Building a Better Test for Piperacillin-Tazobactam Susceptibility Testing: Would that It Were So Simple (It's Complicated)

Extended-spectrum β-lactamase (ESBL)-producing Gram-negative pathogens are a major cause of resistance to expanded-spectrum β-lactam antibiotics. Since their discovery in the early 1980s, they have spread worldwide and an are now endemic in Enterobacterales isolated from both hospital-associated and community-acquired infections. As a result, they are a global public health concern. In the past, TEM- and SHV-type ESBLs were the predominant families of ESBLs. Today CTX-M-type enzymes are the most commonly found ESBL type with the CTX-M-15 variant dominating worldwide, followed in prevalence by CTX-M-14, and CTX-M-27 is emerging in certain parts of the world. The genes encoding ESBLs are often found on plasmids and harboured within transposons or insertion sequences, which has enabled their spread. In addition, the population of ESBL-producing Escherichia coli is dominated globally by a highly virulent and successful clone belonging to ST131. Today, there are many diagnostic tools available to the clinical microbiology laboratory and include both phenotypic and genotypic tests to detect β-lactamases. Unfortunately, when ESBLs are not identified in a timely manner, appropriate antimicrobial therapy is frequently delayed, resulting in poor clinical outcomes. Several analyses of clinical trials have shown mixed results with regards to whether a carbapenem must be used to treat serious infections caused by ESBLs or whether some of the older β-lactam-β-lactamase combinations such as piperacillin/tazobactam are appropriate. Some of the newer combinations such as ceftazidime/avibactam have demonstrated efficacy in patients. ESBL-producing Gram-negative pathogens will continue to be major contributor to antimicrobial resistance worldwide. It is essential that we remain vigilant about identifying them both in patient isolates and through surveillance studies.

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“…This is especially important to note, as Etest strips had previously been noted to be unreliable for testing piperacillin/tazobactam. 217 …”

Section: Current Therapiesmentioning

confidence: 99%

Extended-spectrum β-lactamases: an update on their characteristics, epidemiology and detection

Castanheira

Simner

Bradford³

2021

JAC-Antimicrobial Resistance

392

309

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“…Piperacillin-tazobactam AST in particular was most problematic and gave the highest number of VMEs, most of which occurred with E. coli but also with Klebsiella spp. This is not completely surprising following emerging evidence of performance and consistency issues with piperacillin-tazobactam AST ( 15 ). Previous studies using clinical isolates or samples with the dRAST have shown a low overall VME, ME, and mE rate; however, it seems that the total number of isolates were considered for error rate calculation ( 7 , 10 , 11 ).…”

Section: Discussionmentioning

confidence: 97%

Performance of dRAST on Prospective Clinical Blood Culture Samples in a Simulated Clinical Setting and on Multidrug-Resistant Bacteria

2022

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“…At a later stage, commercial devices may be identified as having significant problems leading to very major errorsda situation where isolates resistant to a trial antimicrobial are incorrectly categorized as susceptible by the local AST device or method [24e27]. In cases where issues with commercial AST devices are identified by standards-setting bodies such as EUCAST, laboratories that continue to use these devices are at increased risk of reporting false susceptibility to one or both of the trial antimicrobials [28,29]. A clear example of this is for colistin, where many laboratories across multiple trials (AIDA, CARE, MAGIC BULLET) used commercial methods with known problems rather than recommended broth microdilution resulting in significant AST error rates for colistin [30e34].…”

Section: Discussionmentioning

confidence: 99%

“…MIC are variable regardless of method used. Reading broth microdilution plates requires training and skill and when target isolates have MICs that challenge the clinical breakpoint of the antimicrobials, high categorical error rates are not unexpected, even if essential agreement is close to 100% (defined as within 1 dilution of the reference method MIC) [28]. Reflecting this issue, six out of ten isolates from excluded patients from RESTORE IMI had a difference of one dilution for colistin and imipenem/relebactam between reference and commercial method [36].…”

Section: Discussionmentioning

confidence: 99%

A systematic review of antimicrobial susceptibility testing as a tool in clinical trials assessing antimicrobials against infections due to gram-negative pathogens

Henderson

Bursle

Stewart

et al. 2021

Clinical Microbiology and Infection

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Background: Antimicrobial susceptibility testing (AST) is the standard of care for treating bacterial infections. In randomized clinical trials of new antimicrobials, AST might not be performed or reported in real time. Objectives: To determine local, real-time laboratory AST performance, its usage in the trial flow, quality control (QC) of the local testing, central AST performance and the effect of using AST categorization on the trials' primary outcomes. Data sources: We systematically searched PubMed, Embase, PsychINFO and Web of Science. Eligibility criteria: We included registered randomized controlled trials published in journals between January 2015 and December 2019. Participants and interventions:We included trials comparing different antibiotics for the treatment of infections caused predominantly by Gram-negative bacteria. Methods: Primary outcomes for different trial populations were extracted and differences between trial arms were compared for patients with infections caused by susceptible versus non-susceptible bacteria. Results are described narratively. Results: Of 32 randomized trials, 25 trials reported that local AST was performed, 1312 reported the local laboratory AST methods, no trial reported QC, but post-hoc referral for AST at a reference laboratory was common. Patients' outcomes were superior when patients with infections due to susceptible and nonsusceptible pathogens were compared post hoc (median difference 14%, interquartile range 8%e24%) in trials allowing this comparison (seven antimicrobials), except for colistin, where 14-day mortality was 9% higher when patients were treated with colistin for colistin-susceptible versus colistin-resistant carbapenem-resistant Acinetobacter baumannii. When excluding patients with pathogens that were non-susceptible to either antimicrobial in the trials, the difference in the primary outcome between the trial arms was reduced in five out of six trials.

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Building a Better Test for Piperacillin-Tazobactam Susceptibility Testing: Would that It Were So Simple (It's Complicated)

Cited by 17 publications

References 8 publications

Extended-spectrum β-lactamases: an update on their characteristics, epidemiology and detection

Extended-spectrum β-lactamases: an update on their characteristics, epidemiology and detection

Performance of dRAST on Prospective Clinical Blood Culture Samples in a Simulated Clinical Setting and on Multidrug-Resistant Bacteria

A systematic review of antimicrobial susceptibility testing as a tool in clinical trials assessing antimicrobials against infections due to gram-negative pathogens

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