fibrin and Haemophilus-Infections

Before applying in clinical practice once-daily dosing of antimicrobials, one must take into consideration several factors that may influence the pharmacodynamic interaction between antimicrobials and microbes at the site of infection. The ideal agent should demonstrate rapid concentration-dependent killing activity and a post-antibiotic effect that could allow for a clinically significant delay with levels below the minimal inhibitory concentration before regrowth of the microorganism. The pharmacokinetic properties of the antibiotic should allow for a good therapeutic ratio (concentration/MIC) at the site of infection. To evaluate the importance of dosage schedule on outcome, investigators have to use animal models where peak levels, half-life, area under the curve, time above MIC in interstitial fluid or infected tissues, and other pharmacodynamic properties can be evaluated simultaneously. The pharmacodynamics of several antibiotics administered at different dosing interval is compared using an animal model of infected fibrin clots. In this model, once-daily therapy resulted in better killing than other modes of administration. Aminoglycosides and quinolones may be better suited for once-daily therapy than beta-lactams unless these latter agents have a long half-life.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Disease Models, Animal; Drug Administration Schedule; Drug Evaluation, Preclinical; Fibrin; Haemophilus Infections; Haemophilus influenzae; Humans; Lactams; Microbial Sensitivity Tests; Rabbits

The extravascular penetration and bactericidal activity of aztreonam, cefuroxime, and ampicillin against beta-lactamase-positive and -negative Haemophilus influenzae strains were compared in a rabbit model. All groups of animals received an identical total dose of 100 mg of either antibiotic per kg given by four different intravenous modes of administration including a single large injection, four intermittent injections, a continuous infusion, and an injection followed by an infusion. Aztreonam had a higher degree of penetration in interstitial fluid and fibrin clots and was the most effective agent against beta-lactamase-positive and -negative H. influenzae. A single large injection of either drug resulted in significantly higher peak levels and higher initial area under the curves of concentrations of drugs in serum, the interstitial fluid, and fibrin clots than those by other modes of administration. Continuous infusions of antibiotics resulted in poor in vivo bactericidal activity. Other modes of administration exhibited good antibacterial activity within the first 6 h of the study. Thereafter, a single large injection of aztreonam resulted in a much more rapid killing of H. influenzae than that by injection of the other drugs. Aztreonam and cefuroxime showed good in vivo stability to beta-lactamase produced by H. influenzae while ampicillin was rapidly hydrolyzed in vivo.

Topics: Ampicillin; Animals; Aztreonam; beta-Lactamases; Cefuroxime; Cephalosporins; Extracellular Space; Female; Fibrin; Haemophilus Infections; Haemophilus influenzae; Microbial Sensitivity Tests; Rabbits