DESCRIPTION

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 (e.g., 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.

Aztreonam is designated chemically as (Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl- 4-oxo-1-sulfo-3 azetidinyl] carbamoyl]methylene] amino] oxy]-2-methylpropionic acid.  Structural formula:

C13H17N5O8S2                                   M.W. 435.44

Aztreonam for injection is a sterile, nonpyrogenic, sodium-free, lyophilized, off-white to slightly yellow solid containing approximately 780 mg arginine per gram of aztreonam.  Following constitution, the product is for intramuscular or intravenous use.  Aqueous solutions of the product have a pH in the range of 4.5 to 7.5.Each 500 mg contains 500 mg aztreonam with approximately 390 mg arginine.

Each 1 gram vial contains 1 gram aztreonam with approximately 780 mg arginine.

Each 2 gram vial contains 2 grams aztreonam with approximately 1.56 grams arginine.

CLINICAL PHARMACOLOGY

Single 30-minute intravenous infusions of 500 mg, 1 g and 2 g doses of aztreonam for injection in healthy subjects produced aztreonam peak serum levels of 54, 90 and 204 mcg/mL, respectively, immediately after administration; at 8 hours, serum levels were 1, 3 and 6 mcg/mL, respectively (Figure 1).  Single 3 minute intravenous injections of the same doses resulted in serum levels of 58, 125 and 242 mcg/mL at 5 minutes following completion of injection.

Serum concentrations of aztreonam in healthy subjects following completion of single intramuscular injections of 500 mg and 1 g doses are depicted in Figure 1; maximum serum concentrations occur at about 1 hour.  After identical single intravenous or intramuscular doses of aztreonam for injection the serum concentrations of aztreonam are comparable at 1 hour (1.5 hours from start of intravenous infusion) with similar slopes of serum concentrations thereafter.

The serum levels of aztreonam following single 500 mg or 1 g (intramuscular or intravenous) or 2 g (intravenous) doses of aztreonam for injection exceed the MIC90 for Neisseria sp., Haemophilus influenzae and most genera of the Enterobacteriaceaefor 8 hours (for Enterobacter sp., the 8-hour serum levels exceed the MIC for 80 % of strains).  For Pseudomonas aeruginosa, a single 2 g intravenous dose produces serum levels that exceed the MIC90 for approximately 4 to 6 hours.  All of the above doses of aztreonam for injection result in average urine levels of aztreonam that exceed the MIC90 for the same pathogens for up to 12 hours.

When aztreonam pharmacokinetics were assessed for adult and pediatric patients, they were found to be comparable (down to 9 months old).  The serum half-life of aztreonam averaged 1.7 hours (1.5 to 2) in subjects with normal renal function, independent of the dose and route of administration.  In healthy subjects, based on a 70 kg person, the serum clearance was 91 mL/min and renal clearance was 56 mL/min; the apparent mean volume of distribution at steady-state averaged 12.6 liters, approximately equivalent to extracellular fluid volume.

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.1-4  The dosage of aztreonam for injection should be adjusted accordingly (see DOSAGE AND ADMINISTRATION: Renal Impairment in Adult Patients).

In patients with impaired renal function, the serum half-life of aztreonam is prolonged (see DOSAGE AND ADMINISTRATION: Renal Impairment in Adult Patients).  The serum half-life of aztreonam is only slightly prolonged in patients with hepatic impairment since the liver is a minor pathway of excretion.

Average urine concentrations of aztreonam were approximately 1100, 3500 and 6600 mcg/mL within the first 2 hours following single 500 mg, 1 g and 2 g intravenous doses of aztreonam for injection (30 minute infusions), respectively.  The range of average concentrations for aztreonam in the 8 to 12 hour urine specimens in these studies was 25 to 120 mcg/mL.  After intramuscular injection of single 500 mg and 1 g doses of aztreonam for injection urinary levels were approximately 500 and 1200 mcg/mL, respectively, within the first 2 hours, declining to 180 and 470 mcg/mL in the 6 to 8 hour specimens.  In healthy subjects, aztreonam is excreted in the urine about equally by active tubular secretion and glomerular filtration.  Approximately 60%  to 70 % of an intravenous or intramuscular dose was recovered in the urine by 8 hours.  Urinary excretion of a single parenteral dose was essentially complete by 12 hours after injection.  About 12 % of a single intravenous radiolabeled dose was recovered in the feces.  Unchanged aztreonam and the inactive beta-lactam ring hydrolysis product of aztreonam were present in feces and urine.

