Each vial contains: Aztreonam 1 g.
AZITRAM (aztreonam for injection, USP) contains the active ingredient aztreonam, a monobactam. It was originally isolated from Chromobacterium violaceum. It is a synthetic bactericidal antibiotic. The monobactams, having a unique monocyclic beta-lactam nucleus, are structurally different from other beta-lactam antibiotics (eg, penicillins, cephalosporins, cephamycins). The sulfonic acid substituent in the 1-position of the ring activates the beta-lactam moiety; an aminothiazolyl oxime side chain in the 3-position and a methyl group in the 4-position confer the specific antibacterial spectrum and beta-lactamase stability.
Pharmacology: Aztreonam is bactericidal and acts similarly to the penicillins by inhibiting synthesis of the bacterial cell wall; it has a high affinity for the penicillin-binding protein 3 (PBP-3) of Gram-negative bacteria. The activity of aztreonam is restricted to Gram-negative aerobic organisms, including beta-lactamase-producing strains, with poor or no activity against Gram-positive aerobes or anaerobic organisms. It is active against most Enterobacteriaceae including Escherichia coli, Klebsiella, Proteus, Providencia, Salmonella, Serratia, Shigella, and Yersinia spp. Some strains of Enterobacter and Citrobacter spp. are resistant. Aztreonam has some activity against Pseudomonas aeruginosa, although most strains of other Pseudomonas spp. are insensitive. Aztreonam has good activity against Haemophilus influenza and Neisseria spp. Synergy has been reported in vitro between aztreonam and aminoglycosides against P. aeruginosa and some Enterobacteriaceae. Aztreonam is stable to hydrolysis by many beta-lactamases and appears to be a poor inducer of beta-lactamase production. Acquired resistance has occasionally been reported.
Pharmacokinetics: Aztreonam is poorly absorbed from the gastrointestinal tract and is therefore given parenterally. Absorption after intramuscular injection is good; peak plasma concentrations of about 46 micrograms/mL have been achieved within 1 hour of a 1-g dose. Aztreonam has a plasma half-life of about 1.7 hours. The half-life may be prolonged in neonates, in the elderly, in patients with renal impairment, and to some extent in those with hepatic impairment. Aztreonam is about 56% bound to plasma proteins. It is widely distributed in body tissues and fluids, including bile. Diffusion into the CSF is poor unless the meninges are inflamed. It crosses the placenta and enters the fetal circulation; small amounts are distributed into breast milk. Aztreonam is not extensively metabolized. The principal metabolite, SQ-26992, is inactive and is formed by opening of the beta-lactam ring; it has a much longer half-life than the parent compound. Aztreonam is excreted mainly in the urine, by renal tubular secretion and glomerular filtration; about 60 to 70% of a dose appears within 8 hours as unchanged drug with only small quantities of metabolites. Only small amounts of unchanged drug and metabolites are excreted in the faeces.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of AZITRAM (aztreonam for injection, USP) and other antibacterial drugs, AZITRAM should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. AZITRAM (aztreonam for injection, USP) is indicated for the treatment of the following infections caused by susceptible gram-negative microorganisms: Urinary Tract Infections (complicated and uncomplicated), including pyelonephritis and cystitis (initial and recurrent) caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Enterobacter cloacae, Klebsiella oxytoca*, Citrobacter species* and Serratia marcescens∗.
Lower Respiratory Tract Infections, including pneumonia and bronchitis caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Haemophilus influenzae, Proteus mirabilis, Enterobacter species and Serratia marcescens*.
Septicemia caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis*, Serratia marcescens* and Enterobacter species.
Skin and Skin-Structure Infections, including those associated with postoperative wounds, ulcers and burns caused by Escherichia coli, Proteus mirabilis, Serratia marcescens, Enterobacter species, Pseudomonas aeruginosa, Klebsiella pneumoniae and Citrobacter species*.
Intra-abdominal Infections, including peritonitis caused by Escherichia coli, Klebsiella species including K. pneumoniae, Enterobacter species including E. cloacae*, Pseudomonas aeruginosa, Citrobacter species* including C. freundii* and Serratia species* including S. marcescens*.
Gynecologic Infections, including endometritis and pelvic cellulitis caused by Escherichia coli, Klebsiella pneumoniae*, Enterobacter species* including E. cloacae* and Proteus mirabilis*.
AZITRAM is indicated for adjunctive therapy to surgery in the management of infections caused by susceptible organisms, including abscesses, infections complicating hollow viscus perforations, cutaneous infections and infections of serous surfaces. AZITRAM is effective against most of the commonly encountered gram-negative aerobic pathogens seen in general surgery.
Dosage in Adult Patients: AZITRAM may be administered intravenously or by intramuscular injection.
