, and then aztreonam. Patients in clinical trials were required to have been off antibiotics for at least 28 days prior to treatment with the study drug. Statistically significant improvements in respiratory symptoms were observed in both adults and pediatrics; however, these improvements were substantially smaller in adult patients. The treatment difference in the percent change in FEV1 between aztreonam and placebo at day 28 of therapy was statistically significant at 10% (95% CI, 6% to 14%). Improvements in FEV1 were comparable between adults and pediatrics. Two weeks after completion of therapy, the difference in FEV1 between aztreonam and placebo had decreased to 6% (95% CI, 2% to 9%). Safety and efficacy have not been demonstrated in patients colonized with Burkholderia cepacia.

    For the treatment of pulmonary exacerbation in patients with cystic fibrosis.
    Intravenous dosage
    Adults

    The FDA-recommended dose in patients with severe infections due to Pseudomonas aeruginosa is 2 g IV every 6 to 8 hours. Doses up to 8 to 12 g/day IV divided every 6 hours may be necessary. These higher doses may be needed to maintain adequate serum concentrations in the treatment of pseudomonal isolates with higher MICs.

    Children >= 2 years and Adolescents

    150 mg/kg/day IV divided every 6 to 8 hours (Max: 8 g/day) is recommended by the Cystic Fibrosis Foundation and European Consensus Committee; 150 to 200 mg/kg/day IV divided every 6 to 8 hours (Max: 8 g/day) is recommended by the UK CF Trust Working Group. However, it has been suggested that doses of 200 to 300 mg/kg/day IV divided every 6 hours (Max: 8 to 12 g/day) may be necessary to maintain adequate serum concentrations in the treatment of pseudomonal isolates with higher MICs. The FDA-approved product labeling does not provide specific dosage recommendations, but states that doses higher than usual may be necessary for patients with cystic fibrosis.

    Infants >= 9 months and Children 1 year

    150 mg/kg/day IV divided every 6 to 8 hours is recommended by the Cystic Fibrosis Foundation and European Consensus Committee; 90 to 120 mg/kg/day IV divided every 6 to 8 hours is recommended by the UK CF Trust Working Group. However, it has been suggested that doses of 200 to 300 mg/kg/day IV divided every 6 hours may be necessary to maintain adequate serum concentrations in the treatment of pseudomonal isolates with higher MICs. The FDA-approved product labeling does not provide specific dosage recommendations, but states that doses higher than usual may be necessary for patients with cystic fibrosis.

    Infants < 9 months†

    150 mg/kg/day IV divided every 6 to 8 hours is recommended by the Cystic Fibrosis Foundation and European Consensus Committee; 90 to 120 mg/kg/day IV divided every 6 to 8 hours is recommended by the UK CF Trust Working Group. However, it has been suggested that doses of 200 to 300 mg/kg/day IV divided every 6 hours may be necessary to maintain adequate serum concentrations in the treatment of pseudomonal isolates with higher MICs.

    For the treatment of gram-negative infections including intraabdominal infections (peritonitis), gynecologic infections (endometritis, pelvic cellulitis), skin and skin structure infections (diabetic foot ulcer, postoperative wounds, burn wound infection), and bacteremia.
    For the treatment of peritonitis in patients receiving peritoneal dialysis.
    Intraperitoneal dosage†
    Adults, Adolescents, Children, and Infants

    1,000 mg/L of peritoneal dialysate as a loading dose followed by a maintenance dose of 250 mg/L. For the loading dose, allow a dwell time of 3 to 6 hours; after the loading dose, all other exchanges should contain the maintenance dose. Treat for 2 to 3 weeks depending on infecting organism and the patient's clinical status.

    Intravenous or Intramuscular dosage
    Adults

    1 to 2 g IV/IM every 8 to 12 hours for moderately severe systemic infections. For severe, life-threatening infections, 2 g IV every 6 to 8 hours (Max: 8 g/day). Doses of more than 1 g/dose or patients with bacteremia, localized parenchymal abscess (i.e., intra-abdominal abscess), peritonitis, or other severe systemic infections should be administered IV.

    Infants 9 months and older, Children, and Adolescents

    30 mg/kg/dose IV every 6 to 8 hours (Max: 120 mg/kg/day or 8 g/day) depending on the severity of the infection. Because of aztreonam's narrow spectrum of activity, some conditions may warrant the addition of an agent with gram-positive and/or anaerobic coverage.

