Fosfomycin Resistance in Escherichia coli Isolates from South Korea and in vitro Activity of Fosfomycin Alone and in Combination with Other Antibiotics

Abstract

We investigated fosfomycin susceptibility in Escherichia coli clinical isolates from South Korea, including community-onset, hospital-onset, and long-term care facility (LTCF)-onset isolates. The resistance mechanisms and genotypes of fosfomycin-resistant isolates were also identified. Finally, the in vitro efficacy of combinations of fosfomycin with other antibiotics were examined in susceptible or extended spectrum β-lactamase (ESBL)-producing E. coli isolates. The fosfomycin resistance rate was 6.7% and was significantly higher in LTCF-onset isolates than community-onset and hospital-onset isolates. Twenty-one sequence types (STs) were identified among 19 fosfomycin-resistant E. coli isolates, showing diverse genotypes. fosA3 was found in only two isolates, and diverse genetic variations were identified in three genes associated with fosfomycin resistance, namely, GlpT, UhpT, and MurA. Some fosfomycin-resistant E. coli isolates carried no mutations. In vitro time-kill assays showed that fosfomycin alone did not exhibit an excellent killing activity, compared with ciprofloxacin in susceptible isolates and with ertapenem in ESBL producers. However, combining fosfomycin with cefixime or piperacillin-tazobactam eradicated susceptible or ESBL-producing isolates, respectively, even with 0.5× minimum inhibitory concentrations. Overall, we found a relatively high fosfomycin resistance rate in E. coli isolates from South Korea. Based on their genotypes and resistance mechanisms, most of the fosfomycin-resistant E. coli isolates might occur independently. Antibiotic combinations with fosfomycin could be a suitable therapeutic option for infections caused by E. coli isolates.

Keywords: cefixime; fosfomycin; in vitro time-kill; piperacillin-tazobactam.

Figure 1

Time-kill curves for ciprofloxacin, cefixime, and fosfomycin against susceptible E. coli isolates, C093 (ST216) and S088 (ST144-slv). (A and B), the results of 1× MICs of single antibiotics, (C and D), the results of 0.5× MICs of single and combination of antibiotics. CIP, ciprofloxacin; CFX, cefixime; FOS, fosfomycin.

Figure 2

Time-kill curves for ertapenem, piperacillin-tazobactam, and fosfomycin against ESBL-producing E. coli isolates, CTX-M-15-producing A038 (ST131) and CTX-M-14-producing C046 (ST1193). (A and B), the results of 1× MICs of single antibiotics, (C and D), the results of 0.5× MICs of single and combination of antibiotics. ETM, ertapenem; P/T, piperacillin-tazobactam; FOS, fosfomycin.