An in vitro pharmacokinetic model was used to study the comparative antibacterial activities of multiple-dose regimens of enoxacin and netilmicin. Strains of Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Staphylococcus aureus were exposed to changing drug concentrations, mimicking human twocompartment pharmacokinetics. Oral administration was simulated for the quinolone, and intravenous administration was simulated for the aminoglycoside. Similar ratios of peak concentration to MIC resulted in similar changes in bacterial concentrations over time with both compounds. Following the initial dose, a rapid bactericidal effect occurred, with a >99% reduction of the bacterial counts within 4 h at peak concentrations more than three times the MIC. However, bacterial regrowth occurred within 24 h un,less the peak concentration/MIC ratio exceeded 8:1 (P < 0.01). For the regrowing bacteria, MICs were four-to eightfold higher, and little or no bactericidal effect occurred following the second and subsequent doses. These data demonstrate the equally potent bactericidal activity of orally administered enoxacin and intravenously administered netilmicin. Selection of resistant subpopulations was similar with each drug. The peak concentration/MIC ratio may be an important parameter in the clinical use of quinolone and aniinoglycoside antibiotics.

Simultaneous administration of two drugs is frequently practised in clinical chemotherapy because of the synergistic potential of drug combinations. During in-vitro testing of the effect of such drug combinations, differences in the pharmacokinetic properties of the two drugs should be considered. This paper presents the mathematical background and the technical components of an in-vitro model that allows the simultaneous simulation of first order elimination kinetics of two drugs with different half-lives. The model allows simulations of multiple dose regimens of either bolus injections or continuous infusions of each drug.

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A two compartment in-vitro model was designed to simulate human pharmacokinetics and to expose bacterial cultures to changing drug concentrations, thereby avoiding limitations of conventional antibiotic testing at constant drug levels. Serially placed bacterial compartments, representing extravascular infection sites, interface with a central compartment through artificial capillaries. Drug concentrations within the culture chambers closely mimic interstitial concentrations in vivo. Simultaneous first order elimination kinetics of two drugs with different half-lives were simulated to study antibacterial effects of drug combinations. This in-vitro model is an efficient tool for optimal dosage regimen design and the study of synergistic/antagonistic effects of antibiotic combinations.