    Infants 1 to 8 months†

    30 mg/kg/dose IV every 6 to 8 hours (Max: 120 mg/kg/day) depending on the severity of the infection. Because of aztreonam's narrow spectrum of activity, some conditions may warrant the addition of an agent with gram-positive and/or anaerobic coverage.

    Neonates older than 7 days and weighing more than 2,000 g†

    30 mg/kg/dose IV every 6 to 8 hours.

    Neonates older than 7 days and weighing 2,000 g or less†

    30 mg/kg/dose IV every 8 to 12 hours.

    Neonates 0 to 7 days†

    30 mg/kg/dose IV every 12 hours.

    For the treatment of complicated and uncomplicated urinary tract infection (UTI) including cystitis and pyelonephritis.
    Intravenous or Intramuscular dosage
    Adults

    500 to 1,000 mg IV or IM every 8 to 12 hours.

    Infants >= 9 months, Children, and Adolescents

    30 mg/kg/dose IV every 6 to 8 hours depending upon the severity of the infection (Max: 120 mg/kg/day or 8 g/day).

    Infants < 9 months†

    30 mg/kg/dose IV every 6 to 8 hours (Max: 120 mg/kg/day) depending on the severity of the infection. Because of aztreonam's narrow spectrum of activity, some conditions may warrant the addition of an agent with gram-positive and/or anaerobic coverage.

    Neonates > 7 days and weighing > 2000 g†

    30 mg/kg/dose IV every 6 to 8 hours.

    Neonates > 7 days and weighing <= 2000 g†

    30 mg/kg/dose IV every 8 to 12 hours.

    Neonates <= 7 days†

    30 mg/kg/dose IV every 12 hours.

    For the treatment of lower respiratory tract infections, including bronchitis and pneumonia (community-acquired pneumonia and nosocomial pneumonia).
    For the treatment of community-acquired pneumonia (CAP).
    Intravenous or Intramuscular dosage
    Adults

    1 to 2 g IV/IM every 8 to 12 hours for moderately severe systemic infections. For severe, life-threatening infections, 2 g IV every 6 to 8 hours (Max: 8 g/day). For ICU patients with a beta-lactam allergy, clinical practice guidelines recommend aztreonam in combination with a respiratory quinolone (i.e., levofloxacin, moxifloxacin). For suspected P. aeruginosa, add ciprofloxacin or levofloxacin or azithromycin plus an aminoglycoside. In patients with risk factors for MRSA, add vancomycin or linezolid. Clinical practice guidelines recommend treatment for a minimum of 5 days; the patient should be afebrile for 48 to 72 hours with no more than 1 sign of clinical instability before discontinuation.

    Infants 9 months and older, Children, and Adolescents

    30 mg/kg/dose IV every 6 to 8 hours (Max: 120 mg/kg/day or 8 g/day) depending on the severity of the infection.

    Infants 1 to 8 months†

    30 mg/kg/dose IV every 6 to 8 hours (Max: 120 mg/kg/day) depending on the severity of the infection.

    Neonates older than 7 days and weighing more than 2,000 g†

    30 mg/kg/dose IV every 6 to 8 hours.

    Neonates older than 7 days and weighing 2,000 g or less†

    30 mg/kg/dose IV every 8 to 12 hours.

    Neonates 0 to 7 days†

    30 mg/kg/dose IV every 12 hours.

    For the treatment of nosocomial pneumonia, including hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).
    Intravenous or Intramuscular dosage
    Adults

    1 to 2 g IV/IM every 8 to 12 hours for moderately severe systemic infections. For severe, life-threatening infections, 2 g IV every 6 to 8 hours (Max: 8 g/day). Clinical practice guidelines recommend 2 g IV every 8 hours for 7 days. For patients with risk factors for gram-negative resistance or with a high mortality risk, add a second non-beta-lactam agent with antipseudomonal activity (i.e., quinolone, aminoglycoside, polymyxin). In patients with risk factors for MRSA, add vancomycin or linezolid.

    Infants 9 months and older, Children, and Adolescents

    30 mg/kg/dose IV every 6 to 8 hours (Max: 120 mg/kg/day or 8 g/day) depending on the severity of the infection.

    Infants 1 to 8 months†

    30 mg/kg/dose IV every 6 to 8 hours (Max: 120 mg/kg/day) depending on the severity of the infection.

