Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial Eradication in Complicated Urinary Tract Infection

Kaye, Keith S.; Bhowmick, Tanaya; Metallidis, Symeon; Bleasdale, Susan C; Sagan, Olexiy; Stus, V.P.; Vázquez, José Antonio; Зайцев, В. И.; Bidair, Mohamed; Chorvat, Erik; Drăgoescu, Petru Octavian; Fedosiuk, Elena; Horcajada, Juan Pablo; Murta, Claudia; Sarychev, Y. V.; Stoev, Ventsislav; Morgan, Elizabeth E.; Fusaro, Karen; Griffith, David C.; Lomovskaya, Olga; Alexander, Elizabeth; Loutit, Jeffery S.; Dudley, Michael N.; Giamarellos‐Bourboulis, Evangelos J.

doi:10.1001/jama.2018.0438

Cited by 246 publications

(206 citation statements)

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“…Gram-negative pathogens is an especially serious threat given the limited treatment options available for patients with these infections (1,2). While new drugs, such as ceftazidime-avibactam, meropenem-vaborbactam, and ceftolozane-tazobactam, have provided much-needed additions to the current antibiotic armamentarium, some pathogens display resistance to these new ␤-lactam combination agents (3)(4)(5). The most significant of these resistant pathogens are multidrug-resistant Pseudomonas aeruginosa, multidrug-resistant Acinetobacter baumannii, and Enterobacteriaceae with metallo-␤-lactamases (MBLs) such as New Delhi MBL (NDM) (6)(7)(8).…”

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confidence: 99%

Evaluation of the MicroScan Colistin Well and Gradient Diffusion Strips for Colistin Susceptibility Testing in Enterobacteriaceae

et al. 2019

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Many laboratories are unable to perform colistin susceptibility testing. Diffusion-based antimicrobial susceptibility testing methods are not recommended, and not all laboratories have the capacity to perform broth microdilution (BMD). Using a multistep tiered approach, we investigated whether the adapted use of the MicroScan colistin well (4 g/ml) could enhance laboratory capacity for the detection and subsequent molecular characterization of colistin-resistant Enterobacteriaceae. For the MicroScan colistin well, categorical agreement with BMD was 92.7%, and the very major error rate was 10.7%. For gradient diffusion strips, the categorical agreement was 86.4%, and the very major error rate was 53.6%. The MicroScan colistin well detected all isolates carrying mcr-1 or mcr-2 genes (n ϭ 16), but gradient diffusion strips identified an MIC of Ն4 for colistin for only 62.5% of these isolates. A 6-month prospective phenotypic and genotypic study performed at a single clinical microbiology laboratory assessed isolates growing in the MicroScan colistin well for concordance. While 37 of 39 isolates growing in the MicroScan colistin well displayed a colistin MIC of Ն4 by BMD, all were determined to be negative for the mcr-1 and mcr-2 genes by PCR. A retrospective review of all Escherichia coli, Klebsiella spp., and Enterobacter spp. tested by MicroScan at this laboratory in 2016 identified 260 of 7,894 (3.3%) isolates that grew in the MicroScan colistin well. Based on the data presented, clinical and public health laboratories could use the MicroScan colistin well as a first screen for the detection of isolates displaying elevated colistin MICs, which could then undergo further characterization.

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confidence: 99%

Evaluation of the MicroScan Colistin Well and Gradient Diffusion Strips for Colistin Susceptibility Testing in Enterobacteriaceae

et al. 2019

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“…Prospective randomized controlled trial data further support that TZP alone is not overtly damaging to the kidney. For instance, when TZP was compared to meropenem-vaborbactam in 545 patients with urinary tract infections, TZP was reported in adverse events to increase SCr a rate of 0.4% vs. 0% in meropenem-vaborbactam (46). In a separate large trial of 391 patients comparing TZP vs. meropenem for resistant Gram-negative bloodstream infections, TZP only resulted in n=1 non-fatal serious adverse event with increased creatinine vs. n=0 for meropenem (47).…”

Section: Discussionmentioning

confidence: 99%

Urinary biomarker and histopathological evaluation of vancomycin and piperacillin-tazobactam nephrotoxicity in comparison with vancomycin in a rat model and a confirmatory cellular model

