Specific gyrA gene mutations predict poor treatment outcome in MDR-TB

Autor: K. J. M. Aung, Nele Coeck, Conor J. Meehan, Leen Rigouts, M A Hossain, B. C. de Jong, W B de Rijk, Hans L. Rieder, A. Van Deun, K Fissette, M Gumusboga
Přispěvatelé: University of Zurich, Rigouts, L
Jazyk: angličtina
Rok vydání: 2015
Předmět:
0301 basic medicine
Oncology
Antitubercular Agents
medicine.disease_cause
DNA gyrase
2726 Microbiology (medical)
Moxifloxacin
Tuberculosis
Multidrug-Resistant
2736 Pharmacology (medical)
Pharmacology (medical)
heterocyclic compounds
Original Research
Mutation
Bangladesh
biology
Pharmacology. Therapy
3. Good health
3004 Pharmacology
Infectious Diseases
Treatment Outcome
DNA Gyrase
medicine.drug
Fluoroquinolones
Microbiology (medical)
medicine.medical_specialty
Tuberculosis
030106 microbiology
Mutation
Missense
610 Medicine & health
Microbial Sensitivity Tests
Microbiology
Mycobacterium tuberculosis
03 medical and health sciences
Internal medicine
medicine
Humans
Gene
Biology
Pharmacology
business.industry
10060 Epidemiology
Biostatistics and Prevention Institute (EBPI)
2725 Infectious Diseases
biology.organism_classification
medicine.disease
bacterial infections and mycoses
Gatifloxacin
Ofloxacin
Human medicine
business
Zdroj: Journal of Antimicrobial Chemotherapy
The journal of antimicrobial chemotherapy
ISSN: 1460-2091
0305-7453
Popis: Objectives Mutations in the gyrase genes cause fluoroquinolone resistance in Mycobacterium tuberculosis. However, the predictive value of these markers for clinical outcomes in patients with MDR-TB is unknown to date. The objective of this study was to determine molecular markers and breakpoints predicting second-line treatment outcomes in M. tuberculosis patients treated with fourth-generation fluoroquinolones. Methods We analysed treatment outcome data in relation to the gyrA and gyrB sequences and MICs of ofloxacin, gatifloxacin and moxifloxacin for pretreatment M. tuberculosis isolates from 181 MDR-TB patients in Bangladesh whose isolates were susceptible to injectable drugs. Results The gyrA 90Val, 94Gly and 94Ala mutations were most frequent, with the highest resistance levels for 94Gly mutants. Increased pretreatment resistance levels (>2 mg/L), related to specific mutations, were associated with lower cure percentages, with no cure in patients whose isolates were resistant to gatifloxacin at 4 mg/L. Any gyrA 94 mutation, except 94Ala, predicted a significantly lower proportion of cure compared with all other gyrA mutations taken together (all non-94 mutants + 94Ala) [OR = 4.3 (95% CI 1.4–13.0)]. The difference in treatment outcome was not explained by resistance to the other drugs. Conclusions Our study suggests that gyrA mutations at position 94, other than Ala, predict high-level resistance to gatifloxacin and moxifloxacin, as well as poor treatment outcome, in MDR-TB patients in whom an injectable agent is still effective.
Databáze: OpenAIRE
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