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      Skipped wells and scientific error during fosfomycin agar dilution and broth microdilution lead to inconsistent minimal inhibitory concentrations and may be cause for reevaluating testing methods for Klebsiella pneumoniae

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          ABSTRACT

          Despite the first-line recommendation of fosfomycin for uncomplicated urinary tract infections (UTIs), there are pressing barriers for optimizing its use for the treatment of non- Escherichia coli Enterobacterales UTI. There are no approved breakpoints for oral use against other Enterobacterales, and the recommended agar dilution (AD) reference method for minimal inhibitory concentration (MIC) determination is largely impractical. Using 160 clinical Klebsiella pneumoniae isolates, we sought to understand rates of skipped wells and MIC imprecision in broth microdilution (BMD) and how that compares to rates of error using AD. Though the Clinical and Laboratory Standards Institute refers to the skipped well phenomena in their recommendation against the use of BMD, there is a paucity of data on its frequency. While AD and BMD produced similar MIC 50/90 values (32/256 µg/mL for AD and 64/256 µg/mL for BMD), essential agreement was poor. No-growth wells at concentrations below the MIC occurred in up to 10.9% of wells at a given concentration, as the most frequent scientific error. Growth in concentrations above the measured MIC occurred in up to 3.3% of wells and was seen within three dilutions of the MIC for BMD. Observation of single colonies either at or beyond the measured MIC for AD was also common and occurred up to 8.3% and 2.5% of the time, respectively. The frequent scientific error in both testing methods should prompt re-evaluation of AD guidelines and expansion of MIC testing methods for fosfomycin susceptibility testing, as poor agreement with another method prone to scientific error should not be the main detractor from BMD use.

          IMPORTANCE

          Despite the recommendation of fosfomycin for uncomplicated urinary tract infections (UTIs), there are barriers for optimizing its use. There are no approved breakpoints for oral use against other Enterobacterales, and the recommended agar dilution (AD) reference method for MIC determination is largely impractical. The use of broth microdilution (BMD) for fosfomycin testing is not recommended by the Clinical and Laboratory Standards Institute due to unsatisfactory precision and skipped wells—occurrence of no-growth in a single well before the minimal inhibitory concentration (MIC)—and trailing endpoints. We sought to understand rates of skipped wells and growth at concentrations above measured MICs in BMD and how that compares to scientific error using AD. No-growth wells at concentrations below the MIC occurred in up to 10.9% of wells for BMD and single colonies at or beyond measured MICs for AD were also common. Frequent scientific error in both methods should prompt re-evaluation of both AD and BMD for fosfomycin susceptibility testing.

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          CLSI Methods Development and Standardization Working Group Best Practices for Evaluation of Antimicrobial Susceptibility Tests

          Effective evaluations of antimicrobial susceptibility tests (ASTs) require robust study design. The Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing has recognized that many published studies reporting the performance of commercial ASTs (cASTs) suffer from major design and/or analysis flaws, rendering the results difficult or impossible to interpret. This minireview outlines the current consensus of the Methods Development and Standardization Working Group of the CLSI Subcommittee on Antimicrobial Susceptibility Testing regarding best practices for systematic evaluation of the performance of an AST, including the analysis and presentation of essential data intended for publication.
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            Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial

            Abstract Background ZTI-01 (fosfomycin for injection) is an epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has broad in vitro spectrum of activity, including multidrug-resistant Gram-negative pathogens, and is being developed for treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States. Methods Hospitalized adults with suspected or microbiologically confirmed cUTI/AP were randomized 1:1 to 6 g ZTI-01 q8h or 4.5 g intravenous (IV) piperacillin-tazobactam (PIP-TAZ) q8h for a fixed 7-day course (no oral switch); patients with concomitant bacteremia could receive up to 14 days. Results Of 465 randomized patients, 233 and 231 were treated with ZTI-01 and PIP-TAZ, respectively. In the microbiologic modified intent-to-treat (m-MITT) population, ZTI-01 met the primary objective of noninferiority compared with PIP-TAZ with overall success rates of 64.7% (119/184 patients) vs 54.5% (97/178 patients), respectively; treatment difference was 10.2% (95% confidence interval [CI]: −0.4, 20.8). Clinical cure rates at test of cure (TOC, day 19–21) were high and similar between treatments (90.8% [167/184] vs 91.6% [163/178], respectively). In post hoc analysis using unique pathogens typed by pulsed-field gel electrophoresis, overall success rates at TOC in m-MITT were 69.0% (127/184) for ZTI-01 versus 57.3% (102/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mild and transient. Conclusions ZTI-01 was effective for treatment of cUTI including AP and offers a new IV therapeutic option with a differentiated MOA for patients with serious Gram-negative infections. Clinical Trial Registration NCT02753946
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              Fosfomycin for the treatment of infections caused by multidrug-resistant non-fermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies.

