Assessment of anti-MRSA activity of auranofin and florfenicol combination: a PK/PD analysis

Methicillin-resistant Staphylococcus aureus (MRSA) is an important zoonotic pathogen with multidrug-resistant phenotypes increasingly prevalent in both human and veterinary clinics. This study evaluated the potential of auranofin (AF) as an antibiotic adjuvant to enhance the anti-MRSA activity of fl...

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Published in:Journal of applied microbiology 2024-12, Vol.135 (12)
Main Authors: Li, Jian-Guo, Zhang, Chuan-Jian, Liang, Liu-Yan, Lu, Ting-Yin, Zhong, Long-Gen, Zhong, Wei-Cheng, Niu, Chao-Yan, Sun, Jian, Liao, Xiao-Ping, Zhou, Yu-Feng
Format: Article
Language:English
Subjects:
Animals
Anti-Bacterial Agents - pharmacokinetics
Anti-Bacterial Agents - pharmacology
Auranofin - pharmacology
Biofilms - drug effects
Drug Synergism
Drug Therapy, Combination
Larva - drug effects
Methicillin-Resistant Staphylococcus aureus - drug effects
Mice
Microbial Sensitivity Tests
Moths - drug effects
Moths - microbiology
Staphylococcal Infections - drug therapy
Staphylococcal Infections - microbiology
Thiamphenicol - analogs & derivatives
Thiamphenicol - pharmacokinetics
Thiamphenicol - pharmacology
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Summary:Methicillin-resistant Staphylococcus aureus (MRSA) is an important zoonotic pathogen with multidrug-resistant phenotypes increasingly prevalent in both human and veterinary clinics. This study evaluated the potential of auranofin (AF) as an antibiotic adjuvant to enhance the anti-MRSA activity of florfenicol (FFC) and established a pharmacokinetic/pharmacodynamic (PK/PD) model to compare the efficacy of FFC alone or in combination with AF against MRSA. We observed an increased susceptibility and significant synergistic effects of MRSA to FFC in the presence of AF. The combination treatment of FFC and AF significantly inhibited MRSA biofilm formation and decreased the metabolic activity of mature biofilms. Importantly, AF fully restored the efficacy of FFC in both Galleria mellonella larvae and murine models. PK/PD studies demonstrated that the AUC24h/MIC targets required to achieve the bacteriostatic and bactericidal effects were significantly lower with the combination therapy compared to florfenicol monotherapy. These results reveal the potential of AF as a novel adjuvant to improve the efficacy of FFC in treating MRSA invasive infections and provide valuable PK/PD insights for designing effective combination therapies.
ISSN:1365-2672
1365-2672
DOI:10.1093/jambio/lxae299