Susceptibility of ESBL Escherichia coli and Klebsiella pneumoniae to fosfomycin in the Netherlands and comparison of several testing methods including Etest, MIC test strip, Vitek2, Phoenix and disc diffusion

Bijllaardt, Wouter van den; Schijffelen, M.J.; Bosboom, Ron; Stuart, James Cohen; Diederen, Bram M. W.; Kampinga, Greetje A.; Le, Thuy-Nga; Overdevest, Ilse; Stals, Frans; Voorn, Paul; Waar, Karola; Mouton, Johan W.; Muller, Anouk E.

doi:10.1093/jac/dky214

Cited by 49 publications

(50 citation statements)

References 24 publications

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“…Both the CLSI and EUCAST specifically recommend against the use of broth microdilution methods, which likely impacts the inaccuracies with most automated susceptibility testing platforms for E. coli or Klebsiella pneumoniae (17, 18). Agar dilution is considered the reference method and is endorsed by the EUCAST; however, it is difficult to execute routinely in a clinical microbiology laboratory.…”

Section: Introductionmentioning

confidence: 99%

The Role of fosA in Challenges with Fosfomycin Susceptibility Testing of Multispecies Klebsiella pneumoniae Carbapenemase-Producing Clinical Isolates

et al. 2019

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With multidrug-resistant (MDR) Enterobacterales on the rise, a nontoxic antimicrobial agent with a unique mechanism of action such as fosfomycin seems attractive. However, establishing accurate fosfomycin susceptibility testing for non-Escherichia coli isolates in a clinical microbiology laboratory remains problematic. We evaluated fosfomycin susceptibility by multiple methods with 96 KPC-producing clinical isolates of multiple strains and species collected at a single center between 2008 and 2016. In addition, we assessed the presence of fosfomycin resistance genes from whole-genome sequencing (WGS) data using NCBI’s AMRFinder and custom HMM search. Susceptibility testing was performed using a glucose-6-phosphate-supplemented fosfomycin Etest and Kirby-Bauer disk diffusion (DD) assays, and the results were compared to those obtained by agar dilution. Clinical Laboratory and Standards Institute (CLSI) breakpoints for E. coli were applied for interpretation. Overall, 63% (60/96) of isolates were susceptible by Etest, 70% (67/96) by DD, and 88% (84/96) by agar dilution. fosA was detected in 80% (70/88) of previously sequenced isolates, with species-specific associations and alleles, and fosA-positive isolates were associated with higher MIC distributions. Disk potentiation testing was performed using sodium phosphonoformate to inhibit fosA and showed significant increases in the zone diameter of DD testing for isolates that were fosA positive compared to those that were fosA negative. The addition of sodium phosphonoformate (PPF) corrected 10/14 (71%) major errors in categorical agreement with agar dilution. Our results indicate that fosA influences the inaccuracy of susceptibility testing by methods readily available in a clinical laboratory compared to agar dilution. Further research is needed to determine the impact of fosA on clinical outcomes.

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Section: Introductionmentioning

confidence: 99%

The Role of fosA in Challenges with Fosfomycin Susceptibility Testing of Multispecies Klebsiella pneumoniae Carbapenemase-Producing Clinical Isolates

et al. 2019

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“…Kasse et al [ 37 ] and Van den Bijllaardt et al [ 38 ] reported VME rates that varied between 16.7% and 12.9%, respectively, in Enterobacteriaceae isolates when comparing disk diffusion and agar dilution for fosfomycin using the breakpoints suggested by Pasteran et al (susceptible: ≥17) [ 39 ] and Epidemiological cut-off values (ECOFFs) of 64 mg/L, concluding that disk diffusion could be overestimating the real MIC value. In order to solve these discrepancies, Mojica et al suggests the interpretation of disk diffusion results in accordance with CLSI established breakpoint taking into account EUCAST recommendations for obtaining the inhibition zone diameter to reach the best performance of DD [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Fosfomycin, Applying Known Methods and Remedies to A New Era