Dosage and route of administration should be determined by susceptibility of the causative organisms, severity and site of infection, and the condition of the patient. The intravenous route is recommended for patients requiring single doses greater than 1 g or those with bacterial septicemia, localized parenchymal abscess (eg, intra-abdominal abscess), peritonitis or other severe systemic or life-threatening infections. The duration of therapy depends on the severity of infection. Generally, AZITRAM should be continued for at least 48 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. Persistent infections may require treatment for several weeks. Doses smaller than those indicated should not be used.
Renal Impairment in Adult Patients: Prolonged serum levels of aztreonam may occur in patients with transient or persistent renal insufficiency. Therefore, the dosage of AZITRAM should be halved in patients with estimated creatinine clearances between 10 mL/min/1.73 m2 and 30 mL/min/1.73 m2 after an initial loading dose of 1 g or 2 g. When only the serum creatinine concentration is available, the following formula (based on sex, weight, and age of the patient) may be used to approximate the creatinine clearance (Clcr). The serum creatinine should represent a steady state of renal function.
Weight (kg) x (140-age)/Males: Clcr = 72 x serum creatinine (mg/dL); Females: 0.85 x above value.
In patients with severe renal failure (creatinine clearance less than 10 mL/min/1.73 m2 ), such as those supported by hemodialysis, the usual dose of 500 mg, 1 g or 2 g should be given initially. The maintenance dose should be one-fourth of the usual initial dose given at the usual fixed interval of 6, 8 or 12 hours.
For serious or life-threatening infections, in addition to the maintenance doses, one-eighth of the initial dose should be given after each hemodialysis session.
Dosage in the Elderly: Renal status is a major determinant of dosage in the elderly; these patients in particular may have diminished renal function. Serum creatinine may not be an accurate determinant of renal status. Therefore, as with all antibiotics eliminated by the kidneys, estimates of creatinine clearance should be obtained, and appropriate dosage modifications made if necessary.
Dosage in Pediatric Patients: AZITRAM (aztreonam for injection, USP) should be administered intravenously to pediatric patients with normal renal function. There are insufficient data regarding intramuscular administration to pediatric patients or dosing in pediatric patients with renal impairment.
If necessary, aztreonam may be cleared from the serum by hemodialysis and/or peritoneal dialysis.
Contraindicated in patients with history of hypersensitivity to the drug, other β-lactam antibiotics or penicillin and/or cephalosphorins.
Both animal and human data suggest that AZITRAM is rarely cross-reactive with other beta-lactam antibiotics and weakly immunogenic. Treatment with aztreonam can result in hypersensitivity reactions in patients with or without prior exposure. Careful inquiry should be made to determine whether the patient has any history of hypersensitivity reactions to any allergens. While cross-reactivity of aztreonam with other beta-lactam antibiotics is rare, this drug should be administered with caution to any patient with a history of hypersensitivity to beta-lactams (eg, penicillins, cephalosporins, and/or carbapenems). Treatment with aztreonam can result in hypersensitivity reactions in patients with or without prior exposure to aztreonam. If an allergic reaction to aztreonam occurs, discontinue the drug and institute supportive treatment as appropriate (eg, maintenance of ventilation, pressor amines, antihistamines, corticosteroids). Serious hypersensitivity reactions may require epinephrine and other emergency measures.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including AZITRAM, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Rare cases of toxic epidermal necrolysis have been reported in association with aztreonam in patients undergoing bone marrow transplant with multiple risk factors including sepsis, radiation therapy and other concomitantly administered drugs associated with toxic epidermal necrolysis.
Aztreonam should not be given to patients who are hypersensitive to it and should be administered with caution to those known to be hypersensitive to other beta-lactams, although the incidence of cross-sensitivity appears to be low. Should be used with caution in patients with renal and hepatic impairment.
Use in Pregnancy & Lactation: Aztreonam crosses the placenta and enters the fetal circulation. Studies in pregnant rats and rabbits, with daily doses up to 15 and 5 times, respectively, the maximum recommended human dose, revealed no evidence of embryo- or fetotoxicity or teratogenicity. No drug induced changes were seen in any of the maternal, fetal, or neonatal parameters that were monitored in rats receiving 15 times the maximum recommended human dose of aztreonam during late gestation and lactation. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, aztreonam should be used during pregnancy only if clearly needed.
Use in Children: The safety and effectiveness of intravenous AZITRAM (aztreonam for injection, USP) have been established in the age groups 9 months to 16 years. Use of AZITRAM in these age groups is supported by evidence from adequate and well-controlled studies of AZITRAM in adults with additional efficacy, safety, and pharmacokinetic data from non-comparative clinical studies in pediatric patients. Sufficient data are not available for pediatric patients under 9 months of age or for the following treatment indications/pathogens: septicemia and skin and skin-structure infections (where the skin infection is believed or known to be due to H. influenzae type b). In pediatric patients with cystic fibrosis, higher doses of AZITRAM may be warranted.
