Pharmacodynamics of Ceftolozane plus Tazobactam Studied in an In Vitro Pharmacokinetic Model of Infection

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 ␤-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 (t 1/2 ) 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. Ceftolozane plus tazobactam is a novel antibacterial consisting of a combination of the new cephalosporin ceftolozane with a well-established ␤-lactamase inhibitor, i.e., tazobactam. The combination has completed phase 3 clinical trials for complicated intra-abdominal and complicated urinary tract infections (1, 2). It was recently approved in the United States for these indications and is undergoing regulatory review in the European Union.The in vitro potency of ceftolozane plus 4 mg/liter tazobactam has been studied against Pseudomonas aeruginosa and members of the Enterobacteriaceae from the United States and Europe (3-5). Ceftolozane plus tazobactam was the most active ␤-lactam agent when tested against multidrug-...

Ceftolozane/tazobactam: place in therapy

“…Similar results were recently obtained in an in vitro pharmacokinetic model of infection, against both E. coli and P. aeruginosa [57]. The %T>MIC for 1-log and 2-log decrease in initial inoculum for E.coli were 33.0% and 39.6%, respectively, and CTX-M-15 production did not affect this pharmacodynamic index [57]. For P. aeruginosa, the %T>MIC for 1-log and 2-log decrease in initial inoculum were 26.6% and 31.2%, respectively [57].…”

“…In the same study, it was shown that ceftolozane had faster rate of in vivo killing of P. aeruginosa A c c e p t e d M a n u s c r i p t than ceftazidime, and that the most potent combination with tazobactam against ESBLproducing Enterobacteriaceae could be obtained using a 2:1 ratio (2000 mg of ceftolozane and 1000 mg of tazobactam) [56]. Similar results were recently obtained in an in vitro pharmacokinetic model of infection, against both E. coli and P. aeruginosa [57]. The %T>MIC for 1-log and 2-log decrease in initial inoculum for E.coli were 33.0% and 39.6%, respectively, and CTX-M-15 production did not affect this pharmacodynamic index [57].…”

“…The %T>MIC for 1-log and 2-log decrease in initial inoculum for E.coli were 33.0% and 39.6%, respectively, and CTX-M-15 production did not affect this pharmacodynamic index [57]. For P. aeruginosa, the %T>MIC for 1-log and 2-log decrease in initial inoculum were 26.6% and 31.2%, respectively [57]. Concerning the desired drug exposure for ESBL producers,…”

Ex vivo Ceftolozane/Tazobactam Clearance during Continuous Renal Replacement Therapy

“…Optimal drug doses were defined as the smallest practical daily dose resulting in at least 90% of the 5,000 virtual patients attaining a predetermined pharmacodynamic target of a free ceftolozane serum concentration above the minimum inhibitory concentration (MIC) of 4 mg/L (fT/MIC) for ≥60% of the dosing interval versus Pseudomonas aeruginosa during the initial 48 h of treatment [24,25]. Given that tazobactam has no activity against Pseudomonas aeruginosa , the target of a free tazobactam serum concentration above an MIC of 2 mg/L for ≥50% of the dosing interval for Enterobacteriaceae was used [25,26,27,28,29]. This >50% fT/MIC threshold is based on in vitro infection models that indicated good correlation between fT/MIC for 50% of a dosing interval and reduction in colony forming units over 24 h [29].…”

Make Sure You Have a Safety Net: Updates in the Prevention and Management of Infectious Complications in Stem Cell Transplant Recipients

“…Ceftolozane-tazobactam (Zerbaxa TM ) pairs a novel anti-pseudomonas cephalosporin with the beta-lactamase inhibitor tazobactam [101]. Ceftolozane-tazobactam's spectrum of activity also includes ESBL producing organisms.…”