    Neonates older than 7 days and weighing more than 2,000 g†

    30 mg/kg/dose IV every 6 to 8 hours.

    Neonates older than 7 days and weighing 2,000 g or less†

    30 mg/kg/dose IV every 8 to 12 hours.

    Neonates 0 to 7 days†

    30 mg/kg/dose IV every 12 hours.

    For the treatment of bronchitis.
    Intravenous or Intramuscular dosage
    Adults

    1 to 2 g IV/IM every 8 to 12 hours for moderately severe systemic infections. For severe, life-threatening infections, 2 g IV every 6 to 8 hours (Max: 8 g/day).

    Infants 9 months and older, Children, and Adolescents

    30 mg/kg/dose IV every 6 to 8 hours (Max: 120 mg/kg/day or 8 g/day) depending on the severity of the infection.

    Infants 1 to 8 months†

    30 mg/kg/dose IV every 6 to 8 hours (Max: 120 mg/kg/day) depending on the severity of the infection.

    Neonates older than 7 days and weighing more than 2,000 g†

    30 mg/kg/dose IV every 6 to 8 hours.

    Neonates older than 7 days and weighing 2,000 g or less†

    30 mg/kg/dose IV every 8 to 12 hours.

    Neonates 0 to 7 days†

    30 mg/kg/dose IV every 12 hours.

    For surgical infection prophylaxis†.
    Intravenous dosage
    Adults

    2 g IV as a single dose within 60 minutes prior to the surgical incision; or alternately, 1 g IV as a single dose for gynecologic procedures. Intraoperative redosing 4 hours from the first preoperative dose and a duration of prophylaxis less than 24 hours for most procedures are recommended by clinical practice guidelines. Clinical practice guidelines recommend aztreonam in combination with cefazolin, or for beta-lactam allergic patients, clindamycin or vancomycin, for urologic procedures involving implanted prosthesis. Aztreonam in combination with an appropriate antimicrobial with gram-positive activity (i.e., clindamycin or vancomycin) is also recommended as an alternate therapy for patients with a beta-lactam allergy undergoing gastrointestinal, biliary tract, uncomplicated appendectomy, colorectal, hysterectomy, or abdominal transplantion procedures.

    Infants, Children, and Adolescents

    30 mg/kg/dose IV as a single dose (Max: 2 g/dose) within 60 minutes prior to the surgical incision. Intraoperative redosing 4 hours from the first preoperative dose and a duration of prophylaxis less than 24 hours for most procedures are recommended by clinical practice guidelines. Clinical practice guidelines recommend aztreonam in combination with cefazolin, or for beta-lactam allergic patients, clindamycin or vancomycin, for urologic procedures involving implanted prosthesis. Aztreonam in combination with an appropriate antimicrobial with gram-positive activity (i.e., clindamycin or vancomycin) is also recommended as an alternate therapy for patients with a beta-lactam allergy undergoing gastrointestinal, biliary tract, uncomplicated appendectomy, colorectal, or abdominal transplantion procedures.

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

    Doses of 2 g IV every 6 to 8 hours or 1.5 g IV every 4 hours have been studied in combination with vancomycin or clindamycin. Aztreonam in combination with vancomycin is recommended in guidelines as an alternative in patients that have significant beta-lactam allergy.

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

    50 mg/kg/dose IV every 6 to 8 hours (Max: 1 to 2 g/dose), in combination with other antimicrobials, has been successfully used for the empiric treatment of febrile neutropenia in pediatric patients. 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, such as aztreonam, is recommended for patients who are clinically unstable, when a resistant infection is suspected, or for centers with high rates of resistant pathogens.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    225 mg/day nebulized; 8 g/day IV/IM is FDA-approved; however, 12 g/day IV has been used.

    Geriatric

    225 mg/day nebulized; 8 g/day IV/IM is FDA-approved; however, 12 g/day IV has been used.

    Adolescents

    225 mg/day nebulized; 120 mg/kg/day (Max: 8 g/day) IV is the FDA-approved maximum dosage; however, up to 300 mg/kg/day (Max: 12 g/day) IV has been used in patients with cystic fibrosis.

    Children

    >= 7 years: 120 mg/kg/day (Max: 8 g/day) IV is the FDA-approved maximum dosage; however, up to 300 mg/kg/day (Max: 12 g/day) IV has been used in patients with cystic fibrosis. The maximum nebulized dosage is 225 mg/day.
    < 7 years: 120 mg/kg/day IV is the FDA-approved maximum dosage; however, up to 300 mg/kg/day IV has been used in patients with cystic fibrosis. Safety and efficacy of nebulization have not been established.

