How and why aztreonam works.

Aztreonam is the first monocyclic beta-lactam antibiotic (monobactam) to be tested clinically. Its synthetic structure determines specific areas of activity, including enhanced activity against Pseudomonas species, exceptional activity against gram-negative bacteria, stability to beta-lactamases and lack of activity against gram-positive bacteria--all of which can be directly related to its chemical composition. Aztreonam has a high affinity for the protein-binding protein 3 (PBP-3) of aerobic gram-negative bacteria. Most of these organisms are inhibited and killed at low concentrations of the drug. Aztreonam binds poorly to PBP sites of the aerobic gram-positive and anaerobic bacteria and consequently has relatively poor inhibitory effects against these bacteria. In vitro, minimum inhibition concentration (MIC) values against almost all of the Enterobacteriaceae and against Neisseria and Haemophilus strains are typically below 1 microgram per milliliter. MIC values against Pseudomonas aeruginosa of 8 micrograms per milliliter are comparable with those of other antipseudomonal beta-lactams and the acylureidopenicillins. As combination therapy with amino-glycosides, aztreonam acts in synergy against P. aeruginosa, Acinetobacter and gentamicin-resistant gram-negative rods. Aztreonam is widely distributed in the body tissues and fluids, and the average elimination half-life is 1.7 hours. Intramuscular dosing results in peak serum levels in approximately one hour, while intravenous dosing results in peak levels within five minutes. After a 2 gram dose given intravenously, MIC90 values for most of the Enterobacteriaceae are exceeded for eight hours, and those for P. aeruginosa, for almost six hours. The steady-state volume of distribution is approximately 0.18 liter per kilogram. Concentrations above the MIC90 for most gram-negative bacteria are also present within bone, prostate and cerebrospinal fluid. Between 60 and 70 per cent of the drug is excreted unchanged in the urine, resulting in concentrations approximating 3,000 micrograms per milliliter two hours after a 1 gram dose given intravenously. Serum clearance of aztreonam is directly proportional to creatinine clearance. Dosage adjustment must, therefore, be made in the presence of reduced clearance. Dosing varies between 0.5 and 2.0 grams every six to 12 hours, depending on the severity of the infection. The characteristics of aztreonam suggest that it is a useful nonnephrotoxic drug for treatment of aerobic gram-negative infection.