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

Figure 1

The serum levels of aztreonam following single 500 mg or 1 g (intramuscular or intravenous) or 2 g (intravenous) doses of AZACTAM exceed the MIC₉₀ for Neisseria sp., Haemophilus influenzae and most genera of the Enterobacteriaceae for 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 AZACTAM 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 2.0) 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 AZACTAM 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 µg/mL, 3500 µg/mL, and 6600 µg/mL within the first 2 hours following single 500 mg, 1 g, and 2 g intravenous doses of AZACTAM (30-minute infusions), respectively. The range of average concentrations for aztreonam in the 8- to 12-hour urine specimens in these studies was 25 µg/mL to 120 µg/mL. After intramuscular injection of single 500 mg and 1 g doses of AZACTAM (aztreonam for injection, USP), urinary levels were approximately 500 µg/mL and 1200 µg/mL, respectively, within the first 2 hours, declining to 180 µg/mL and 470 µg/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 AZACTAM 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-β-glucosaminidase, alanine aminopeptidase and β₂-microglobulin) were used. No abnormal results were obtained.

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

EXTRAVASCULAR CONCENTRATIONS OF AZTREONAM AFTER A SINGLE PARENTERAL DOSE¹

The concentration of aztreonam in saliva at 30 minutes after a single 1 g intravenous dose (9 patients) was 0.2 µg/mL; in human milk at 2 hours after a single 1 g intravenous dose (6 patients), 0.2 µg/mL, and at 6 hours after a single 1 g intramuscular dose (6 patients), 0.3 µg/mL; in amniotic fluid at 6 to 8 hours after a single 1 g intravenous dose (5 patients), 2 µg/mL. The concentration of aztreonam in peritoneal fluid obtained 1 to 6 hours after multiple 2 g intravenous doses ranged between 12 µg/mL and 90 µg/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 AZACTAM (aztreonam for injection, USP) 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 (ie, 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 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 µg/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, eg, 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 influenzae^a:

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:

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 µg 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 µg aztreonam disk should be interpreted according to the following criteria:

For testing aerobic microorganisms other than Haemophilus influenzae:

When testing Haemophilus influenzae^a:

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 µg aztreonam disk should provide the following zone diameters in these laboratory test quality control strains.

Clinical Studies

A total of 612 pediatric patients aged 1 month to 12 years were enrolled in uncontrolled clinical trials of aztreonam in the treatment of serious gram-negative infections, including urinary tract, lower respiratory tract, skin and skin-structure, and intra-abdominal infections.

REFERENCES

1. Naber KG, Dette GA, Kees F, Knothe H, Grobecker H. Pharmacokinetics, in vitro activity, therapeutic efficacy, and clinical safety of aztreonam vs. cefotaxime in the treatment of complicated urinary tract infections. J Antimicrob Chemother 1986; 17:517-527.

2. Creasey WA, Platt TB, Frantz M, Sugerman AA. Pharmacokinetics of aztreonam in elderly male volunteers. Br J Clin Pharmacol 1985; 19:233-237.

3. Meyers BR, Wilkinson P, Mendelson MH, et al. Pharmacokinetics of aztreonam in healthy elderly and young adult volunteers. J Clin Pharmacol 1993; 33:470-474.

4. Sattler FR, Schramm M, Swabb EA. Safety of aztreonam and SQ 26,992 in elderly patients with renal insufficiency. Rev Infect Dis 1985; 7 (suppl 4):S622-S627.

5. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January 2000.

6. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests—Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January 2000.

Last reviewed on RxList: 8/28/2009
This monograph has been modified to include the generic and brand name in many instances.