Intravenous or intramuscular administration of a single 500 mg or 1 g dose of aztreonam for injection every 8 hours for 7 days to healthy subjects produced no apparent accumulation of aztreonam or modification of its disposition characteristics; serum protein binding averaged 56 % and was independent of dose.  An average of about 6 % of a 1 g intramuscular dose was excreted as a microbiologically inactive open beta-lactam ring hydrolysis product (serum half-life approximately 26 hours) of aztreonam in the 0 to 8 hour urine collection on the last day of multiple dosing.

Renal function was monitored in healthy subjects given aztreonam; standard tests (serum creatinine, creatinine clearance, BUN, urinalysis and total urinary protein excretion) as well as special tests (excretion of N-acetyl-ß-glucosaminidase, alanine aminopeptidase and ß2- microglobulin) were used.  No abnormal results were obtained.

Aztreonam achieves measurable concentrations in the following body fluids and tissues:

1 Tissue penetration is regarded as essential to therapeutic efficacy, but specific tissue levels have not been correlated with specific therapeutic effects.

The concentration of aztreonam in saliva at 30 minutes after a single 1 g intravenous dose (9 patients) was 0.2 mcg/mL; in human milk at 2 hours after a single 1 g intravenous dose (6 patients), 0.2 mcg/mL, and at 6 hours after a single 1 g intramuscular dose (6 patients), 0.3 mcg/mL; in amniotic fluid at 6 to 8 hours after a single 1 g intravenous dose (5 patients), 2 mcg/mL.  The concentration of aztreonam in peritoneal fluid obtained 1 to 6 hours after multiple 2 g intravenous doses ranged between 12 and 90 mcg/mL in 7 of 8 patients studied.

Aztreonam given intravenously rapidly reaches therapeutic concentrations in peritoneal dialysis fluid; conversely, aztreonam given intraperitoneally in dialysis fluid rapidly produces therapeutic serum levels.

Concomitant administration of probenecid or furosemide and aztreonam for injection causes clinically insignificant increases in the serum levels of aztreonam.  Single-dose intravenous pharmacokinetic studies have not shown any significant interaction between aztreonam and concomitantly administered gentamicin, nafcillin sodium, cephradine, clindamycin or metronidazole.  No reports of disulfiram-like reactions with alcohol ingestion have been noted; this is not unexpected since aztreonam does not contain a methyl-tetrazole side chain.

Microbiology

Aztreonam exhibits potent and specific activity in vitro against a wide spectrum of gram-negative aerobic pathogens including Pseudomonas aeruginosa.  The bactericidal action of aztreonam results from the inhibition of bacterial cell wall synthesis due to a high affinity of aztreonam for penicillin binding protein 3 (PBP3).  Aztreonam, unlike the majority of beta-lactam antibiotics, does not induce beta-lactamase activity and its molecular structure confers a high degree of resistance to hydrolysis by beta-lactamases (i.e., penicillinases and cephalosporinases) produced by most gram-negative and gram-positive pathogens; it is, therefore, usually active against gram-negative aerobic microorganisms that are resistant to antibiotics hydrolyzed by beta-lactamases.  It is active against many strains that are multiply-resistant to other antibiotics, such as certain cephalosporins, penicillin, and aminoglycosides.  Aztreonam maintains its antimicrobial activity over a pH range of 6 to 8 in vitro, as well as in the presence of human serum and under anaerobic conditions.

Aztreonam has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic gram-negative microorganisms:

Citrobacter species, including C. freundii

Enterobacter species, including E. cloacae

Escherichia coli

Haemophilus influenzae (including ampicillin-resistant and other penicillinase-producing strains)

Klebsiella oxytoca

Klebsiella pneumoniae

Proteus mirabilis

Pseudomonas aeruginosa

Serratia species, including S. marcescens

The following in vitro data are available, but their clinical significance is unknown.

