Oral fosfomycin is indicated for uncomplicated urinary tract infections with activity against MDR-uropathogens. Despite off-label use of giving 3 doses every 2-3 days, limited supporting data are available. We performed pharmacodynamic profiling using a dynamic bladder infection in vitro model to assess adequacy of repeat doses of fosfomycin.
A bladder infection in vitro model simulating urinary fosfomycin concentrations after 3g (equiv.) oral doses was used with Mueller-Hinton broth (MHB) with 25mg/L glucose-6-phosphate. Fosfomycin exposures were validated by LC-MS/MS measurements. Pharmacodynamic response of 16 clinical Enterobacteriaceae isolates were examined (8 E. coli, 4 E. cloacae, 4 K. pneumoniae; agar dilution MIC 0.25–64mg/L) following 3 doses of fosfomycin given every 72h, 48h or 24h, compared to single dose therapy. Pathogen kill and resistance was assessed by quantitative cultures on drug-free and fosfomycin-containing Mueller-Hinton agar (MHA +64mg/L, +512mg/L).
Fosfomycin exposure following single and multiple doses were accurately reproduced (mean deviation from target 5.0% ±3.4%, max 11.8%) with minimal variability (mean relative SD 2.7% ±1.7%, max 8.8%). Fosfomycin high-level heteroresistance was detected prior to drug exposure in 8/16 isolates (proportion 0.00002-0.001% of total population). All isolates with high-level heteroresistance regrew following single dose fosfomycin. Following 3-doses given every 72h, one additional K. pneumoniae isolate was killed. All other isolates regrew with amplification of HLR subpopulation (median proportion: 71.4%, IQR 57.5-100%). Despite dosing 48- and 24-hourly, the same isolates regrew, although HLR subpopulation amplification was reduced (48h dosing: 32.0%, IQR 0.005-83.3%; 24h dosing: 0.3%, IQR 0.0004-81.3%).
Dynamic in vitro modelling of multiple doses of oral fosfomycin fails to additionally suppress regrowth in the majority of isolates compared to single dose therapy. Baseline high-level heteroresistance is an important predictor for regrowth. These results suggest that giving multiple doses of fosfomycin is not necessarily better than standard single dose therapy. Earlier timing of repeat doses may help suppress the emergence of resistance.
N. Broos, None
A. Peleg, None
J. Mouton, None