Increased activity of linezolid in combination with rifampicin in a murine pneumonia model due to MRSA. (20th April 2018)

• Record Type: Journal Article
• Authors: Zhou, Yu-Feng; Xiong, Yan Q; Tao, Meng-Ting; Li, Liang; Bu, Ming-Xiao; Sun, Jian; Liao, Xiao-Ping; Liu, Ya-Hong
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 73:Number 7(2018)
• Page Start: 1899
• Page End: 1907
• Publication Date: 2018-04-20
• Subjects: Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dky129
• Languages: English
• ISSNs: 0305-7453

Abstract

Abstract: Objectives: The chloramphenicol/florfenicol resistance gene cfr, which mediates cross-resistance to linezolid and other classes of antimicrobial agents, represents a global therapeutic challenge due to its dissemination among MDR nosocomial pathogens, including MRSA. This study aimed to compare the efficacy of the linezolid/rifampicin combination in a murine pneumonia model caused by cfr -positive and cfr -negative clinical MRSA strains. Methods: Synergistic activity between linezolid and rifampicin was evaluated by chequerboard and time–kill assays. Pharmacokinetic profiles in plasma and epithelial lining fluid (ELF) as well as the therapeutic efficacy of linezolid alone and in combination with rifampicin were investigated in a murine pneumonia model. The E max Hill equation was used to model the dose–response relationship. Results: Increased susceptibility of the study MRSA strains to linezolid was observed with the rifampicin combination (MIC decreased 2- to 16-fold versus linezolid alone). The combination had synergistic activity (fractional inhibitory concentration index ≤0.5) against all cfr -positive MRSA isolates. Linezolid demonstrated excellent pulmonary penetration with an ELF/ f plasma AUC ratio of 2.68 ± 0.17. The addition of rifampicin significantly improved the efficacy of linezolid in the pneumonia model due to cfr -positive and cfr -negative MRSA strains. The f AUC/MIC targets of linezolid associated with stasis, 1 log10 kill and 2 log10 kill were 15.9, 38.8 and 175 in plasma, and 43.5, 108 and 415 in ELF, respectively. Importantly, the linezolid f AUC/MIC targets in both plasma and ELF were 2.4–6.7 times lower in combined linezolid/rifampicin therapy versus linezolid monotherapy ( P < 0.005). Conclusions: Combination of linezolid with rifampicin significantly improved the efficacy of linezolid in the murine pneumonia model caused by MRSA strains in the presence and absence of the cfr gene.