              The treatment of multidrug-resistant (MDR), extensively drug-resistant or pandrug-resistant non-fermenting Gram-negative bacterial infections constitutes a challenge in an era of few new antibiotic choices. This mandates the re-evaluation of already existing antibiotics such as fosfomycin. We systematically reviewed the literature to assess the clinical and microbiological effectiveness of fosfomycin in the treatment of these infections by searching PubMed, Scopus and the Cochrane Library databases. In 23 microbiological studies identified, 1859 MDR non-fermenting Gram-negative bacterial isolates were examined. The susceptibility rate to fosfomycin of MDR Pseudomonas aeruginosa isolates was >or=90% and 50-90% in 7/19 and 4/19 relevant studies, respectively. Cumulatively, 511/1693 (30.2%) MDR P. aeruginosa isolates were susceptible to fosfomycin. Serotype O12 isolates exhibited greater susceptibility. Only 3/85 (3.5%) MDR Acinetobacter baumannii and 0/31 MDR Burkholderia spp. isolates were susceptible to fosfomycin. Variable criteria of susceptibility were used in the included studies. Fosfomycin was synergistic in combination with a beta-lactam, aminoglycoside or ciprofloxacin in 46/86 (53.5%) MDR P. aeruginosa isolates. One animal study found a good therapeutic effect of the combination fosfomycin/gentamicin against MDR P. aeruginosa endocarditis. In six clinical studies, 33 patients with MDR P. aeruginosa infections (mainly pulmonary exacerbations of cystic fibrosis) received fosfomycin (25/33 in combination with other antibiotics); 91% of the patients clinically improved. In conclusion, fosfomycin could have a role as a therapeutic option against MDR P. aeruginosa infections. Further research is needed to clarify the potential utility of this agent.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review and editing
                Role: Data curationRole: InvestigationRole: Writing – review and editing
                Role: Data curationRole: InvestigationRole: SupervisionRole: Writing – review and editing
                Role: Data curationRole: InvestigationRole: Writing – review and editing
                Role: ConceptualizationRole: MethodologyRole: Writing – review and editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review and editing
                Role: Editor
                Journal
                Microbiol Spectr
                Microbiol Spectr
                spectrum
                Microbiology Spectrum
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2165-0497
                August 2024
                28 June 2024
                28 June 2024
                : 12
                : 8
                : e04205-23
                Affiliations
                [1 ]University of Minnesota College of Pharmacy; , Minneapolis, Minnesota, USA
                [2 ]Virginia Commonwealth University Health System; , Richmond, Virginia, USA
                City of Hope Department of Pathology; , Duarte, California, USA
                Author notes
                Address correspondence to Elizabeth B. Hirsch, ebhirsch@ 123456umn.edu

                E.B.H. has received advisory board honoraria from GSK. All other authors declare no relevant conflicts of interest.

                Author information
                https://orcid.org/0009-0004-8897-5191
                https://orcid.org/0000-0002-2957-7829
                https://orcid.org/0000-0002-0462-0421
                Article
                spectrum04205-23 spectrum.04205-23
                10.1128/spectrum.04205-23
                11302225
                38940588
                b00d499f-82e4-4017-8b3b-d5a7fa94fdbc
                Copyright © 2024 Bixby et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 18 December 2023
                : 29 May 2024
                Page count
                supplementary-material: 0, authors: 6, Figures: 4, Tables: 2, References: 31, Pages: 9, Words: 5519
                Categories
                Research Article
                clinical-microbiology, Clinical Microbiology
                Custom metadata
                August 2024

                klebsiella,uti,fosfomycin,broth microdilution,susceptibility

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