    Infants

    >= 9 months: 120 mg/kg/day IV is the FDA-approved maximum dosage; however, up to 300 mg/kg/day IV has been used in patients with cystic fibrosis. Safety and efficacy of nebulization have not been established.
    < 9 months: Safety and efficacy have not been established. Doses up to 120 mg/kg/day IV have been used off-label for most infections; up to 300 mg/kg/day IV has been used in patients with cystic fibrosis.

    Neonates

    > 7 days and weighing > 2000 g: Safety and efficacy have not been established; however, doses of 120 mg/kg/day IV have been used off-label.
    > 7 days and weighing <= 2000 g: Safety and efficacy have not been established; however, doses of 90 mg/kg/day IV have been used off-label.
    <= 7 days: Safety and efficacy have not been established; however, doses of 60 mg/kg/day IV have been used off-label.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is needed. The half-life of systemically administered aztreonam is only slightly prolonged in patients with hepatic impairment. The low systemic exposure of aztreonam for inhalation would not warrant dosage adjustments.

    Renal Impairment

    Dosage adjustment due to renal impairment is necessary for systemic dosage only. Nebulized aztreonam does not require dosage adjustment due to low systemic exposure.
     
    The FDA-labeled dosage adjustment in adults with renal impairment reduces the dose and maintains the fixed dosing intervals.
    CrCl > 30 mL/min/1.73 m2: No dosage adjustment needed.
    CrCl 10—30 mL/min/1.73 m2: After a normal loading dose, administer 50% of the standard dose and give at standard dosing intervals.
    CrCl < 10 mL/min/1.73 m2: After a normal loading dose, administer 25% of the standard dose and give at standard dosing intervals.
     
    Dosage adjustments in pediatric patients:
    According to the FDA-approved product labeling, there are insufficient data in pediatric patients with renal failure to determine appropriate dosage adjustments. However, other experts recommend the following dosage adjustments :
    GFR 30—50 mL/min/1.73 m2: No dosage adjustment necessary.
    GFR 10—29 mL/min/1.73 m2: 15—20 mg/kg/dose IV every 8 hours.
    GFR < 10 mL/min/1.73 m2: 7.5—10 mg/kg/dose IV every 12 hours.
     
    Intermittent hemodialysis
    Aztreonam is cleared by hemodialysis with 27—58% of the dose removed. The FDA-approved dosage adjustment for adult hemodialysis patients is to give the normal loading dose followed by 25% of the usual dose given at the standard dosing interval. For serious or life-threatening infections, one-eighth of the initial dose should be given after each hemodialysis session in addition to maintenance dosing.[44907] For pediatric patients, 7.5—10 mg/kg/dose IV every 12 hours is recommended.
     
    Peritoneal dialysis
    For adults, administer 25% of the standard dose. For pediatric patients, 7.5—10 mg/kg/dose IV every 12 hours is recommended.
     
    Continuous renal replacement therapy (CRRT)
    For adults, a loading dose of 2 g IV is suggested for CRRT. Recommended doses for various types of CRRT include 1—2 g IV/IM every 12 hours for continuous venovenous hemofiltration (CVVH) and 1 g IV/IM every 8 hours or 2 g IV/IM every 12 hours for continuous venovenous hemodialysis (CVVHD) or continuous venovenous hemodiafiltration (CVVHDF). For pediatric patients, 100% of the dose is recommended.

    ADMINISTRATION

    Injectable Administration

    Aztreonam is administered intravenously or intramuscularly.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Powder vials for injection:
    Reconstitution:
    For IV push, reconstitute each vial with 6—10 mL of Sterile Water for Injection.
    For intermittent IV infusion, reconstitute with at least 3 mL of Sterile Water for Injection per gram of aztreonam. FURTHER DILUTION IS NECESSARY FOR IV INFUSION.
    Shake immediately and vigorously.
    Storage: Use within 48 hours if kept at room temperature (15—30 degrees C or 59—98 degrees F) or within 7 days if kept under refrigeration (2—8 degrees C or 38—48 degrees F).
    Dilution for intermittent IV infusion:
    Further dilute the appropriate dose in a compatible IV solution.
    If using a volume control administration set, the aztreonam volume should not exceed 20 mg/mL.
    Shake immediately and vigorously.
    Storage: For solutions at concentrations not exceeding 20 mg/mL (2% w/v), use within 48 hours if kept at room temperature (15—30 degrees C or 59—98 degrees F) or within 7 days if kept under refrigeration (2—8 degrees C or 38—48 degrees F). For solutions at concentrations exceeding 20 mg/mL (2% w/v), use promptly after preparation.
     