Pais

Liu

Avedissian

et al. 2019

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word count: 294 34 2 | Page Abstract: 35Introduction: Vancomycin and piperacillin tazobactam (VAN+TZP) are two of the most 36 commonly utilized antibiotics in the hospital setting and are reported in clinical studies to 37 increase acute kidney injury (AKI). However, no clinical study has demonstrated that synergistic 38 toxicity occurs, only that serum creatinine (SCr) increases with VAN+TZP. The purpose of this 39 study was to assess biologic plausibility by quantifying kidney injury between VAN, TZP, and 40 VAN+TZP treatments using a translational rat model of AKI and rat kidney epithelial cell studies. 41 Methods: (i) Male Sprague-Dawley rats (n=32) received either saline, VAN 150 mg/kg/day 42 intravenously, TZP 1400 mg/kg/day via intraperitoneal injection, or VAN+TZP. Animals were 43 placed in metabolic cages pre-study and on drug dosing days 1-3. Urinary biomarkers and 44 histopathology were analyzed. (ii) Cellular injury of VAN+TZP was assessed in serum-deprived 45 rat kidney cells (NRK-52E) using an alamarBlue® viability assay. Cells were incubated with 46 antibiotics VAN, TZP, cefepime, and gentamicin alone or combined with the same drugs plus 47 VAN 1 mg/mL. 48Results: In the VAN-treated rats, urinary KIM-1 and clusterin were increased on days 1, 2, and 3 49 compared to controls (P<0.001). Elevations were seen only after 3 days of treatment with 50 VAN+TZP (P<0.001 KIM-1, P<0.05 clusterin). Histopathology was only elevated in the VAN 51 group when compared to TZP as a control (P=0.04). Results were consistent across biomarkers 52and histopathology suggesting that adding TZP did not worsen VAN induced AKI and may even 53 be protective. In NRK-52E cells, VAN alone caused moderate cell death with high doses (IC50 54 48.76 mg/mL). TZP alone did not cause cellular death under the same conditions. VAN+TZP 55 was not different from VAN alone in NRK-52E cells (P>0.2). 56Conclusions: VAN+TZP does not cause more kidney injury than VAN alone in a rat model of 57 VIKI or in rat kidney epithelial cells. 58 59 3 | Page

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“…As part of the 21st Centuries Cures Act, the Limited Population Antimicrobial Drug pathway emerged allowing for smaller, more feasible trials in limited populations [71]. The recent positive opinion adopted by the Committee for Medicinal Products for Human Use on meropenem/vaborbactam for the treatment of cUTI, cIAI and HAP/VAP on the basis of a large Phase III study in cUTI [72], and a study in 77 subjects with confirmed or suspected CRE infection at a range of body sites [42], further demonstrates the welcome and forward-thinking approach by regulators to help address the challenge of antimicrobial resistance (AMR). Many other active and expert groups continue to propose innovative approaches to clinical trials [73,74].…”

Section: Innovation and Stewardshipmentioning

confidence: 99%

Combating Resistance While Maintaining Innovation: The Future of Antimicrobial Stewardship

et al. 2019

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Antimicrobial resistance represents a significant global health threat. However, a commercial model that does not offer a return on investment resulting in a lack of investment in antibiotic R&D, means that the current pipeline of antibiotics lacks sufficient innovation to meet this challenge. Those responsible for defining, promoting and monitoring the rationale use of antibiotics (the antimicrobial stewardship programme) are key to addressing current shortcomings. In this personal perspective, we discuss the future role stewardship can play in stimulating innovation, a need to move away from a pharmacy budget dominated view of antibiotic use, and the impact of the ever-increasing sophistication and interdisciplinary nature of antimicrobial control programs. Changes are needed to optimize clinical outcomes for patients.

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Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial Eradication in Complicated Urinary Tract Infection

Abstract: clinicaltrials.gov Identifier: NCT02166476.

Cited by 246 publications

References 19 publications

Evaluation of the MicroScan Colistin Well and Gradient Diffusion Strips for Colistin Susceptibility Testing in Enterobacteriaceae

Evaluation of the MicroScan Colistin Well and Gradient Diffusion Strips for Colistin Susceptibility Testing in Enterobacteriaceae

Urinary biomarker and histopathological evaluation of vancomycin and piperacillin-tazobactam nephrotoxicity in comparison with vancomycin in a rat model and a confirmatory cellular model

Combating Resistance While Maintaining Innovation: The Future of Antimicrobial Stewardship

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