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® (aztreonamfor 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 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 is a sterile, nonpyrogenic, sodium-free,white powder 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.

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 54mcg/mL, 90 mcg/mL, and 204 mcg/mL,respectively, immediately after administration; at 8 hours, serum levels were1 mcg/mL, 3mcg/mL, and 6 mcg/mL, respectively (Figure 1).Single 3-minute intravenous injections of the same doses resulted in serumlevels of 58 mcg/mL, 125mcg/mL, and 242 mcg/mL at 5 minutesfollowing completion of injection.

Serum concentrationsof aztreonam in healthy subjects following completion of single intramuscularinjections of 500 mg and 1 g doses are depicted in Figure 1; maximum serumconcentrations occur at about 1 hour. After identical single intravenous orintramuscular doses of AZACTAM, the serum concentrations of aztreonam arecomparable at 1 hour (1.5 hours from start of intravenous infusion) with similarslopes of serum concentrations thereafter.

FIGURE 1

The serum levels of aztreonam following single 500 mg or1 g (intramuscular or intravenous) or 2 g (intravenous) doses of AZACTAM exceedthe 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,a single 2g intravenous dose produces serum levels thatexceed the MIC90 for approximately 4 to 6 hours. Allof the above doses of AZACTAM result in average urine levels of aztreonamthat exceed the MIC90 for the same pathogens for upto 12 hours.

When aztreonam pharmacokinetics were assessedfor adult and pediatric patients, they were found to be comparable (down to9 months old). The serum half-life of aztreonam averaged 1.7 hours (1.5-2.0)in subjects with normal renal function, independent of the dose and routeof administration. In healthy subjects, based on a 70 kg person, the serumclearance was 91mL/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.

Inelderly patients, the mean serum half-life of aztreonam increased and therenal clearance decreased, consistent with the age-related decrease in creatinineclearance.1-4 The dosage of AZACTAM should be adjustedaccordingly (see DOSAGE AND 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. After intramuscularinjection of single 500 mg and 1 g doses of AZACTAM, urinary levels were approximately500 mcg/mL and 1200 mcg/mL, respectively, within the first 2 hours, decliningto 180 mcg/mL 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 secretionand glomerular filtration. Approximately 60% to 70% of an intravenous or intramusculardose was recovered in the urine by 8 hours. Urinary excretion of a singleparenteral 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.

Intravenousor intramuscular administration of a single 500 mg or 1 g dose of AZACTAMevery 8 hours for 7 days to healthy subjects produced no apparent accumulationof aztreonam or modification of its disposition characteristics; serum proteinbinding averaged 56% and was independent of dose. An average of about 6% ofa 1 g intramuscular dose was excreted as a microbiologically inactive openbeta-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 multipledosing.

Renal function was monitored in healthy subjectsgiven 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.

Aztreonamachieves measurable concentrations in the following body fluids and tissues: