Influence of four modes of administration on penetration of aztreonam, cefuroxime, and ampicillin into interstitial fluid and fibrin clots and on in vivo efficacy against Haemophilus influenzae

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.