AZTREONAM Clinical Pharmacology

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

FIGURE 1

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 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 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. 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 1,100 mcg/mL, 3,500 mcg/mL, and 6,600 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 mcg/mL and 1,200 mcg/mL, respectively, within the first 2 hours, declining to 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 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-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:

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 mcg/mL 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 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.