Wild-Type and Non-Wild-Type Mycobacterium tuberculosis MIC Distributions for the Novel Fluoroquinolone Antofloxacin Compared with Those for Ofloxacin, Levofloxacin, and Moxifloxacin.
Antofloxacin (AFX) is a novel fluoroquinolone that has been approved in China for the treatment of infections caused by a variety of bacterial species. We investigated whether it could be repurposed for the treatment of tuberculosis by studying its in vitro activity. We determined the wild-type and non-wild-type MIC ranges for AFX as well as ofloxacin (OFX), levofloxacin (LFX), and moxifloxacin (MFX), using the microplate alamarBlue assay, of 126 clinical Mycobacterium tuberculosis strains from Beijing, China, of which 48 were OFX resistant on the basis of drug susceptibility testing on Löwenstein-Jensen medium. The MIC distributions were correlated with mutations in the quinolone resistance-determining regions of gyrA (Rv0006) and gyrB (Rv0005). Pharmacokinetic/pharmacodynamic (PK/PD) data for AFX were retrieved from the literature. AFX showed lower MIC levels than OFX but higher MIC levels than LFX and MFX on the basis of the tentative epidemiological cutoff values (ECOFFs) determined in this study. All strains with non-wild-type MICs for AFX harbored known resistance mutations that also resulted in non-wild-type MICs for LFX and MFX. Moreover, our data suggested that the current critical concentration of OFX for Löwenstein-Jensen medium that was recently revised by the World Health Organization might be too high, resulting in the misclassification of phenotypically non-wild-type strains with known resistance mutations as wild type. On the basis of our exploratory PK/PD calculations, the current dose of AFX is unlikely to be optimal for the treatment of tuberculosis, but higher doses could be effective.
National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China.
Xia
X
Yu
National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China.
Guirong
G
Wang
National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China.
Suting
S
Chen
National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China.
Guomei
G
Wei
National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China.
Yuanyuan
Y
Shang
National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China.
Lingling
L
Dong
Department of Medical Microbiology, Linköping University Hospital, Linköping, Sweden Department of Clinical Microbiology and Infectious Diseases, Kalmar County Hospital, Kalmar, Sweden.
Thomas
T
Schön
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Danesh
D
Moradigaravand
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Julian
0000-0002-7069-5958
J
Parkhill
Wellcome Trust Sanger Institute, Hinxton, United Kingdom Department of Medicine, University of Cambridge, Cambridge, United Kingdom London School of Hygiene & Tropical Medicine, London, United Kingdom.
Sharon J
SJ
Peacock
Department of Medicine, University of Cambridge, Cambridge, United Kingdom cuk21@cam.ac.uk huanghairong@tb123.org.
Claudio U
0000-0002-0232-846X
CU
Köser
National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China cuk21@cam.ac.uk huanghairong@tb123.org.
Hairong
H
Huang
D000995:Antitubercular Agents / Q000494:pharmacology*; D002681:China; D027081:DNA Gyrase / Q000235:genetics; D054796:Drug Dosage Calculations; D024881:Drug Resistance, Bacterial / Q000235:genetics; D024841:Fluoroquinolones / Q000494:pharmacology*; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D064704:Levofloxacin / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification; D015242:Ofloxacin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014397:Tuberculosis, Pulmonary / Q000382:microbiology
D000995:Antitubercular Agents; D024841:Fluoroquinolones; C522674:antofloxacin; D064704:Levofloxacin; D015242:Ofloxacin; D027081:DNA Gyrase; D000077266:Moxifloxacin