Dataset Information

Chemical Stability of Ceftolozane/Tazobactam in Polyvinylchloride Bags and Elastomeric Pumps.

ABSTRACT: BACKGROUND:Elastomeric pumps are often used to administer intravenous antibiotics in the outpatient setting, but effective infusion requires that the drug remain stable in solution throughout the procedure. OBJECTIVE:To determine the chemical stability of ceftolozane/tazobactam when reconstituted and stored over an extended time in the AccuFlo (EMED Technologies, El Dorado Hills, California) and I-Flow Homepump Eclipse (Halyard, Alpharetta, Georgia) elastomeric pumps compared with the results of the label-supporting studies in polyvinylchloride (PVC) bags. METHODS:Two ceftolozane/tazobactam dosages were tested for the elastomeric pump studies: 1500 mg (1 g ceftolozane/0.5 g tazobactam) and 150 mg (100 mg ceftolozane/50 mg tazobactam). The solution hold time was evaluated for 10 days at 5°C (±3°C) (tolerance ±3 hours) and for 1 day (24 hours) at ambient room temperature (tolerance ±3 hours). Results of a previously conducted label-supporting PVC intravenous bag study were used as a comparator. RESULTS:At each time point, the visual appearance of all pump and PVC bag solutions remained clear and free of visible particulates, and subvisible particulate matter did not differ significantly between the initial time point and at 10 days. No notable changes in pH in any of the pump or PVC solutions occurred throughout the study. Recovery of ceftolozane and tazobactam was greater than 93% and 94%, respectively, for all samples (elastomeric pump and PVC bag) at 10 days. CONCLUSIONS:Ceftolozane/tazobactam remains physically and chemically stable for at least 7 days, as indicated on the US label, when reconstituted, diluted, and stored in the AccuFlo and I-Flow Homepump Eclipse elastomeric pumps and in PVC intravenous bags.

SUBMITTER: Terracciano J

PROVIDER: S-EPMC5522980 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Chemical Stability of Ceftolozane/Tazobactam in Polyvinylchloride Bags and Elastomeric Pumps.

Terracciano Joseph J Rhee Elizabeth G EG Walsh Jacqueline J

Current therapeutic research, clinical and experimental 20170306

<h4>Background</h4>Elastomeric pumps are often used to administer intravenous antibiotics in the outpatient setting, but effective infusion requires that the drug remain stable in solution throughout the procedure.<h4>Objective</h4>To determine the chemical stability of ceftolozane/tazobactam when reconstituted and stored over an extended time in the AccuFlo (EMED Technologies, El Dorado Hills, California) and I-Flow Homepump Eclipse (Halyard, Alpharetta, Georgia) elastomeric pumps compared with ...[more]

PMID: 28761575

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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: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 ?-lactamases, especially metallo-?-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 ?-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.IMPORTANCE Pseudomonas 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 ?-lactam/?-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 ?-lactams and ?-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.

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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.

Dataset Information

Chemical Stability of Ceftolozane/Tazobactam in Polyvinylchloride Bags and Elastomeric Pumps.

Publications

Chemical Stability of Ceftolozane/Tazobactam in Polyvinylchloride Bags and Elastomeric Pumps.

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