Dataset Information

Activity of Ceftolozane-Tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae Isolates Collected from Respiratory Tract Specimens of Hospitalized Patients in the United States during 2013 to 2015.

ABSTRACT: The activities of ceftolozane-tazobactam and comparator agents against organisms deemed to be the cause of pneumonia among patients hospitalized in the United States during 2013 to 2015 were evaluated. Organisms included 1,576 Pseudomonas aeruginosa and 2,362 Enterobacteriaceae isolates susceptibility tested using reference broth microdilution methods. Ceftolozane-tazobactam, cefepime, ceftazidime, meropenem, and piperacillin-tazobactam inhibited 96.3%, 84.8%, 83.5%, 80.0%, and 78.6%, respectively, of the P. aeruginosa isolates. Ceftolozane-tazobactam inhibited 77.5 to 85.1% of isolates nonsusceptible to antipseudomonal ?-lactams and 86.6% and 71.0% of the 372 (23.6% overall) multidrug- and 155 (9.8%) extensively drug-resistant isolates tested. The activity of this combination was greater than those of other ?-lactams evaluated against P. aeruginosa groups across all U.S. census divisions. Ceftolozane-tazobactam was active against 90.6% of the Enterobacteriaceae, being less active than only meropenem (95.6% susceptible) among the ?-lactams evaluated. Against 145 Escherichia coli and Klebsiella pneumoniae isolates carrying extended-spectrum-?-lactamase (ESBL)-encoding genes without carbapenemases, ceftolozane-tazobactam inhibited 82.8% of these isolates and was more active than cefepime and piperacillin-tazobactam (15.2% and 74.3% susceptible, respectively). ESBL genes included in this analysis were mainly blaCTX-M-15-like (89 isolates) and blaCTX-M-14-like (22) genes but also blaSHV (31) and blaTEM (3). Ceftolozane-tazobactam also displayed activity (84.6% susceptible) against 13 isolates harboring acquired AmpC genes. All ?-lactams displayed limited activity against blaKPC-carrying isolates. Ceftolozane-tazobactam was the most active ?-lactam tested against P. aeruginosa isolates from isolates that were the probable cause of pneumonia and displayed in vitro activity against Enterobacteriaceae, including isolates resistant to cephalosporins and carrying ESBL genes.

SUBMITTER: Castanheira M

PROVIDER: S-EPMC5826161 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Activity of Ceftolozane-Tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae Isolates Collected from Respiratory Tract Specimens of Hospitalized Patients in the United States during 2013 to 2015.

Castanheira Mariana M Duncan Leonard R LR Mendes Rodrigo E RE Sader Helio S HS Shortridge Dee D

Antimicrobial agents and chemotherapy 20180223 3

The activities of ceftolozane-tazobactam and comparator agents against organisms deemed to be the cause of pneumonia among patients hospitalized in the United States during 2013 to 2015 were evaluated. Organisms included 1,576 <i>Pseudomonas aeruginosa</i> and 2,362 <i>Enterobacteriaceae</i> isolates susceptibility tested using reference broth microdilution methods. Ceftolozane-tazobactam, cefepime, ceftazidime, meropenem, and piperacillin-tazobactam inhibited 96.3%, 84.8%, 83.5%, 80.0%, and 78. ...[more]

PMID: 29263073

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Project description:This study established the in vitro activity of ceftolozane/tazobactam (C/T) and its genotypic resistance mechanisms by whole-genome sequencing (WGS) in 195 carbapenem-nonsusceptible Pseudomonas aeruginosa (CNSPA) clinical isolates recovered from Singapore between 2009 and 2020. C/T susceptibility rates were low, at 37.9%. Cross-resistance to ceftazidime/avibactam was observed, although susceptibility to the agent was slightly higher, at 41.0%. Whole-genome sequencing revealed that C/T resistance was largely mediated by the presence of horizontally acquired β-lactamases, especially metallo-β-lactamases. These were primarily disseminated in well-recognized high-risk clones belonging to sequence types (ST) 235, 308, and 179. C/T resistance was also observed in several non-carbapenemase-producing isolates, in which resistance was likely mediated by β-lactamases and, to a smaller extent, mutations in AmpC-related genes. There was no obvious mechanism of resistance observed in five isolates. The high C/T resistance highlights the limited utility of the agent as an empirical agent in our setting. Knowledge of local molecular epidemiology is crucial in determining the potential of therapy with novel agents.IMPORTANCEPseudomonas aeruginosa infection is one of the most difficult health care-associated infections to treat due to the ability of the organism to acquire a multitude of resistance mechanisms and express the multidrug resistance phenotype. Ceftolozane/tazobactam (C/T), a novel β-lactam/β-lactamase inhibitor combination, addresses an unmet medical need in patients with these multidrug-resistant P. aeruginosa infections. Our findings demonstrate geographical variation in C/T susceptibility owing to the distinct local molecular epidemiology. This study adds on to the growing knowledge of C/T resistance, particularly mutational resistance, and will aid in the design of future β-lactams and β-lactamase inhibitors. WGS proved to be a useful tool to understand the P. aeruginosa resistome and its contribution to emerging resistance in novel antimicrobial agents.

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.

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:The rise in resistant Gram-negative pathogens continues to challenge clinicians treating infections. These resistant infections have inspired the development of new antimicrobial agents, including ceftolozane-tazobactam, a novel ?-lactam/?-lactamase inhibitor combination approved by the US Food and Drug Administration for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) in combination with metronidazole. Ceftolozane exhibits bactericidal activity by inhibiting penicillin-binding proteins (PBPs), with high affinity for PBP1b, PBP1c, and PBP3. The addition of tazobactam protects ceftolozane from hydrolysis by irreversibly binding to some ?-lactamase enzymes. Ceftolozane-tazobactam is active against a wide range of Gram-negative pathogens, including extended-spectrum ?-lactamase (ESBL)-producing Enterobacteriaceae and multidrug-resistant (MDR) Pseudomonas aeruginosa, several streptococcal species, and Bacteroides fragilis. When anaerobic coverage is needed, it should be used in combination with metronidazole. Ceftolozane demonstrates linear pharmacokinetics, low protein binding, and minimal accumulation with repeated dosing. The major pharmacokinetic/pharmacodynamic index for ceftolozane is the percentage of the dosing interval in which the plasma free drug concentration remains higher than the minimum inhibitory concentration (%T.MIC). Phase III clinical trials for the treatment of cUTIs and cIAIs have been completed, showing that it is an effective and safe alternative for the treatment of these infections. The approved dose for cUTIs and cIAIs is 1.5 g (1 g ceftolozane and 500 mg tazobactam) infused over 1 hour every 8 hours. A higher 3 g dose is currently in Phase III trials for the treatment of ventilated nosocomial pneumonia. Dosage adjustments are necessary for patients with moderate-to-severe renal impairment. Current data suggest that ceftolozane-tazobactam is a promising carbapenem-sparing alternative agent for the treatment of cUTIs and cIAIs, including those caused by ESBL-producing Enterobacteriaceae and MDR P. aeruginosa.

Dataset Information

Activity of Ceftolozane-Tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae Isolates Collected from Respiratory Tract Specimens of Hospitalized Patients in the United States during 2013 to 2015.

Publications

Activity of Ceftolozane-Tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae Isolates Collected from Respiratory Tract Specimens of Hospitalized Patients in the United States during 2013 to 2015.

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