Oral fosfomycin activity against Klebsiella pneumoniae in a dynamic bladder infection in vitro model.

Abstract

INTRODUCTION:

The use of oral fosfomycin for urinary tract infections (UTIs) caused by non-Escherichia coli uropathogens is uncertain, including Klebsiella pneumoniae, the second most common uropathogen.

METHODS:

A multicompartment bladder infection in vitro model was used with standard media and synthetic human urine (SHU) to simulate urinary fosfomycin exposure after a single 3 g oral dose (fAUC0-72 16884 mg·h/L, t½ 5.5 h) against 15 K. pneumoniae isolates including ATCC 13883 (MIC 2 to >1024 mg/L) with a constant media inflow (20 mL/h) and 4-hourly voiding of each bladder. The impact of the media (CAMHB + G6P versus SHU) on fosfomycin MIC measurements, drug-free growth kinetics and regrowth after fosfomycin administration was assessed. A low and high starting inoculum (5.5 versus 7.5 log10 cfu/mL) was assessed in the bladder infection model.

RESULTS:

Compared with CAMHB, isolates in SHU had a slower growth rate doubling time (37.7 versus 24.1 min) and reduced growth capacity (9.0 ± 0.3 versus 9.4 ± 0.3 log10 cfu/mL), which was further restricted with increased inflow rate (40 mL/h) and more frequent voids (2-hourly). Regrowth was commonly observed in both media with emergence of fosfomycin resistance promoted by a high starting inoculum in CAMHB (MIC rise to ≥1024 mg/L in 13/14 isolates). Resistance was rarely detected in SHU, even with a high starting inoculum (MIC rise to ≥1024 mg/L in 2/14 isolates).

CONCLUSIONS:

Simulated in an in vitro UTI model, the regrowth of K. pneumoniae urinary isolates was inadequately suppressed following oral fosfomycin therapy. Efficacy was further reduced by a high starting inoculum.

• Authors: Iain J Abbott, Elke van Gorp, Kelly L Wyres, Steven C Wallis, Jason A Roberts, Joseph Meletiadis, Anton Y Peleg
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 77 Issue 5 Pg. 1324-1333 (04 27 2022) ISSN: 1460-2091 [Electronic] England
• PMID: 35211736 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.

Chemical References

• Anti-Bacterial Agents
• Culture Media
• Fosfomycin

Topics

• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Culture Media
• Cystitis (drug therapy)
• Escherichia coli
• Female
• Fosfomycin
• Humans
• Klebsiella Infections (drug therapy)
• Klebsiella pneumoniae
• Male
• Microbial Sensitivity Tests
• Urinary Bladder
• Urinary Tract Infections (drug therapy)