Use in Elderly: Clinical studies of AZITRAM did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In elderly patients, the mean serum half-life of aztreonam increased and the renal clearance decreased, consistent with the age-related decrease in creatinine clearance. 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. Because elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments made accordingly.
Aztreonam crosses the placenta and enters the fetal circulation. Studies in pregnant rats and rabbits, with daily doses up to 15 and 5 times, respectively, the maximum recommended human dose, revealed no evidence of embryo- or fetotoxicity or teratogenicity. No drug induced changes were seen in any of the maternal, fetal, or neonatal parameters that were monitored in rats receiving 15 times the maximum recommended human dose of aztreonam during late gestation and lactation. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, aztreonam should be used during pregnancy only if clearly needed.
Local reactions such as phlebitis/thrombophlebitis following IV administration, and discomfort/swelling at the injection site following IM administration occurred at rates of approximately 1.9% and 2.4%, respectively.
Systemic reactions (considered to be related to therapy or of uncertain etiology) occurring at an incidence of 1% to 1.3% include diarrhea, nausea and/or vomiting, and rash.
Reactions occurring at an incidence of less than 1% are listed within each body system in order of decreasing severity: Hypersensitivity:
Anaphylaxis, angioedema, bronchospasm.
Pancytopenia, neutropenia, thrombocytopenia, anemia, eosinophilia, leukocytosis, thrombocytosis.
Abdominal cramps; rare cases of C. difficile
-associated diarrhea, including pseudomembranous colitis, or gastrointestinal bleeding have been reported. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment.
Oral Anticoagulant: Patients receiving aztreonam and oral anticoagulant therapy because of the possibility of increased prothrombin time.
Probenecid: Concomitant administration of probenecid slows the rate of renal tubular secretion of aztreonam.
Aminoglycosides: Antimicrobial activity of aztreonam and aminoglycosides is additive or synergistic in vitro against most strains of Pseudomonas aeruginosa and some strains of P. cepacia, P. fluorescens, or P. maltophilia. Combination of aztreonam and aminoglycoside also is synergistic against some Enterobacteriaceae, including some strains of Enterobacter, Escherichia coli, Klebsiella, or Serratia.
β-lactam Antibiotics: Additive or synergistic effect has occurred in vitro against some strains of P. aeruginosa when aztreonam was used concomitantly with piperacillin, cefoperazone, or cefotaxime. Aztreonam is relatively stable against hydrolysis by inducible β-lactamases however it has been suggested that the enzyme may inactivate aztreonam by binding to the drug and preventing access to penicillin-binding proteins. Because combinations may be antagonistic, anti-infective agents that are potent inducers of β-lactamase production (i.e. cefoxitin, imipenem) should not be used concomitantly with aztreonam.
Furosemide: Increase serum aztreonam concentrations, but such increases are not clinically unimportant.
Direction for Reconstitution: For direct intermittent IV injection, the contents of the vial containing 1 g of aztreonam should be reconstituted by adding 6-10 mL of sterile water for injection. The appropriate dose of reconstituted solution may then be injected slowly over a period of 3-5 minutes either directly into a vein or into the tubing of a compatible IV solution.
For Intravenous Injection the following intravenous solutions can be used:
Sodium Chloride Injection, USP, 0.9% Ringer's Injection, USP Lactated Ringer's Injection, USP Dextrose Injection, USP, 5% or 10% Dextrose and Sodium Chloride Injection, USP, 5%:0.9%, 5%:0.45% or 5%:0.2% Sodium Lactate Injection, USP (M/6 Sodium Lactate).
For Intramuscular Injection the following solutions can be used:
Sterile Water for Injection, USP Sterile Bacteriostatic Water for Injection, USP (with benzyl alcohol or with methyl- and propylparabens) Sodium Chloride Injection, USP, 0.9% Bacteriostatic Sodium Chloride Injection, USP (with benzyl alcohol).
For IM administration, 500 mg and 1 g of aztreonam may be reconstituted by adding 1.5 mL and 3 mL respectively of sterile water for injection, 0.9% sodium chloride injection, bacteriostaic water for injection (with benzyl alcohol or methyl-and-propylparabens), or bacteriostatic sodium chloride injection (with benzyl alcohol).
Store at temperatures not exceeding 30°C.
J01DF01 - aztreonam ; Belongs to the class of monobactams. Used in the systemic treatment of infections.
Powd for inj (vial) 1 g x 20 mL x 1's.