    Pre-mixed Galaxy IV solution:
    Preparation:
    Thaw frozen containers at room temperature (25 degrees C or 77 degrees F) or under refrigeration (2—8 degrees C or 36—46 degrees F). Do not force thaw by immersion in water baths or by microwave irradiation. Check for leaks by squeezing bag firmly. Do not add supplementary medication.
    Contents of the solution may precipitate in the frozen state and should dissolve with little or no agitation once the solution has reached room temperature.
    Storage: The thawed solution is stable for 48 hours at room temperature or for 14 days under refrigeration.
    Do not use plastic containers in series connections as this could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.
     
    Intermittent IV injection:
    Slowly inject directly into a vein or the tubing of a suitable administration set over a period of 3—5 minutes.
     
    Intermittent IV infusion:
    Infuse appropriate dose IV over 20—60 minutes.

    Intramuscular Administration

    Reconstitution:
    Reconstitute vials with at least 3 mL of an appropriate diluent per gram of aztreonam.
    Shake immediately and vigorously.
    Storage: When prepared with Sterile Water for Injection, the reconstituted solution is stable for 48 hours at room temperature (15—30 degrees C or 59—86 degrees F) or for 7 days refrigerated (2—8 degrees C or 36—46 degrees F). When prepared with other solutions, use promptly after preparation.
     
    Intramuscular injection:
    In adults, inject doses of 1 g or less deeply into a large muscle (i.e., upper outer quadrant of the gluteus maximus or lateral part of the thigh). Aspirate to avoid injection into a blood vessel.
    Aztreonam is well tolerated and should not be admixed with any local anesthetic agent.

    Inhalation Administration
    Oral Inhalation Administration

    Reconstitution of nebulized solution:
    Do not reconstitute aztreonam for inhalation until ready to administer a dose.
    Remove the rubber stopper from the aztreonam vial.
    Twist the tip off of the 1 mL sterile diluent (0.17% Sodium Chloride provided by the manufacturer) ampule and squeeze contents into the aztreonam vial.
    Gently swirl the vial until the contents have completely dissolved.
     
    Administration of nebulized solution:
    Prior to the administration of the aztreonam nebulized solution, the patient should use a bronchodilator. A short-acting bronchodilator can be administered 15 minutes to 4 hours prior to the administration of aztreonam. Alternatively, a long-acting bronchodilator can be administered 30 minutes to 12 hours prior to the administration of aztreonam. For patients taking multiple inhaled therapies, the recommended order of administration is: bronchodilator, mucolytic, and then aztreonam.
    Aztreonam nebulized solution should be administered immediately after reconstitution of the solution.
    Administer via an Altera Nebulizer System only. Do not administer via any other nebulizer.
    Do not mix any with any other drugs.
    Administration typically takes 2—3 minutes via the nebulizer mouthpiece.

    STORAGE

    Azactam:
    - Avoid excessive heat (above 104 degrees F)
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in original package until time of use
    Cayston:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Reconstituted product should be used immediately. Discard unused portion
    - Refrigerate (between 36 and 46 degrees F)
    - Unrefrigerated product can be stored at temperatures not exceeding 77 degrees F for 28 days

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    A false-positive reaction for glucose in the urine has been observed in patients receiving aztreonam and using Benedict's solution, Fehling's solution, and Clinitest tablets. This reaction, however, has not been observed with Tes-tape (glucose Enzymatic Test Strip, USP, Lilly).

    Viral infection

    Aztreonam does not treat viral infection (e.g., common cold). Prescribing aztreonam in the absence of a proven or strongly suspected 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. Patients should complete the full course of treatment.

