Influence of three modes of administration on the penetration of latamoxef into interstitial fluid and fibrin clots and its in-vivo activity against Haemophilus influenzae.

The extravascular penetration and bactericidal activity of latamoxef against beta-lactamase positive Haemophilus influenzae were studied in a rabbit model. All groups of animals received over 24 h an identical dose of 100 mg/kg of latamoxef given by three different intravenous modes of administration including a single large injection of 100 mg/kg, four 25 mg/kg intermittent injections every 6 h, and a continuous infusion of 100 mg/kg over 24 h. A single large injection resulted in significantly higher peak levels and higher initial area under the curve of concentrations of drug in serum, interstitial fluid, and fibrin clots than other modes of administration. Continuous infusion resulted in an accumulation of drug in clots which rose from 1.0 microgram/g at 4 h to 4.9 micrograms/g at 24 h (P value less than 0.01). The rate of killing of H. influenzae imbedded in fibrin clots was greatly influenced by the different modes of therapy. Even though all regimens resulted in peak concentrations which were more than 80 times the MIC (0.03 mg/l) in the fibrin clots, rapid killing (from 10(7) to less than 10(2) micro-organisms per g of clots in less than 6 h) was only observed with a single bolus. Continuous infusion and intermittent injections of latamoxef resulted in limited in-vivo bactericidal activity. Large doses of latamoxef given at long intervals may be more effective than intermittent dosing or continuous infusion.