Dataset Information

Combinatorial Pharmacodynamics of Ceftolozane-Tazobactam against Genotypically Defined ?-Lactamase-Producing Escherichia coli: Insights into the Pharmacokinetics/Pharmacodynamics of ?-Lactam-?-Lactamase Inhibitor Combinations.

ABSTRACT: Despite a dearth of new agents currently being developed to combat multidrug-resistant Gram-negative pathogens, the combination of ceftolozane and tazobactam was recently approved by the Food and Drug Administration to treat complicated intra-abdominal and urinary tract infections. To characterize the activity of the combination product, time-kill studies were conducted against 4 strains ofEscherichia colithat differed in the type of ?-lactamase they expressed. The four investigational strains included 2805 (no ?-lactamase), 2890 (AmpC ?-lactamase), 2842 (CMY-10 ?-lactamase), and 2807 (CTX-M-15 ?-lactamase), with MICs to ceftolozane of 0.25, 4, 8, and >128 mg/liter with no tazobactam, and MICs of 0.25, 1, 4, and 8 mg/liter with 4 mg/liter tazobactam, respectively. All four strains were exposed to a 6 by 5 array of ceftolozane (0, 1, 4, 16, 64, and 256 mg/liter) and tazobactam (0, 1, 4, 16, and 64 mg/liter) over 48 h using starting inocula of 10(6)and 10(8)CFU/ml. While ceftolozane-tazobactam achieved bactericidal activity against all 4 strains, the concentrations of ceftolozane and tazobactam required for a ?3-log reduction varied between the two starting inocula and the 4 strains. At both inocula, the Hill plots (R(2)> 0.882) of ceftolozane revealed significantly higher 50% effective concentrations (EC50s) at tazobactam concentrations of ?4 mg/liter than those at concentrations of ?16 mg/liter (P< 0.01). Moreover, the EC50s at 10(8)CFU/ml were 2.81 to 66.5 times greater than the EC50s at 10(6)CFU/ml (median, 10.7-fold increase;P= 0.002). These promising results indicate that ceftolozane-tazobactam achieves bactericidal activity against a wide range of ?-lactamase-producingE. colistrains.

SUBMITTER: Soon RL

PROVIDER: S-EPMC4808171 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Publications

Combinatorial Pharmacodynamics of Ceftolozane-Tazobactam against Genotypically Defined β-Lactamase-Producing Escherichia coli: Insights into the Pharmacokinetics/Pharmacodynamics of β-Lactam-β-Lactamase Inhibitor Combinations.

Soon Rachel L RL Lenhard Justin R JR Bulman Zackery P ZP Holden Patricia N PN Kelchlin Pamela P Steenbergen Judith N JN Friedrich Lawrence V LV Forrest Alan A Tsuji Brian T BT

Antimicrobial agents and chemotherapy 20160325 4

Despite a dearth of new agents currently being developed to combat multidrug-resistant Gram-negative pathogens, the combination of ceftolozane and tazobactam was recently approved by the Food and Drug Administration to treat complicated intra-abdominal and urinary tract infections. To characterize the activity of the combination product, time-kill studies were conducted against 4 strains ofEscherichia colithat differed in the type of β-lactamase they expressed. The four investigational strains i ...[more]

PMID: 26729494

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Project description: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 ?-lactamase-producing bacteria, including most extended-spectrum-?-lactamase (ESBL)-positive Enterobacteriaceae. The pharmacodynamics of ?-lactam-?-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 ?-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.

Project description:Background and objectivesCurrent recommendations for piperacillin-tazobactam dosing in patients receiving continuous renal replacement therapy originate from studies with relatively few patients and lower continuous renal replacement therapy doses than commonly used today. This study measured the pharmacokinetic and pharmacodynamic characteristics of piperacillin-tazobactam in patients treated with continuous renal replacement therapy using contemporary equipment and prescriptions.Design, setting, participants, & measurementsA multicenter prospective observational study in the intensive care units of two academic medical centers was performed, enrolling patients with AKI or ESRD receiving piperacillin-tazobactam while being treated with continuous renal replacement therapy. Pregnant women, children, and patients with end stage liver disease were excluded from enrollment. Plasma and continuous renal replacement therapy effluent samples were analyzed for piperacillin and tazobactam levels using HPLC. Pharmacokinetic and pharmacodynamic parameters were calculated using standard equations. Multivariate analyses were used to examine the association of patient and continuous renal replacement therapy characteristics with piperacillin pharmacokinetic parameters.ResultsForty-two of fifty-five subjects enrolled had complete sampling. Volume of distribution (median=0.38 L/kg, intraquartile range=0.20 L/kg) and elimination rate constants (median=0.104 h(-1), intraquartile range=0.052 h(-1)) were highly variable, and clinical parameters could explain only a small fraction of the large variability in pharmacokinetic parameters. Probability of target attainment for piperacillin was 83% for total drug but only 77% when the unbound fraction was considered.ConclusionsThere is significant patient to patient variability in pharmacokinetic/pharmacodynamic parameters in patients receiving continuous renal replacement therapy. Many patients did not achieve pharmacodynamic targets, suggesting that therapeutic drug monitoring might optimize therapy.

Dataset Information

Combinatorial Pharmacodynamics of Ceftolozane-Tazobactam against Genotypically Defined ?-Lactamase-Producing Escherichia coli: Insights into the Pharmacokinetics/Pharmacodynamics of ?-Lactam-?-Lactamase Inhibitor Combinations.

Publications

Combinatorial Pharmacodynamics of Ceftolozane-Tazobactam against Genotypically Defined β-Lactamase-Producing Escherichia coli: Insights into the Pharmacokinetics/Pharmacodynamics of β-Lactam-β-Lactamase Inhibitor Combinations.

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