    Carbapenem hypersensitivity, cephalosporin hypersensitivity, penicillin hypersensitivity

    Aztreonam is a monocyclic beta-lactam. The incidence of allergic drug reactions to aztreonam is estimated at roughly 2% from reported clinical trial literature, and some reactions are consistent with IgE-mediated responses. Use would usually be contraindicated in any patient with direct aztreonam hypersensitivity. The manufacturer states that aztreonam should be used cautiously in patients with sensitivity to any beta-lactam related antibiotic (e.g., penicillin hypersensitivity, cephalosporin hypersensitivity, carbacephem hypersensitivity, carbapenem hypersensitivity) due to the minor chemical structural similarities in the agents. However, in actuality, such cross-sensitive reactions to aztreonam are thought quite rare, and there is clinical evidence to support aztreonam's low potential for such events. Patients with known and established penicillin allergy who receive skin testing to determine if they will cross-react to aztreonam rarely have positive skin tests, and many such patients have received full therapeutic dosing with aztreonam without incident. Clinicians should be aware that it is certainly possible to have cross-hypersensitivity, but such reactions do not appear common.

    Renal disease, renal failure, renal impairment

    Aztreonam is renally excreted. Therefore, in patients with renal disease resulting in renal impairment with a glomerular filtration rate of less than 30 mL/min or renal failure requiring dialysis, systemic dosage adjustment is necessary. Since aztreonam is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Given the low systemic exposure after nebulization, clinically relevant accumulation is unlikely to occur. Nebulized aztreonam may be administered to patients with all degrees of renal impairment.

    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 antibacterial 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.

    Acute bronchospasm

    Like with other inhaled therapies, acute bronchospasm has been associated with aztreonam solution for inhalation. Reduction of FEV1 by 15% or more immediately after administration with nebulized aztreonam was observed in 3% of patients in clinical trials despite the use of a bronchodilator prior to the administration of aztreonam. In clinical trials, patients with increased FEV1 during the 28 day treatment period were sometimes treated for pulmonary exacerbations when FEV1 declined after the 28 day treatment period. Healthcare providers should consider the patient's baseline FEV1 prior to aztreonam therapy and the presence of other symptoms when evaluating post-treatment changes in FEV1.

    Children, infants, neonates

    Aztreonam solution for inhalation is approved for use in children >= 7 years old and adolescents. Safety and efficacy of nebulized aztreonam in neonates, infants and children  less than 7 years old has not been established. Systemic aztreonam is approved for use in infants >= 9 months, children, and adolescents. However, systemic aztreonam is not approved in pediatric patients with septicemia and skin and skin-structure infections where the skin infection is believed or known to be due to H. influenzae type b. Safety and efficacy of systemic aztreonam in neonates and infants  less than 9 months has not been established.

    Pregnancy

    Aztreonam is classified as FDA pregnancy risk category B. There have been no adequate, well-controlled studies of aztreonam in pregnant women and it is, therefore, recommended during pregnancy only if clearly needed. Aztreonam does cross the placenta and enter fetal circulation. Systemic exposure after nebulized aztreonam is minimal.

    Breast-feeding

    Aztreonam is excreted in breast milk at very low concentrations. While laboratory and clinical effects in breast-fed infants are not available, the American Academy of Pediatrics (AAP) considers aztreonam to be usually compatible with breast-feeding. After a single intramuscular (IM) dose (1 gram) in 6 women, average peak milk concentrations, occurring 6 hours after the dose, were 0.3 mg/L. After a single intravenous (IV) dose (1 gram) in 6 other women, average peak milk concentrations, occurring 2.4 hours after the dose were 0.2 mg/L. Aztreonam was detectable in milk between 2 and 8 hours after an IM dose and 1.5 and 8 hours after an IV dose. In another report, a single IV dose (1 gram) produced milk concentrations ranging 0.4—1 mg/L 1 to 5 hours after the dose with little variation in milk concentrations during this time in each woman. On average, concentrations were slightly higher 2 hours after the dose, but in individuals the peak level occurred at various times between 1 and 4 hours. Peak plasma concentrations of aztreonam after nebulization are approximately 1% of peak concentrations observed after IV administration (500 mg). The manufacturer states that the use of nebulized aztreonam is unlikely to pose risk to the breast-feeding infant.

    Geriatric

    Clinical studies of systemic and nebulized aztreonam in geriatric patients have not included sufficient numbers of patients over 65 years of age to determine if they respond differently to treatment than younger adults. However, clinical experience has not identified differences between older and younger patients. In general, systemic aztreonam dosage selection for elderly patients should be cautious, starting at the lower end of the dosage range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and concomitant disease. Because elderly patients are more likely to have decreased renal function that will decrease aztreonam elimination, renal function should be monitored;systemic dosage adjustments made accordingly. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. 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.

