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Identification of Persister Drug Combination Clinafloxacin+Cefuroxime+Gentamicin That Eradicates Persistent Pseudomonas aeruginosa Infection in a Murine Cystic Fibrosis Model

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Infectious Microbes & Diseases 2023年第1期5卷 21-28页

作者： Yuting Yuan Rebecca Yee Naina Gour Xinzhong Dong Jie Feng Wanliang Shi Ying Zhang Department of Molecular Microbiology and Immunology Johns Hopkins Bloomberg School of Public HealthBaltimoreMarylandUSA The Solomon H.Snyder Department of Neuroscience and the Center for Sensory Biology Johns Hopkins University School of MedicineBaltimoreMarylandUSA State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina Research Units of Infectious Disease and Microecology Chinese Academy of Medical SciencesHangzhouZhejiangChina Jinan Microecological Biomedicine Shandong Laboratory JinanShandongChina

Pseudomonas aeruginosa can cause persistent infections,such as biofilm infections,in cystic fibrosis patients,which are difficult to cure due to non-growing persister bacteria that are not effectively killed by the current *** antibiotic activity against growing *** is well documented,their activity against non-growing stationary phase cultures is less ***,we evaluated six major classes of antibiotics,including cell wall and cell membrane inhibitors,protein synthesis inhibitors,DNA synthesis inhibitors,RNA synthesis inhibitors,sulfa drugs and nitrofurantoin,for their activity against growing and non-growing *** foundthat cell wall and cell membrane inhibitors(cefuroxime and colistin),DNA synthesis inhibitors(clinafloxacin)and sulfa drugs(sulfamethoxazole)had good activity against stationary-phase bacteria,while protein synthesis inhibitors(gentamicin),RNA synthesis inhibitor(rifampin)and nitrofurantoin showed relatively poor *** was the only drug able to completely eradicate stationary-phase bacteria within four *** cefuroxime+gentamicin+clinafloxacin combination was able to kill all bacteria from a biofilm within two days,whereas the clinically used drug combination cefuroxime+gentamicin/colistin only partially killed the *** amurine persistent cystic fibrosis lung infectionmodel,only the cefuroxime+gentamicin+clinafloxacin drug combination eradicated all bacteria from the lungs,whereas clinafloxacin alone,cefuroxime+clinafloxacin or the currently recommended drug combination cefuroxime+gentamicin failed to do *** complete eradication is a property of the clinafloxacin combination,as the otherwise identical levofloxacin combination did not clear the bacterial loads from the *** findings offer new therapeutic options for more effective treatment of persistent *** infections,with possible implications for treating other persistent infections.

关键词： Pseudomonas aeruginosa persisters stationary-phase bacteria biofilm clinafloxacin cystic fibrosis

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