Efficacy of single and multiple oral doses of fosfomycin against Pseudomonas aeruginosa urinary tract infections in a dynamic in vitro bladder infection model Iain J. Abbott 1,2 , Elke van Gorp 2 , Rixt A. Wijma 2,3 , Jordy Dekker 2 , Peter D. Croughs 2 , Joseph Meletiadis 4 , Johan W. Mouton 2 and Anton Y. Peleg 1,5 * 1 Department of Infectious Diseases, The Alfred Hospital and Central Clinical School, Monash University, Melbourne, VIC, Australia; 2 Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands; 3 Department of Hospital Pharmacy, Erasmus University Medical Centre, Rotterdam, The Netherlands; 4 Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Haidari, Athens, Greece; 5 Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, VIC, Australia *Corresponding author. E-mail: anton.peleg@monash.edu Received 6 January 2020; returned 25 February 2020; revised 7 March 2020; accepted 11 March 2020 Objectives: We used a dynamic bladder infection in vitro model with synthetic human urine (SHU) to examine fosfomycin exposures to effectively kill, or prevent emergence of resistance, among Pseudomonas aeruginosa isolates. Methods: Dynamic urinary fosfomycin concentrations after 3g oral fosfomycin were simulated, comparing single and multiple (daily for 7days) doses. Pharmacodynamic response of 16 P. aeruginosa (MIC range 1 to >1024mg/L) were examined. Baseline disc diffusion susceptibility, broth microdilution MIC and detection of heteroresistance were assessed. Pathogen kill and emergence of resistance over 72h following a single dose, and over 216 h following daily dosing for 7 days, were investigated. The fAUC 0–24 /MIC associated with stasis and 1, 2 and 3 log 10 kill were determined. Results: Pre-exposure high-level resistant (HLR) subpopulations were detected in 11/16 isolates after drug-free incubation in the bladder infection model. Five of 16 isolates had >2 log 10 kill after single dose, reducing to 2/16 after seven doses. Post-exposure HLR amplification occurred in 8/16 isolates following a single dose and in 11/16 isolates after seven doses. Baseline MIC 8 mg/L with an HLR subpopulation predicted post-exposure emergence of resistance following the multiple doses. A PK/PD target of fAUC 0–24 /MIC >5000 was associated with 3 log 10 kill at 72 h and 7 day-stasis. Conclusions: Simulated treatment of P. aeruginosa urinary tract infections with oral fosfomycin was ineffective, despite exposure to high urinary concentrations and repeated daily doses for 7days. Emergence of resistance was observed in the majority of isolates and worsened following prolonged therapy. Detection of a baseline resistant subpopulation predicted treatment failure. Introduction Fosfomycin trometamol is a recommended first-line agent for un- complicated urinary tract infections (uUTIs) as a single 3 g oral dose, 1 active against MDR uropathogens, including Pseudomonas spp. 2 Although uUTIs are commonly caused by Escherichia coli (in approximately 75% of cases), Pseudomonas spp. are seen in 2%–4% of cases, with a higher proportion in complicated UTIs, hospital-acquired UTIs and those associated with indwelling urin- ary catheter use. 3–5 Given the intrinsic and acquired antimicrobial resistance mechanisms that Pseudomonas spp. express, and increasing rates of MDR isolates (15%–30%), 6 these infections represent challenging clinical cases with limited treatment options. Fluoroquinolones are the only orally active antipseudomo- nal agents that are readily available. When resistance is identified, parenteral therapy is often relied upon. Oral fosfomycin, therefore, is an attractive alternative agent. Fosfomycin has a unique chemical structure, lacks cross- resistance to other antimicrobials, and its small molecular mass (138 Da) and polarity mean it can readily cross the outer mem- brane of Gram-negative bacteria through porins. High urinary concentrations of fosfomycin are observed after a 3 g oral dose, with peak concentrations of 1000–2000 mg/L. 7,8 There is V C The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. 1879 J Antimicrob Chemother 2020; 75: 1879–1888 doi:10.1093/jac/dkaa127 Advance Access publication 3 May 2020 Downloaded from https://academic.oup.com/jac/article/75/7/1879/5828355 by guest on 29 January 2022