Abstract
The chemotherapeutic options for methicillin-resistant Staphylococcus aureus (MRSA) infections are limited. Due to the multiple resistant MRSA, therapeutic failure has occurred frequently, even using antibiotics belonging to different categories in clinical scenarios, very recently. This study aimed to investigate the interactions between 11 antibiotics representing different mechanisms of action against MRSA strains and provide therapeutic strategies for clinical infections. Susceptibilities for MRSA strains were determined by broth microdilution or agar dilution according to CLSI guideline. By grouping with each other, a total of 55 combinations were evaluated. The potential synergism was detected through drug interaction assays and further investigated for time-killing curves and an in vivo neutropenic mouse infection model. A total of six combinations (vancomycin with rifampicin, vancomycin with oxacillin, levofloxacin with oxacillin, gentamycin with oxacillin, clindamycin with oxacillin, and clindamycin with levofloxacin) showed synergistic activity against the MRSA ATCC 43300 strain. However, antibacterial activity against clinical isolate #161402 was only observed when vancomycin combined with oxacillin or rifampicin in time-killing assays. Next, therapeutic effectiveness of vancomycin/oxacillin and vancomycin/rifampicin was verified by an in vivo mouse infection model inoculated with #161402. Further investigations on antimicrobial synergism of vancomycin plus oxacillin and vancomycin plus rifampicin against 113 wild-type MRSA strains were evidenced by combined antibiotic MICs and bacterial growth inhibition and in vitro dynamic killing profiles. In summary, vancomycin/rifampicin and vancomycin/oxacillin are the most potential combinations for clinical MRSA infection upon both in vitro and in vivo tests. Other synergetic combinations of levofloxacin/oxacillin, gentamycin/oxacillin, clindamycin/oxacillin, and clindamycin/fosfomycin are also selected but may need more assessment for further application.
Highlights
The inappropriate use and overuse of antibiotics have facilitated the emergence of drug-resistant or even multiple-drug-resistant (MDR) Staphylococcus aureus worldwide (Rodríguez-Lázaro et al, 2017)
Antibacterial activity against clinical isolate #161402 was only observed when vancomycin combined with oxacillin or rifampicin in time-killing assays
The further experimental verification elucidated that vancomycin combined with oxacillin or rifampicin has synergistic antibacterial activity against the clinical wild-type
Summary
The inappropriate use and overuse of antibiotics have facilitated the emergence of drug-resistant or even multiple-drug-resistant (MDR) Staphylococcus aureus worldwide (Rodríguez-Lázaro et al, 2017). Methicillin-resistant S. aureus (MRSA) is a common pathogen for nosocomial infections and exhibits essential resistance to methicillin, oxacillin, nafcillin, carbapenems, and other β-lactams. Due to the rapid evaluation of antimicrobial resistance, MRSA strains have possessed reduced susceptibilities to vancomycin, daptomycin, levofloxacin, clindamycin, and sulfamethoxazole (Richter et al., 2011). Given that the monotherapy is limited in clinical treatment and the new drug development is a lengthy process, the combination therapy has currently become one of the most effective approaches against bacterial infections benefiting from the enlarged spectrum, enhanced antibacterial activity, minimized doses, and reduced drug toxicity of antibiotic combinations. Fosfomycin is a promising option to treat infections caused by multi-drug resistant (MDR) pathogens when combining with daptomycin or β-lactams (Coronado-Álvarez et al, 2019)
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