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Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and ?-lactamase-inhibitor combination.

ABSTRACT: The management of infections caused by multidrug-resistant Gram-negative bacteria, particularly Pseudomonas aeruginosa, continues to be a significant challenge to clinicians. Ceftolozane/tazobactam is a novel antibacterial and ?-lactamase-inhibitor combination that has shown appreciable activity against wild-type Enterobacteriaceae and potent activity against P. aeruginosa. Moreover, ceftolozane/tazobactam has not demonstrated cross-resistance to other antimicrobial classes, particularly those affected by extended-spectrum ?-lactamases, AmpC ?-lactamase, a loss in porin channels, or the overexpression of efflux pumps in P. aeruginosa. Ceftolozane/tazobactam has completed two Phase II clinical trials in complicated intra-abdominal and complicated urinary tract infections. A Phase III, multicenter, prospective, randomized, open-label study has been initiated to evaluate the safety and efficacy of ceftolozane/tazobactam versus piperacillin/tazobactam for the treatment of ventilator-associated pneumonia. A Medline search of articles from inception to May 2013 and references for selected citations was conducted. Data from abstracts presented at conferences were also appraised. This article reviews the antimicrobial, pharmacokinetic, and pharmacodynamic profile of ceftolozane/tazobactam, and discusses its potential role in therapy.

SUBMITTER: Hong MC

PROVIDER: S-EPMC3848746 | biostudies-other | 2013 Nov

REPOSITORIES: biostudies-other

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Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and β-lactamase-inhibitor combination.

Hong Mai-Chi MC Hsu Donald I DI Bounthavong Mark M

Infection and drug resistance 20131129

The management of infections caused by multidrug-resistant Gram-negative bacteria, particularly Pseudomonas aeruginosa, continues to be a significant challenge to clinicians. Ceftolozane/tazobactam is a novel antibacterial and β-lactamase-inhibitor combination that has shown appreciable activity against wild-type Enterobacteriaceae and potent activity against P. aeruginosa. Moreover, ceftolozane/tazobactam has not demonstrated cross-resistance to other antimicrobial classes, particularly those a ...[more]

PMID: 24348053

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Project description:Pseudomonas aeruginosa produces a class C ?-lactamase (e.g., PDC-3) that robustly hydrolyzes early generation cephalosporins often at the diffusion limit; therefore, bacteria possessing these ?-lactamases are resistant to many ?-lactam antibiotics. In response to this significant clinical threat, ceftolozane, a 3' aminopyrazolium cephalosporin, was developed. Combined with tazobactam, ceftolozane promised to be effective against multidrug-resistant P. aeruginosa Alarmingly, ?-loop variants of the PDC ?-lactamase (V213A, G216R, E221K, E221G, and Y223H) were identified in ceftolozane/tazobactam-resistant P. aeruginosa clinical isolates. Herein, we demonstrate that the Escherichia coli strain expressing the E221K variant of PDC-3 had the highest minimum inhibitory concentrations (MICs) against a panel of ?-lactam antibiotics, including ceftolozane and ceftazidime, a cephalosporin that differs in structure largely in the R2 side chain. The k cat values of the E221K variant for both substrates were equivalent, whereas the Km for ceftolozane (341?±?64?µM) was higher than that for ceftazidime (174?±?20?µM). Timed mass spectrometry, thermal stability, and equilibrium unfolding studies revealed key mechanistic insights. Enhanced sampling molecular dynamics simulations identified conformational changes in the E221K variant ?-loop, where a hidden pocket adjacent to the catalytic site opens and stabilizes ceftolozane for efficient hydrolysis. Encouragingly, the diazabicyclooctane ?-lactamase inhibitor avibactam restored susceptibility to ceftolozane and ceftazidime in cells producing the E221K variant. In addition, a boronic acid transition state inhibitor, LP-06, lowered the ceftolozane and ceftazidime MICs by 8-fold for the E221K-expressing strain. Understanding these structural changes in evolutionarily selected variants is critical toward designing effective ?-lactam/?-lactamase inhibitor therapies for P. aeruginosa infections.IMPORTANCE The presence of ?-lactamases (e.g., PDC-3) that have naturally evolved and acquired the ability to break down ?-lactam antibiotics (e.g., ceftazidime and ceftolozane) leads to highly resistant and potentially lethal Pseudomonas aeruginosa infections. We show that wild-type PDC-3 ?-lactamase forms an acyl enzyme complex with ceftazidime, but it cannot accommodate the structurally similar ceftolozane that has a longer R2 side chain with increased basicity. A single amino acid substitution from a glutamate to a lysine at position 221 in PDC-3 (E221K) causes the tyrosine residue at 223 to adopt a new position poised for efficient hydrolysis of both cephalosporins. The importance of the mechanism of action of the E221K variant, in particular, is underscored by its evolutionary recurrences in multiple bacterial species. Understanding the biochemical and molecular basis for resistance is key to designing effective therapies and developing new ?-lactam/?-lactamase inhibitor combinations.

Project description:Guidelines for the treatment of sepsis, febrile neutropenia, and hospital-acquired pneumonia caused by Pseudomonas aeruginosa include empirical regimens incorporating two antibiotics from different classes with activity against P. aeruginosa for select at-risk patients to increase the likelihood that the organism will be susceptible to at least one agent. The activity against P. aeruginosa and the rates of cross-resistance of ceftolozane-tazobactam were compared to those of the ?-lactam comparators cefepime, ceftazidime, piperacillin-tazobactam, and meropenem alone and cumulatively with ciprofloxacin or tobramycin. Nonurine P. aeruginosa isolates were collected from adult inpatients at 44 geographically diverse U.S. hospitals. MICs were determined using reference broth microdilution methods. Of the 1,257 isolates collected, 29% were from patients in intensive care units and 39% were from respiratory sites. The overall rate of susceptibility to ceftolozane-tazobactam was high at 97%, whereas it was 72 to 76% for cefepime, ceftazidime, piperacillin-tazobactam, and meropenem. The rate of nonsusceptibility to all four comparator ?-lactams was 11%; of the isolates nonsusceptible to the four comparator ?-lactams, 80% remained susceptible to ceftolozane-tazobactam. Among the isolates nonsusceptible to the tested ?-lactam comparators, less than half were susceptible to ciprofloxacin. By comparison, approximately 80% of the ?-lactam-nonsusceptible isolates were susceptible to tobramycin, for overall cumulative susceptibility rates of 94 to 95%, nearly 10% higher than that of the ciprofloxacin-?-lactam combinations and approaching that of ceftolozane-tazobactam as a single agent. The rates of susceptibility to ceftolozane-tazobactam were consistently high, with little observable cross-resistance. Ceftolozane-tazobactam monotherapy performed at or above the level of commonly utilized combination therapies on the basis of in vitro susceptibilities. Ceftolozane-tazobactam should be considered for use in patients at high risk for resistant P. aeruginosa infection and as an alternative to empirical combination therapy, especially for patients unable to tolerate aminoglycosides.

Dataset Information

Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and ?-lactamase-inhibitor combination.

Publications

Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and β-lactamase-inhibitor combination.

Similar Datasets

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