Edward A. Swabb

Investigation into the immunologic cross-reactivity of aztreonam with other beta-lactam antibiotics☆

The cross-reactivity between the monobactam antibiotic aztreonam and the commonly used beta-lactam antibiotics, penicillins, and cephalosporins was investigated. Antibodies to aztreonam, penicillin, and cephalothin were raised in rabbits. The ability of the homologous or heterologous drug or drug conjugates to inhibit antibody binding was assessed in a solid-phase radioimmunoassay. Aztreonam demonstrated very little ability to interact with anti-penicillin or anti-cephalothin antibodies as it required 10,000-fold higher concentrations than other beta-lactams to achieve equivalent blocking. Similarly, penicillin and cephalothin conjugates did not cross-react, to any significant degree, with anti-aztreonam rabbit antiserums. Interestingly, free aztreonam was as effective as conjugated aztreonam in reacting with antibodies raised against conjugated aztreonam. This result suggested that, in contrast to the other beta-lactams, antibodies to aztreonam recognize the side chain rather than the nuclear structures. Studies with other beta-lactam analogs confirmed that the IgG rabbit anti-aztreonam binding was indeed side chain-specific. Thirty-six volunteers were given a seven-day course of therapeutic doses of aztreonam and in none did any detectable IgE anti-aztreonam antibodies develop. Four of these subjects had evidence of preexisting IgG antibodies cross-reactive with aztreonam, but the levels rose in only one patient following drug exposure. This human IgG anti-aztreonam was also directed to the side chain and did not cross-react with cephalothin or penicillin. The ability of aztreonam to cross-react with human IgE to various penicillin determinants was also investigated. Aztreonam determinants analogous to the penicillin determinants (penicillin, penicilloyl, and penicilloate) were constructed and the maximal concentration that did not evoke false-positive skin test results was determined to be 6 X 10(-3) mol/liter. None of 41 patients with documented IgE-reactive skin tests to various penicillin determinants concurrently demonstrated reproducible reactivity to any aztreonam reagents. IgE anti-penicilloyl antibodies from three persons were also tested in vitro for their ability to cross-react with conjugated or free aztreonam. Minimal, if any, reactivity was observed between the IgE anti-penicilloyl and any of the aztreonam materials. These results indicate that there is very little cross-reactivity between the monobactam aztreonam and other beta-lactam antibiotics.

Prediction of aztreonam pharmacokinetics in humans based on data from animals

Interspecies correlations of pharmacokinetic parameters obtained in animals were used to predict human pharmacokinetics in order to design the first clinical study of an investigational drug. The serum pharmacokinetics of aztreonam, a novel monocyclic beta-lactam antibiotic, were described for mice, rats, rabbits, and monkeys, using serum clearance and apparent volume of distribution. A one-compartment pharmacokinetic model yielded predictions for aztreonam clinical pharmacokinetics that were very helpful in choosing doses and serum sampling times for the first kinetic study in healthy male volunteers. Predicted serum aztreonam concentrations agreed well with subsequently measured values in man.

Review of the clinical pharmacology of the monobactam antibiotic aztreonam

Serum and urine levels of aztreonam after 0.5, 1, and 2 g doses are potentially therapeutic for susceptible gram-negative organisms. Aztreonam is widely distributed in body fluids and tissues, and concentrations exceeding the minimal inhibitory concentrations of important gram-negative pathogens are attained in those compartments in which infections are most common. Aztreonam is eliminated primarily in the urine in unchanged form, although it is also secreted into the bile and is metabolized to a minor extent. Renal insufficiency may significantly impair the elimination of aztreonam, thus requiring modification of the dosage regimen. The monobactam can be cleared by hemodialysis but is only minimally cleared by peritoneal dialysis. Parenterally and orally administered aztreonam can selectively reduce the population of aerobic gram-negative bacteria in the gut without notably altering the number of anaerobic organisms.

Renal handling of the monobactam azthreonam in healthy subjects

Azthreonam is a new completely synthetic, monocyclic beta‐lactam antibiotic with potent activity in vitro against most gram‐negative aerobic bacteria. Its renal handling was studied in six healthy men after an intravenous loading dose of 1200 mg over 2 min followed by a continuous infusion of 500 mg/hr for 4 hr with and without oral probenecid (1 gm b.i.d. for 2 days before azthreonam infusion and during the day of infusion). To assess glomerular filtration, each subject also received an intravenous loading dose and continuous infusion of inulin. Azthreonam was excreted in the urine by glomerular filtration and tubular secretion in essentially equal proportions. Probenecid reduced plasma clearance of azthreonam by suppressing renal tubular secretion, without altering glomerular filtration rate or nonrenal elimination. Probenecid increased total and free azthreonam levels and the azthreonam plasma t½ while reducing plasma protein binding and the apparent steady‐state volume of distribution.