ABSTRACTAnin vitrodilutional pharmacokinetic model of infection was used to study the pharmacodynamics of doripenem in terms of the ability to killPseudomonas aeruginosaorAcinetobacter baumanniiand also changes in their population profiles. In dose-ranging studies, the cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMICs) required for doripenem to produce a 24-h bacteriostatic effect and a −2-log-unit reduction in viable count were 25% ± 11% and 35% ± 13%, respectively, forP. aeruginosa(MIC range, 0.24 to 3 mg/liter) and 20% ± 11% and 33% ± 12%, respectively, forAcinetobacterspp. (MIC range, 0.45 to 3.0 mg/liter). ATMICof >40 to 50% produced a maximum response with both species at 24 h or 48 h of exposure. After 24 h of exposure to doripenem at aTMICin the range of 12.5 to 37.5%,P. aeruginosaandA. baumanniipopulation profiles revealed mutants able to grow on 4× MIC-containing medium; such changes were further amplified by 48 h of exposure. Dose-fractionation experiments targetingTMICs of 12.5%, 25%, or 37.5% as six exposures, two exposures, or a single exposure over 48 h with a single strain ofP. aeruginosaindicated that changes in population profiles were greatest with multiple exposures atTMICtargets of 12.5 or 25%. In contrast, multiple exposures at 37.5%TMICmost effectively suppressed total bacterial counts and changes in population profiles. Simulations of human doses of doripenem of 500 mg, 1,000 mg, 2,000 mg, and 3,000 mg every 8 h over 96 h showed marked initial killing up to 6 h but growback thereafter. Changes in population profiles occurred only in the regimen of 500 mg every 8 h againstP. aeruginosabut occurred with all dose regimens forA. baumanniistrains. A doripenemTMICof ≥40 to 50% is maximally effective in killingP. aeruginosaorA. baumanniiand suppressing changes in population profiles in short-term experiments for up to 48 h; however, aTMICof 12.5 to 25% amplifies population changes, especially with exposures every 8 h. In longer-term experiments, up to 96 h, even doripenem doses of 4 to 6 times those used in human studies proved incapable of pathogen eradication and prevention of changes in population profiles. The association of aTMICof 25 to 37.5% with changes in population profiles has implications in terms of future clinical breakpoint setting.
Yoğun Bakım Ünitelerinden İzole Edilen Çok İlaca Dirençli Pseudomonas aeruginosa ve Acinetobacter baumannii Suşlarına Karşı Çeşitli Antimikrobiyallerin İn Vitro Aktiviteleri