Mariño-Brito

Villavicencio

et al. 2020

Diseases

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The exponential increase in the numbers of isolates of Carbapenem-Resistant Enterobacteriaceae (CRE) creates the need for using novel therapeutic approaches to save the lives of patients. Fosfomycin has long been considered a rational option for the treatment of CRE to be used as part of a combined therapy scheme. However, the assessment of fosfomycin susceptibility in the laboratory presents a great challenge due to the discrepancies found between different methodologies. Thus, our goal was to evaluate fosfomycin susceptibility in a group of 150 Enterobacteriaceae bacterial isolates using agar dilution as the gold standard technique to compare the results with those obtained by disk diffusion. We found a fosfomycin susceptibility of 79.3% in general terms. By comparing both methodologies, we reported a categorical agreement of 96% without Very Major Errors (VMEs) or Major Errors (MEs) and 4% of minor Errors (mEs). Our results suggest that fosfomycin could provide a rational alternative treatment for those patients that are infected by a Multidrug-Resistant (MDR) microorganism that is currently untreatable and that the disk diffusion and classical agar dilution techniques are adequate to assess the resistance profile of CRE to fosfomycin.

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“…Treating physicians may look to increase urinary fosfomycin exposure for a number of reasons: in anticipation of the variability in urinary drug concentrations, limited alternative antimicrobial options, vulnerable patient groups (such as after kidney transplantation) (43, 44), urinary tract infections (UTIs) in male patients, E. coli isolates with elevated fosfomycin MIC values, and for the treatment of other species of Gram-negative uropathogens. Concerningly, discrepancies have been reported between different fosfomycin susceptibility methods (45)(46)(47)(48), and the gold-standard MIC method by agar dilution may not be the best predictor of clinical efficacy (49). Furthermore, in one study, patients with UTIs with carbapenem-resistant K. pneumoniae had a microbiological cure rate of only 46% when treated with fosfomycin, despite an in vitro susceptibility of 92% (17).…”

Section: Figmentioning

confidence: 99%

Oral Fosfomycin Efficacy with Variable Urinary Exposures following Single and Multiple Doses against Enterobacterales : the Importance of Heteroresistance for Growth Outcome

Abbott

Gorp

Wijma

et al. 2020

Antimicrob Agents Chemother

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Oral fosfomycin trometamol is licensed as a single oral dose for the treatment of uncomplicated urinary tract infections, with activity against multidrug-resistant uropathogens. The impact of interindividual variability in urinary concentrations on antimicrobial efficacy, and any benefit of giving multiple doses, is uncertain. We therefore performed pharmacodynamic profiling of oral fosfomycin, using a dynamic bladder infection in vitro model, to assess high and low urinary exposures following a single oral dose and three repeat doses given every 72 h, 48 h, and 24 h against 16 clinical isolates with various MICs of fosfomycin (8 Escherichia coli, 4 Enterobacter cloacae, and 4 Klebsiella pneumoniae isolates). Baseline fosfomycin high-level-resistant (HLR) subpopulations were detected prior to drug exposure in half of the isolates (2 E. coli, 2 E. cloacae, and 4 K. pneumoniae isolates; proportion, 1 × 10−5 to 5 × 10−4% of the total population). Fosfomycin exposures were accurately reproduced compared to mathematical modeling (linear regression slope, 1.1; R2, 0.99), with a bias of 3.8% ± 5.7%. All 5/5 isolates with MICs of ≤1 μg/ml had no HLR and were killed, whereas 8/11 isolates with higher MICs regrew regardless of exposure to high or low urinary concentrations. A disk diffusion zone of <24 mm was a better predictor for baseline HLR and regrowth. Administering 3 doses with average exposures provided very limited additional kill. These results suggest that baseline heteroresistance is important for treatment response, while increased drug exposure and administering multiple doses may not be better than standard single-dose fosfomycin therapy.

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Susceptibility of ESBL Escherichia coli and Klebsiella pneumoniae to fosfomycin in the Netherlands and comparison of several testing methods including Etest, MIC test strip, Vitek2, Phoenix and disc diffusion

Abstract: Overall, it was concluded that none of the test methods is suitable as an alternative to agar dilution in the routine laboratory.

Cited by 49 publications

References 24 publications

The Role of fosA in Challenges with Fosfomycin Susceptibility Testing of Multispecies Klebsiella pneumoniae Carbapenemase-Producing Clinical Isolates

The Role of fosA in Challenges with Fosfomycin Susceptibility Testing of Multispecies Klebsiella pneumoniae Carbapenemase-Producing Clinical Isolates

Fosfomycin, Applying Known Methods and Remedies to A New Era

Oral Fosfomycin Efficacy with Variable Urinary Exposures following Single and Multiple Doses against Enterobacterales : the Importance of Heteroresistance for Growth Outcome

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