    ADVERSE REACTIONS

    Severe

    bronchospasm / Rapid / 0-3.0
    GI bleeding / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    exfoliative dermatitis / Delayed / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    pancytopenia / Delayed / 0-1.0
    angioedema / Rapid / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    seizures / Delayed / 0-1.0

    Moderate

    elevated hepatic enzymes / Delayed / 0-20.0
    wheezing / Rapid / 0-16.0
    neutropenia / Delayed / 0-11.3
    eosinophilia / Delayed / 0-6.3
    thrombocytosis / Delayed / 0-3.6
    erythema / Early / 0.5-2.9
    phlebitis / Rapid / 0.5-2.1
    pseudomembranous colitis / Delayed / 0-1.0
    candidiasis / Delayed / 0-1.0
    hepatitis / Delayed / 0-1.0
    jaundice / Delayed / 0-1.0
    oral ulceration / Delayed / 0-1.0
    chest pain (unspecified) / Early / 0-1.0
    dyspnea / Early / 0-1.0
    anemia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    hypotension / Rapid / 0-1.0
    premature ventricular contractions (PVCs) / Early / 0-1.0
    confusion / Early / 0-1.0
    vaginitis / Delayed / 0-1.0
    superinfection / Delayed / Incidence not known

    Mild

    cough / Delayed / 54.0-54.0
    nasal congestion / Early / 0-16.0
    fever / Early / 0-13.0
    injection site reaction / Rapid / 0.5-12.0
    abdominal pain / Early / 7.0-7.0
    vomiting / Early / 1.0-6.0
    rash (unspecified) / Early / 1.0-4.3
    diarrhea / Early / 1.0-1.4
    nausea / Early / 1.0-1.3
    halitosis / Early / 0-1.0
    dysgeusia / Early / 0-1.0
    sneezing / Early / 0-1.0
    purpura / Delayed / 0-1.0
    urticaria / Rapid / 0-1.0
    diaphoresis / Early / 0-1.0
    petechiae / Delayed / 0-1.0
    headache / Early / 0-1.0
    weakness / Early / 0-1.0
    malaise / Early / 0-1.0
    leukocytosis / Delayed / 0-1.0
    flushing / Rapid / 0-1.0
    dizziness / Early / 0-1.0
    vertigo / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    insomnia / Early / 0-1.0
    tinnitus / Delayed / 0-1.0
    diplopia / Early / 0-1.0
    arthralgia / 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.
    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.
    Warfarin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including aztreonam, 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

    Aztreonam is classified as FDA pregnancy risk category B. There have been no adequate, well-controlled studies of aztreonam in pregnant women and it is, therefore, recommended during pregnancy only if clearly needed. Aztreonam does cross the placenta and enter fetal circulation. Systemic exposure after nebulized aztreonam is minimal.

    Aztreonam is excreted in breast milk at very low concentrations. While laboratory and clinical effects in breast-fed infants are not available, the American Academy of Pediatrics (AAP) considers aztreonam to be usually compatible with breast-feeding. After a single intramuscular (IM) dose (1 gram) in 6 women, average peak milk concentrations, occurring 6 hours after the dose, were 0.3 mg/L. After a single intravenous (IV) dose (1 gram) in 6 other women, average peak milk concentrations, occurring 2.4 hours after the dose were 0.2 mg/L. Aztreonam was detectable in milk between 2 and 8 hours after an IM dose and 1.5 and 8 hours after an IV dose. In another report, a single IV dose (1 gram) produced milk concentrations ranging 0.4—1 mg/L 1 to 5 hours after the dose with little variation in milk concentrations during this time in each woman. On average, concentrations were slightly higher 2 hours after the dose, but in individuals the peak level occurred at various times between 1 and 4 hours. Peak plasma concentrations of aztreonam after nebulization are approximately 1% of peak concentrations observed after IV administration (500 mg). The manufacturer states that the use of nebulized aztreonam is unlikely to pose risk to the breast-feeding infant.

