Iain J Abbott1,2, Joseph Meletiadis2,3, Imane Belghanch2, Rixt A Wijma2, Lamprini Kanioura2, Jason A Roberts4,5, Anton Y Peleg1,6, Johan W Mouton2. 1. Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia. 2. Department of Medical Microbiology and Infectious Diseases, Research and Development Unit, Erasmus Medical Centre, Rotterdam, The Netherlands. 3. Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Haidari, Athens, Greece. 4. Faculty of Medicine and School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia. 5. Royal Brisbane and Women's Hospital, Herston, Queensland, Australia. 6. Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria, Australia.
Abstract
Background: Urinary tract infections (UTIs) are among the most common bacterial infections and a frequent indication for antibiotic use. Fosfomycin, an important oral antibiotic for outpatient UTIs, remains a viable option for MDR uropathogens. We aimed to perform pharmacodynamic profiling simulating urinary concentrations to assess the adequacy of the current dosing regimen. Methods: A dynamic in vitro bladder infection model was developed, replicating urinary fosfomycin concentrations after gastrointestinal absorption, systemic distribution and urinary elimination. Concentrations were measured by LC-MS/MS. Twenty-four Enterobacteriaceae strains (Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae; MIC range 0.25-64 mg/L) were examined. Pathogen kill and emergence of resistance was assessed over 72 h. Results: Observed in vitro fosfomycin concentrations accurately simulated urinary fosfomycin exposures (Tmax 3.8 ± 0.5 h; Cmax 2630.1 ± 245.7 mg/L; AUC0-24 33 932.5 ± 1964.2 mg·h/L). Fifteen of 24 isolates regrew, with significant rises in fosfomycin MIC (total population MIC50 4 to 64 mg/L, MIC90 64 to > 1024 mg/L, P = 0.0039; resistant subpopulation MIC50 128 to > 1024 mg/L, MIC90 >1024 mg/L, P = 0.0020). E. coli and E. cloacae isolates were killed with pharmacokinetic/pharmacodynamic EI50 of fAUC0-24/MIC = 1922, fCmax/MIC = 149 and fTime>4×MIC = 44 h. In contrast, K. pneumoniae isolates were not reliably killed. Conclusions: Using dynamic in vitro simulations of urinary fosfomycin exposures, E. coli and E. cloacae isolates with MIC >16 mg/L, and all K. pneumoniae isolates, were not reliably killed. Emergence of resistance was significant. This challenges fosfomycin dosing and clinical breakpoints, and questions the utility of fosfomycin against K. pneumoniae. Further work on in vitro dose optimization is required.
Background: Urinary tract infections (UTIs) are among the most common bacterial infections and a frequent indication for antibiotic use. Fosfomycin, an important oral antibiotic for outpatient UTIs, remains a viable option for MDR uropathogens. We aimed to perform pharmacodynamic profiling simulating urinary concentrations to assess the adequacy of the current dosing regimen. Methods: A dynamic in vitro bladder infection model was developed, replicating urinary fosfomycin concentrations after gastrointestinal absorption, systemic distribution and urinary elimination. Concentrations were measured by LC-MS/MS. Twenty-four Enterobacteriaceae strains (Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae; MIC range 0.25-64 mg/L) were examined. Pathogen kill and emergence of resistance was assessed over 72 h. Results: Observed in vitro fosfomycin concentrations accurately simulated urinary fosfomycin exposures (Tmax 3.8 ± 0.5 h; Cmax 2630.1 ± 245.7 mg/L; AUC0-24 33 932.5 ± 1964.2 mg·h/L). Fifteen of 24 isolates regrew, with significant rises in fosfomycin MIC (total population MIC50 4 to 64 mg/L, MIC90 64 to > 1024 mg/L, P = 0.0039; resistant subpopulation MIC50 128 to > 1024 mg/L, MIC90 >1024 mg/L, P = 0.0020). E. coli and E. cloacae isolates were killed with pharmacokinetic/pharmacodynamic EI50 of fAUC0-24/MIC = 1922, fCmax/MIC = 149 and fTime>4×MIC = 44 h. In contrast, K. pneumoniae isolates were not reliably killed. Conclusions: Using dynamic in vitro simulations of urinary fosfomycin exposures, E. coli and E. cloacae isolates with MIC >16 mg/L, and all K. pneumoniae isolates, were not reliably killed. Emergence of resistance was significant. This challenges fosfomycin dosing and clinical breakpoints, and questions the utility of fosfomycin against K. pneumoniae. Further work on in vitro dose optimization is required.
Authors: E Wenzler; K M Meyer; S C Bleasdale; M Sikka; R E Mendes; K L Bunnell; M Finnemeyer; S L Rosenkranz; L H Danziger; K A Rodvold Journal: Antimicrob Agents Chemother Date: 2020-01-27 Impact factor: 5.191
Authors: J M Rodríguez-Martínez; F Docobo-Pérez; M Ortiz-Padilla; I Portillo-Calderón; B de Gregorio-Iaria; J Blázquez; J Rodríguez-Baño; A Pascual Journal: Antimicrob Agents Chemother Date: 2021-02-17 Impact factor: 5.191
Authors: Iain J Abbott; Elke van Gorp; Aart van der Meijden; Rixt A Wijma; Joseph Meletiadis; Jason A Roberts; Johan W Mouton; Anton Y Peleg Journal: Antimicrob Agents Chemother Date: 2020-05-21 Impact factor: 5.191
Authors: Iain J Abbott; Elke van Gorp; Rixt A Wijma; Joseph Meletiadis; Jason A Roberts; Johan W Mouton; Anton Y Peleg Journal: Antimicrob Agents Chemother Date: 2020-02-21 Impact factor: 5.191