Aztreonam exhibits in vitro minimal inhibitory concentrations (MICs) of 8 mcg/mL or less against most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of aztreonam in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-negative microorganisms:

Aeromonas hydrophila

Morganella morganii

Neisseria gonorrhoeae (including penicillinase-producing strains)

Pasteurella multocida

Proteus vulgaris

Providencia stuartii

Providencia rettgeri

Yersinia enterocolitica

Aztreonam and aminoglycosides have been shown to be synergistic in vitro against most strains of P. aeruginosa, many strains of Enterobacteriaceae, and other gram-negative aerobic bacilli.

Alterations of the anaerobic intestinal flora by broad spectrum antibiotics may decrease colonization resistance, thus permitting overgrowth of potential pathogens, e.g., Candida and Clostridium species.  Aztreonam has little effect on the anaerobic intestinal microflora in in vitro studies.  Clostridium difficile and its cytotoxin were not found in animal models following administration of aztreonam (see ADVERSE REACTIONS: Gastrointestinal).

Susceptibility Tests

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs).  These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds.  The MICs should be determined using a standardized procedure.  Standardized procedures are based on a dilution method5 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of aztreonam powder.  The MIC values should be interpreted according to the following criteria:

For testing aerobic microorganisms other than Haemophilus influenzae:

When testing Haemophilus influenzaea:

aInterpretative criteria applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM)5.

bThe current absence of data on resistant strains precludes defining any categories other than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable.  A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated.  This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used.  This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation.  A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.

Standard aztreonam powder should provide the following MIC values:

aRange applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM)5.

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds.  One such standardized procedure6 requires the use of standardized inoculum concentrations.  This procedure uses paper disks impregnated with 30 mcg aztreonam to test the susceptibility of microorganisms to aztreonam.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mcg aztreonam disk should be interpreted according to the following criteria:

For testing aerobic microorganisms other than Haemophilus influenzae:

When testing Haemophilus influenzaea:

aInterpretative criteria applicable only to tests performed by disk diffusion method using Haemophilus Test Medium (HTM)6.

bThe current absence of data on resistant strains precludes defining any categories other than “Susceptible”.  Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

Interpretation should be as stated above for results using dilution techniques.  Interpretation involves correlation of the diameter obtained in the disk test with the MIC for aztreonam.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures.  For the diffusion technique, the 30-mcg aztreonam disk should provide the following zone diameters in these laboratory test quality control strains.

aRange applicable only to tests performed by disk diffusion method using Haemophilus Test Medium (HTM)6.

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of aztreonam for injection and other antibacterial drugs, aztreonam for injection should only be used 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.

Aztreonam for Injection 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*.

Aztreonam for injection 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.  Aztreonam for injection is effective against most of the commonly  encountered gram-negative aerobic pathogens seen in general surgery.

*Efficacy for this organism in this organ system was studied in fewer than ten infections

Concurrent Therapy

Concurrent initial therapy with other antimicrobial agents and aztreonam for injection is recommended before the causative organism(s) is known in seriously ill patients who are also at risk of having an infection due to gram-positive aerobic pathogens.  If anaerobic organisms are also suspected as etiologic agents, therapy should be initiated using an anti-anaerobic agent concurrently with aztreonam for injection (see DOSAGE AND ADMINISTRATION).  Certain antibiotics (e.g., cefoxitin, imipenem) may induce high levels of beta-lactamase in vitro in some gram-negative aerobes such as Enterobacter and Pseudomonas species, resulting in antagonism to many beta-lactam antibiotics including aztreonam.  These in vitro findings suggest that such beta-lactamase inducing antibiotics not be used concurrently with aztreonam.  Following identification and susceptibility testing of the causative organism(s), appropriate antibiotic therapy should be continued.

CONTRAINDICATIONS

This preparation is contraindicated in patients with known hypersensitivity to aztreonam or any other component in the formulation.

WARNINGS

Both animal and human data suggest that aztreonam for injection 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 (see CONTRAINDICATIONS).

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 (e.g., 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 (e.g., maintenance of ventilation, pressor amines, antihistamines, corticosteroids).  Serious hypersensitivity reactions may require epinephrine and other emergency measures (see ADVERSE REACTIONS).

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including aztreonam for injection, 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 sin