    MECHANISM OF ACTION

    Unlike the penicillins and cephalosporins, aztreonam is a monobactam. It contains a sulfonic acid group that gives the beta-lactam of aztreonam its activity. Like the penicillins and cephalosporins, aztreonam is mainly bactericidal and 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. Penicillin-binding proteins 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. Penicillin-binding proteins vary among different bacterial species. In particular, aztreonam preferentially binds to PBP-3 of the gram-negative rods, and the sulfonic acid group assists in the acetylation of PBP-3. Since PBP-3 is responsible for formation of the septum during cell division, aztreonam's inhibition of these proteins causes elongation of the bacteria, inhibition of bacterial cell division, and breakage of the cell wall, which results in cell lysis and death. Aztreonam has no affinity for the PBPs of gram-positive organisms and poor affinity for anaerobic PBPs. In vitro, aztreonam has little ability to induce chromosomally mediated beta-lactamase production, although the selection of preexisting resistant organisms is still possible during clinical use. Bacterial resistance to aztreonam occurs via hydrolysis by beta-lactamase, alteration of the PBP, and decreased intracellular permeability.

    PHARMACOKINETICS

    Aztreonam is administered via nebulization, intravenously, and intramuscularly. Approximately 56—65% of aztreonam is protein-bound. Systemic aztreonam is distributed into most body tissues and fluids including lungs, liver, kidneys, bone, uterus, ovary, intestine, saliva, sputum, bile, as well as peritoneal, pleural, pericardial, and synovial fluids. It reaches high enough concentrations within CSF to inhibit most Enterobacteriaceae when administered systemically, although it is not indicated for the treatment of meningitis. It also crosses the placenta.
     
    Hepatic metabolism is a minor pathway of excretion. Aztreonam and the inactive metabolites are excreted primarily into the urine via tubular secretion and glomerular filtration. A small percentage is excreted in feces. The drug is also excreted in breast milk. The elimination half-life of aztreonam is 1.7 hours after systemic administration and 2.1 hours after nebulization in patients with normal renal function. Concomitant administration of probenecid or furosemide and aztreonam does not result in clinically significant increases in aztreonam serum concentrations.

    Oral Route

    Aztreonam is poorly absorbed from the GI tract.

    Intravenous Route

    After single aztreonam 500—1000 mg IV doses, the serum levels exceeded the MIC90 for Neisseria sp, H. influenzae, most genera of Enterobacteriaceae and 80% of Enterobacter sp. for 8 hours. For P. aeruginosa, a single 2 g IV dose of aztreonam will maintain levels exceeding the MIC90 for 4—6 hours. The same doses of aztreonam result in urine concentrations of aztreonam that exceed the MIC90 for these organisms for up to 12 hours. Approximately 60—70% of an IV or IM dose of aztreonam is recovered in the urine in 8 hours. Urinary excretion of a single dose is essentially complete 12 hours after the injection.

    Intramuscular Route

    Peak plasma levels of aztreonam occur within 60 minutes after an IM dose. Serum concentrations are comparable between IM and IV dosing at 1 hour (1.5 hours from the start of the IV infusion) after the dose. Following single aztreonam 500—1000 mg IM doses, the serum levels exceeded the MIC90 for Neisseria sp, H. influenzae, most genera of Enterobacteriaceae, and 80% of Enterobacter sp. for 8 hours. The same doses of aztreonam result in urine concentrations of aztreonam that exceed the MIC90 for these organisms for up to 12 hours. Approximately 60—70% of an IV or IM dose of aztreonam is recovered in the urine in 8 hours. Urinary excretion of a single dose is essentially complete 12 hours after the injection.

    Inhalation Route

    Sputum and plasma concentrations exhibited considerable variability between patients receiving nebulized aztreonam in clinical trials. The mean sputum concentration 10 minutes after the first dose of nebulized aztreonam (75 mg) was 726 mcg/g. In patients receiving nebulized aztreonam 3 times daily, mean sputum concentrations 10 minutes after dose administration on days 0, 14, and 28 were 984 mcg/g, 793 mcg/g, and 715 mcg/g, respectively, indicating no drug accumulation. The mean peak plasma concentration one hour after the first dose of nebulized aztreonam was 0.59 mcg/mL. Mean peak plasma concentrations in patients receiving nebulized aztreonam 3 times daily were 0.55 mcg/mL, 0.67 mcg/mL, and 0.65 mcg/mL on days 0, 14, and 28, respectively. These are low systemic concentrations compared to peak serum concentrations after an IV dose (approximately 54 mcg/mL after a 500 mg dose). Evaluation of plasma and urine concentrations indicates a low systemic absorption of nebulized aztreonam. Approximately 10% of the total nebulized dose is excreted in the urine as unchanged drug compared to 60—65% after IV administration. The elimination half-life of nebulized aztreonam is 2.1 hours.