Genomic and in vitro pharmacodynamic analysis of rifampicin resistance in multidrug‐resistant canine Staphylococcus pseudintermedius isolates
Genomic and in vitro pharmacodynamic analysis of rifampicin resistance in multidrug‐resistant canine Staphylococcus pseudintermedius isolates
复制标题
多重耐药犬假中间葡萄球菌分离株利福平耐药性的基因组和体外药效学分析
DOI：
10.1111/vde.12959
复制
发表时间：
2021
影响因子：
1.4
通讯作者：
White, Amelia
中科院分区：
文献类型：
--
作者：
Hicks, Karly;Tan, Yongjun;Cao, Wenqi;Hathcock, Terri;Boothe, Dawn;Kennis, Robert;Zhang, Dapeng;Wang, Xu;White, Amelia
背景：犬假中间葡萄球菌皮炎的耐药性越来越受到关注.仅在耐甲氧西林和多药耐药假中间链球菌中考虑利福平（RFP）治疗（MDR-MRSP）。假设/目的为了确定MDR-MRSP治疗的最佳RFP剂量而不诱导RFP抗性并鉴定抗微生物剂抗性的因果突变。方法和材料在对照分离株和三种MDR-MRSP分离株中以六种临床相关浓度进行时间杀灭测定[32比1，024 × MIC（最小抑菌浓度）]。全基因组重测序和生物信息学分析进行耐药菌株在本assay.ResultsThe基因组分析确定了9个抗菌药物耐药基因（ARG）在MDR-MRSP分离株，这是负责耐7类抗生素。RFP对所有4种分离株的活性与时间依赖性和抑菌反应一致。在28项时间-杀灭试验中的6项中观察到RFP耐药性，包括MDR-MRSP 1分离株在24 h时的浓度64 × MIC、MDR-MRSP 2在48 h时的浓度32 × MIC、MDR-MRSP 3在48 h时的浓度32 × MIC和MDR-MRSP 3在24 h时的浓度256 × MIC。对这些RFP耐药菌株的全基因组突变分析发现了therpoB基因编码区的致病突变。结论和临床相关性一项研究表明，口服6 mg/kg导致假中间链球菌的血浆浓度为600- 1，000 × MIC。根据我们的数据，该剂量应达到最低MIC（×512），以防止RFP耐药性发展;因此，当抗生素选择有限时，我们建议MDR‐MRSP脓毒症治疗的最低日剂量为6 mg/kg。
BackgroundAntimicrobial resistance is a growing concern in canineStaphylococcus pseudintermediusdermatitis. Treatment with rifampicin (RFP) is considered only in meticillin‐resistant and multidrug‐resistantS. pseudintermedius(MDR‐MRSP).Hypothesis/ObjectivesTo determine an optimal RFP dosing for MDR‐MRSP treatment without induction of RFP resistance and identify causal mutations for antimicrobial resistance.Methods and materialsTime–kill assays were performed in a control isolate and three MDR‐MRSP isolates at six clinically relevant concentrations [32 to 1,024 × MIC (the minimum inhibitory concentration)]. Whole‐genome resequencing and bioinformatic analysis were performed in the resistant strains developed in this assay.ResultsThe genomic analysis identified nine antimicrobial resistance genes (ARGs) in MDR‐MRSP isolates, which are responsible for resistance to seven classes of antibiotics. RFP activity against all four isolates was consistent with a time‐dependent and bacteriostatic response. RFP resistance was observed in six of the 28 time–kill assays, including concentrations 64 × MIC in MDR‐MRSP1 isolates at 24 h, 32 × MIC in MDR‐MRSP2 at 48 h, 32 × MIC in MDR‐MRSP3 at 48 h and 256 × MIC in MDR‐MRSP3 at 24 h. Genome‐wide mutation analyses in these RFP‐resistant strains discovered the causal mutations in the coding region of therpoBgene.Conclusions and clinical relevanceA study has shown that 6 mg/kg per os results in plasma concentrations of 600–1,000 × MIC ofS. pseudintermedius. Based on our data, this dose should achieve the minimum MIC (×512) to prevent RFP resistance development; therefore, we recommend a minimum daily dose of 6 mg/kg for MDR‐MRSP pyoderma treatment when limited antibiotic options are available.