Toreduce the development of drug-resistant bacteria and maintain the effectivenessof AZACTAM® and other antibacterial drugs, AZACTAMshould be used only to treat or prevent infections that are proven or stronglysuspected to be caused by bacteria.

DESCRIPTION

AZACTAM® (aztreonaminjection) contains the active ingredient aztreonam, a monobactam. It wasoriginally isolated from Chromobacterium violaceum. It isa synthetic bactericidal antibiotic.

The monobactams,having a unique monocyclic beta-lactam nucleus, are structurally differentfrom other beta-lactam antibiotics (eg, penicillins, cephalosporins, cephamycins).The sulfonic acid substituent in the 1-position of the ring activates thebeta-lactam moiety; an aminothiazolyl oxime side chain in the 3-position anda methyl group in the 4-position confer the specific antibacterial spectrumand beta-lactamase stability.

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

C13H17N5O8S2MW435.44

AZACTAM in the GALAXY plastic container (PL 2040) is afrozen, iso-osmotic, sterile, sodium-free, nonpyrogenic intravenous solution.Each 50 mL of solution contains 1 g, or 2 g aztreonam with approximately 1.7g, or 700 mg Dextrose Hydrous, USP added to adjust osmolality,and approximately 780 mg, or 1.6 g of arginine added for pH adjustment, respectively.Thawed solutions have a pH in the range of 4.5 to 7.5. The solution is forintravenous administration following thawing at room temperature or underrefrigeration.

This GALAXY container is fabricatedfrom a specially designed multilayer plastic (PL 2040). Solutions are in contactwith the polyethylene layer of this container and can leach out certain chemicalcomponents of the plastic in very small amounts within the expiration period.The suitability of the plastic has been confirmed in tests in animals accordingto the USP biological tests for plastic containers as well as by tissue culturetoxicity studies.

CLINICAL PHARMACOLOGY

Single 30-minute intravenous infusionsof 500 mg, 1 g, and 2 g doses of AZACTAM in healthy subjects produced aztreonampeak serum levels of 54 mcg/mL, 90 mcg/mL, and 204mcg/mL,respectively, immediately after administration; at 8 hours, serum levels were1mcg/mL, 3mcg/mL, and 6 mcg/mL, respectively(Figure 1). Single 3-minute intravenous injections of the same doses resultedin serum levels of 58 mcg/mL, 125 mcg/mL, and 242 mcg/mL at 5 minutes followingcompletion of injection.

Serum concentrations of aztreonamfollowing completion of single intravenous infusions of 500 mg, 1 g, and 2g doses are depicted in Figure 1.

FIGURE 1

The serum levels of aztreonam following single 500 mg,1 g, or 2 g intravenous doses of AZACTAM exceed the MIC90 for Neisseria sp., Haemophilusinfluenzae, and most genera of the Enterobacteriaceae for8 hours (for Enterobacter sp., the 8-hour serum levels exceedthe MIC for 80% of strains). For Pseudomonas aeruginosa, asingle 2g intravenous dose produces serum levels that exceedthe MIC90 for approximately 4 to 6 hours. All of theabove doses of AZACTAM result in average urine levels of aztreonam that exceedthe MIC90 for the same pathogens for up to 12 hours.

Whenaztreonam pharmacokinetics were assessed for adult and pediatric patients,they were found to be comparable (down to 9 months old). The serum half-lifeof aztreonam averaged 1.7 hours (1.5-2.0) in subjects with normal renal function,independent of the dose. In healthy subjects, based on a 70 kg person, theserum clearance was 91 mL/min and renal clearance was 56 mL/min; the apparentmean volume of distribution at steady-state averaged 12.6 liters, approximatelyequivalent to extracellular fluid volume.

In elderlypatients, the mean serum half-life of aztreonam increased and the renal clearancedecreased, consistent with the age-related decrease in creatinine clearance.1-4 Thedosage of AZACTAM should be adjusted accordingly (see DOSAGEAND ADMINISTRATION: Renal Impairment in Adult Patients).

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

Averageurine concentrations of aztreonam were approximately 1100 mcg/mL, 3500 mcg/mL,and 6600 mcg/mL within the first 2 hours following single 500 mg, 1 g, and2 g intravenous doses of AZACTAM (30-minute infusions), respectively. Therange of average concentrations for aztreonam in the 8- to 12-hour urine specimensin these studies was 25 to 120mcg/mL. In healthysubjects, aztreonam is excreted in the urine about equally by active tubularsecretion and glomerular filtration. Approximately 60% to 70% of an intravenousdose was recovered in the urine by 8 hours. Urinary excretion of a singleintravenous dose was essentially complete by 12 hours after injection. About12% of a single intravenous radiolabeled dose was recovered in the feces.Unchanged aztreonam and the inactive beta-lactam ring hydrolysis product ofaztreonam were present in feces and urine.

Intravenousadministration of a single 500 mg or 1 g dose of AZACTAM every 8 hours for7 days to healthy subjects produced no apparent accumulation of aztreonamor modification of its disposition characteristics; serum protein bindingaveraged 56% and was independent of dose.

Renal functionwas 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, alanineaminopeptidase, and β2-microglobulin) were used. Noabnormal results were obtained.

Aztreonam achievesmeasurable concentrations in the following body fluids and tissues: