ABSTRACT
Ceftolozane plus tazobactam is an antipseudomonal cephalosporin combined with tazobactam, an established beta-lactamase inhibitor, and has in vitro potency against a range of clinically important ß-lactamase-producing bacteria, including most extended-spectrum-ß-lactamase (ESBL)-positive Enterobacteriaceae. The pharmacodynamics of ß-lactam-ß-lactamase inhibitor combinations presents a number of theoretical and practical challenges, including modeling different half-lives of the compounds. In this study, we studied the pharmacodynamics of ceftolozane plus tazobactam against Escherichia coli and Pseudomonas aeruginosa using an in vitro pharmacokinetic model of infection. Five strains of E. coli, including three clinical strains plus two CTX-M-15 (one high and one moderate) producers, and five strains of P. aeruginosa, including two with OprD overexpression and AmpC ß-lactamases, were employed. Ceftolozane MICs (E. coli, 0.12 to 0.25 mg/liter, and P. aeruginosa, 0.38 to 8 mg/liter) were determined in the presence of 4 mg/liter tazobactam. Dose ranging of ceftolozane (percentage of time in which the free-drug concentration exceeds the MIC [fT>MIC], 0 to 100%) plus tazobactam (human pharmacokinetics) was simulated every 8 hours, with half-lives (t1/2) of 2.5 and 1 h, respectively. Ceftolozane and tazobactam concentrations were confirmed by high-performance liquid chromatography (HPLC). The ceftolozane-plus-tazobactam fT>MIC values at 24 h for a static effect and a 1-log and 2-log drop in initial inoculum for E. coli were 27.8% ± 5.6%, 33.0% ± 5.6%, and 39.6% ± 8.5%, respectively. CTX-M-15 production did not affect the 24-h fT>MIC for E. coli strains. The ceftolozane-plus-tazobactam fT>MIC values for a 24-h static effect and a 1-log and 2-log drop for P. aeruginosa were 24.9% ± 3.0%, 26.6% ± 3.9%, and 31.2% ± 3.6%. Despite a wide range of absolute MICs, the killing remained predictable as long as the MICs were normalized to the corresponding fT>MIC. Emergence of resistance on 4× MIC plates and 8× MIC plates occurred maximally at an fT>MIC of 10 to 30% and increased as time of exposure increased. The fT>MIC for a static effect for ceftolozane plus tazobactam is less than that observed with other cephalosporins against E. coli and P. aeruginosa and is more similar to the fT>MIC reported for carbapenems.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Cephalosporins/pharmacokinetics , Escherichia coli/drug effects , Models, Statistical , Penicillanic Acid/analogs & derivatives , Pseudomonas aeruginosa/drug effects , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Bioreactors , Cephalosporins/pharmacology , Chromatography, High Pressure Liquid , Colony Count, Microbial , Computer Simulation , Escherichia coli/enzymology , Escherichia coli/genetics , Gene Expression , Half-Life , Infusion Pumps , Microbial Sensitivity Tests , Penicillanic Acid/pharmacokinetics , Penicillanic Acid/pharmacology , Porins/genetics , Porins/metabolism , Pseudomonas aeruginosa/enzymology , Pseudomonas aeruginosa/genetics , Tazobactam , beta-Lactamases/genetics , beta-Lactamases/metabolismABSTRACT
An in vitro dilutional pharmacokinetic model of infection was used to study the pharmacodynamics of doripenem in terms of the ability to kill Pseudomonas aeruginosa or Acinetobacter baumannii and 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 (T(MIC)s) 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, for P. aeruginosa (MIC range, 0.24 to 3 mg/liter) and 20% ± 11% and 33% ± 12%, respectively, for Acinetobacter spp. (MIC range, 0.45 to 3.0 mg/liter). A T(MIC) of >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 a T(MIC) in the range of 12.5 to 37.5%, P. aeruginosa and A. baumannii population profiles revealed mutants able to grow on 4× MIC-containing medium; such changes were further amplified by 48 h of exposure. Dose-fractionation experiments targeting T(MIC)s of 12.5%, 25%, or 37.5% as six exposures, two exposures, or a single exposure over 48 h with a single strain of P. aeruginosa indicated that changes in population profiles were greatest with multiple exposures at T(MIC) targets of 12.5 or 25%. In contrast, multiple exposures at 37.5% T(MIC) most 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 against P. aeruginosa but occurred with all dose regimens for A. baumannii strains. A doripenem T(MIC) of ≥40 to 50% is maximally effective in killing P. aeruginosa or A. baumannii and suppressing changes in population profiles in short-term experiments for up to 48 h; however, a T(MIC) of 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 a T(MIC) of 25 to 37.5% with changes in population profiles has implications in terms of future clinical breakpoint setting.
