A unique mechanism of action of fosfomycin made cross-resistance to other antibiotic classes less common, which motivated physicians to reevaluate its ability to destroy drug-resistant pathogens, including MRSA [16]. In our study, elderly patients seemingly had the tendency of acquisition of fofsomycin-resistant MRSA infections, and the vast majority of those resistant strains were isolated from those hospitals located in central or southern Taiwan. The background mechanisms of this phenomenon need further investigation. Although the MRSA isolates exhibited high in vitro susceptibility to fosfomycin higher than 90%, a significant increase in fosfomycin resistance rate during past decades (from 3.4% in 2002 to 11.0% in 2012) was observed in Taiwan. Among the fosfomycin-resistant isolates, a higher resistance rate to clindamycin, ciprofloxacin, erythromycin, and rifampicin was noted; however, trimethoprim/sulfamethoxazole and tetracycline displayed more favorable susceptibility. Type IuhpT and type IglpT mutations predominantly caused fosfomycin resistance in our MRSA isolates, and the vast majority of isolates belonged to spa type t002.
Little was known about the MRSA fosfomycin resistance mechanism in epidemiological research, and very few literature reports were previously published [15, 28, 29]. Of those studies, a large-scale surveillance conducted by Fu et al. [15] in China demonstrated a 13.4% (9/67) fosB-positive rate with two-thirds (6/9) belonging to ST5. A research study by Etienne et al. [28] revealed that 18 of 39 (46.2%) S. aureus isolates, containing the fosB gene, were highly resistant to fosfomycin, but only one MRSA isolate had the fosB gene (Zhejiang, China) [29]. In our present study, approximately one-fifth of the MRSA isolates with fosfomycin resistance carried the fosB gene with the dominant t002 spa typing (11/12), which belonged to ST5. Our finding was similar to that described in Fu’s report; it implicated the presence of clonal spread among the fosB-positive MRSA isolates, despite the previously reported triviality of fosB [30].
MurA, a target enzyme involved in the biosynthesis of bacterial peptidoglycan, could be inactivated by fosfomycin via its binding to the active site of the enzyme [16]. However, mutations of the murA gene resulted in amino acid substitutions, rendering susceptible clinical isolates resistant to fosfomycin [16]. Fu et al. [15] illustrated that a murA mutation played an unclear role in the fosfomycin resistance in their study, and a type IImurA mutant was the most common among all murA mutations. Our results were different in this regard. The difference in the source of clinical specimens in these two studies might indicate that the mechanisms of fosfomycin resistance are different in Taiwan and mainland China.
The vast majority of the MRSA isolates in the present study possessed at least one of glpT and/or uhpT mutations, implicating that the genes, encoding transporter mutants, contributed to fosfomycin resistance substantially. This result contrasted to the findings of the preceding study [15]. The prevailing subtype of mutations in the glpT and uhpT genes was also different from that reported by Fu et al [15]. Forty-eight fosfomycin-resistant MRSA isolates with dual resistance mechanisms (glpT and uhpT mutations) belonged to spa type t002, again implying clonal spread of fosfomycin-resistant MRSA.
The most prevalent and the second most common spa types were t002 and t037 in our study, respectively, revealing that Fosfomycin-resistant MRSA isolates were concentrated in some specific molecular types. A similar distribution was noticed in other countries, including Sweden, Korea, China, Iran, Africa, Canada, and Brazil [31]. An international, or even intercontinental spread of specific fosfomycin-resistant MRSA clones may be occurring.
In the present study, the susceptibility of the MRSA isolates to various antibiotics was similar to that reported in the previous studies from Taiwan [8, 27] but different from that in other countries [32–34]. Variation in drug susceptibility between geographic areas might be due to the presence of different prevalent MRSA clones and the difference in antibiotic selective pressure.
The major limitation of the present study is that it was conducted using the clinical MRSA isolates in Taiwan; thus, worldwide generalization of the results should be made carefully.