Dataset Information

Reconciling the Potentially Irreconcilable? Genotypic and Phenotypic Amoxicillin-Clavulanate Resistance in Escherichia coli.

ABSTRACT: Resistance to amoxicillin-clavulanate, a widely used beta-lactam/beta-lactamase inhibitor combination antibiotic, is rising globally, and yet susceptibility testing remains challenging. To test whether whole-genome sequencing (WGS) could provide a more reliable assessment of susceptibility than traditional methods, we predicted resistance from WGS for 976 Escherichia coli bloodstream infection isolates from Oxfordshire, United Kingdom, comparing against phenotypes from the BD Phoenix (calibrated against EUCAST guidelines). A total of 339/976 (35%) isolates were amoxicillin-clavulanate resistant. Predictions based solely on beta-lactamase presence/absence performed poorly (sensitivity, 23% [78/339]) but improved when genetic features associated with penicillinase hyperproduction (e.g., promoter mutations and copy number estimates) were considered (sensitivity, 82% [277/339]; P < 0.0001). Most discrepancies occurred in isolates with MICs within ±1 doubling dilution of the breakpoint. We investigated two potential causes: the phenotypic reference and the binary resistant/susceptible classification. We performed reference standard, replicated phenotyping in a random stratified subsample of 261/976 (27%) isolates using agar dilution, following both EUCAST and CLSI guidelines, which use different clavulanate concentrations. As well as disagreeing with each other, neither agar dilution phenotype aligned perfectly with genetic features. A random-effects model investigating associations between genetic features and MICs showed that some genetic features had small, variable and additive effects, resulting in variable resistance classification. Using model fixed-effects to predict MICs for the non-agar dilution isolates, predicted MICs were in essential agreement (±1 doubling dilution) with observed (BD Phoenix) MICs for 691/715 (97%) isolates. This suggests amoxicillin-clavulanate resistance in E. coli is quantitative, rather than qualitative, explaining the poorly reproducible binary (resistant/susceptible) phenotypes and suboptimal concordance between different phenotypic methods and with WGS-based predictions.

SUBMITTER: Davies TJ

PROVIDER: S-EPMC7269502 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Reconciling the Potentially Irreconcilable? Genotypic and Phenotypic Amoxicillin-Clavulanate Resistance in <i>Escherichia coli</i>.

Davies Timothy J TJ Stoesser Nicole N Sheppard Anna E AE Abuoun Manal M Fowler Philip P Swann Jeremy J Quan T Phuong TP Griffiths David D Vaughan Alison A Morgan Marcus M Phan Hang T T HTT Jeffery Katie J KJ Andersson Monique M Ellington Matt J MJ Ekelund Oskar O Woodford Neil N Mathers Amy J AJ Bonomo Robert A RA Crook Derrick W DW Peto Tim E A TEA Anjum Muna F MF Walker A Sarah AS

Antimicrobial agents and chemotherapy 20200521 6

Resistance to amoxicillin-clavulanate, a widely used beta-lactam/beta-lactamase inhibitor combination antibiotic, is rising globally, and yet susceptibility testing remains challenging. To test whether whole-genome sequencing (WGS) could provide a more reliable assessment of susceptibility than traditional methods, we predicted resistance from WGS for 976 <i>Escherichia coli</i> bloodstream infection isolates from Oxfordshire, United Kingdom, comparing against phenotypes from the BD Phoenix (cal ...[more]

PMID: 32205351

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Project description:This study analyzed the enzymatic basis and molecular epidemiology of amoxicillin-clavulanate-resistant Escherichia coli isolated by the microbiology laboratory of a United States tertiary care hospital. From October 1998 to December 1999, all E. coli isolates were screened for ampicillin-sulbactam resistance. Of 283 isolates that tested resistant to ampicillin-sulbactam, 69 unique patient isolates were also resistant to amoxicillin-clavulanate by disk diffusion testing (zone diameter </= 13 mm). These amoxicillin-clavulanate-resistant E. coli isolates underwent agar dilution testing, pulsed-field gel electrophoresis, PCR analysis, and isoelectric focusing. The mean age of study patients was 52 years; 78% were female. Among the isolates, 12 were nosocomial (rate of amoxicillin-clavulanate resistance = 4.7%) and 57 were community acquired (rate of amoxicillin-clavulanate resistance = 2.8%). No predominant strain was identified. By agar dilution testing, 67 isolates were nonsusceptible (39 resistant and 28 intermediate) to amoxicillin-clavulanate and 37 were piperacillin-tazobactam resistant but only 8 were ceftazidime resistant (ceftazidime MIC >/= 32 micro g/ml). Two isolates were susceptible to amoxicillin-clavulanic acid by agar dilution, although they were resistant by disk diffusion testing. The distribution of beta-lactamases was as follows: the TEM type alone was found in 52 isolates, the AmpC type was found in 4 isolates (2 identified as containing CMY-2), the TEM type and CMY-2 were found in 2 isolates, and the OXA type was found in 1 isolate. Also, there was one isolate with the TEM type and the SHV type and one with the TEM type and a second, unidentified enzyme. Among the isolates with TEM-type enzymes, two extended-spectrum beta-lactamase-producing isolates were identified but two isolates with inhibitor-resistant TEM (IRT) enzymes (one with TEM-34 [IRT-6] and the other with a novel enzyme [tentatively assigned the designation TEM-122]) were more interesting.

Dataset Information

Reconciling the Potentially Irreconcilable? Genotypic and Phenotypic Amoxicillin-Clavulanate Resistance in Escherichia coli.

Publications

Reconciling the Potentially Irreconcilable? Genotypic and Phenotypic Amoxicillin-Clavulanate Resistance in <i>Escherichia coli</i>.

Similar Datasets

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