Synergistic Potential of Antimicrobial Combinations Against Methicillin-Resistant Staphylococcus aureus

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.

In Vitro Activity of Peptide Antibiotics in Combination With Other Antimicrobials on Extensively Drug-Resistant Acinetobacter baumannii in the Planktonic and Biofilm Cell

“…However, in our study, these three peptide antibiotics combined with rifampicin had 100% additive effects. We proposed that rifampicin inhibited the β subunit of bacterial RNA polymerase, while these three peptide antibiotics disrupted the bacterial cell wall synthesis, these combinations may disturb cell reproduction in different steps to enhance the antibacterial effects ( Douthit et al, 2020 ; Yu et al, 2020 ). Therefore, rifampicin could become an ideal choice for combination therapy with peptide antibiotics.…”

Quercetin Rejuvenates Sensitization of Colistin-Resistant Escherichia coli and Klebsiella Pneumoniae Clinical Isolates to Colistin

“…Of note, quercetin can scavenge free radicals to prevent lipid peroxidation, inhibiting tumor proliferation ( Reyes-Farias and Carrasco-Pozo, 2019 ). Also, it has been reported that the combination of quercetin with other antibiotics such as vancomycin and tetracycline possess synergistic antibacterial activity against E. coli and Staphylococcus aureus ( Qu et al, 2019 ; Yu et al, 2020 ). In addition, quercetin possesses low cytotoxicity and can increase intracellular oxidative stress in tumor cells usually at concentrations >40 mM( Vargas and Burd, 2010 ).…”

“…The checkerboard assay was conducted to explore the synergy effect between colistin and quercetin via determining the fractional inhibitory concentration (FIC) index ( Yu et al, 2020 ). Briefly, colistin was continuously dilute 2-fold along the x -axis, while quercetin was continuously diluted 2-fold along the y -axis to establish a matrix in 96-well plates, where each well contained different concentrations of two drugs.…”

The Fusaric Acid Derivative qy17 Inhibits Staphylococcus haemolyticus by Disrupting Biofilm Formation and the Stress Response via Altered Gene Expression

“…The kinetics of the bactericidal action of qy17 and qy20 on S. haemolyticus were studied with an improved method ( Yu et al, 2020 ). A 96-well plate contained a bacterial suspension (5 × 10 7 CFUs/mL, final concentration) and MHB containing qy17 and qy20 (8, 16, and 32 μg/mL, final concentrations).…”