Dataset Information

Rifampicin reduces susceptibility to ofloxacin in rifampicin-resistant Mycobacterium tuberculosis through efflux.

ABSTRACT:

Rationale

Central dogma suggests that rifampicin resistance in Mycobacterium tuberculosis develops solely through rpoB gene mutations.

Objective

To determine whether rifampicin induces efflux pumps activation in rifampicin resistant M. tuberculosis strains thereby defining rifampicin resistance levels and reducing ofloxacin susceptibility.

Methods

Rifampicin and/or ofloxacin minimum inhibitory concentrations (MICs) were determined in rifampicin resistant strains by culture in BACTEC 12B medium. Verapamil and reserpine were included to determine their effect on rifampicin and ofloxacin susceptibility. RT-qPCR was applied to assess expression of efflux pump/transporter genes after rifampicin exposure. To determine whether verapamil could restore susceptibility to first-line drugs, BALB/c mice were infected with a MDR-TB strain and treated with first-line drugs with/without verapamil.

Measurements and main findings

Rifampicin MICs varied independently of rpoB mutation and genetic background. Addition reserpine and verapamil significantly restored rifampicin susceptibility (p = 0.0000). RT-qPCR demonstrated that rifampicin induced differential expression of efflux/transporter genes in MDR-TB isolates. Incubation of rifampicin mono-resistant strains in rifampicin (2 μg/ml) for 7 days induced ofloxacin resistance (MIC > 2 μg/ml) in strains with an rpoB531 mutation. Ofloxacin susceptibility was restored by exposure to efflux pump inhibitors. Studies in BALB/c mice showed that verapamil in combination with first-line drugs significantly reduced pulmonary CFUs after 1 and 2 months treatment (p < 0.05).

Conclusion

Exposure of rifampicin resistant M. tuberculosis strains to rifampicin can potentially compromise the efficacy of the second-line treatment regimens containing ofloxacin, thereby emphasising the need for rapid diagnostics to guide treatment. Efflux pump inhibitors have the potential to improve the efficacy of anti-tuberculosis drug treatment.

SUBMITTER: Louw GE

PROVIDER: S-EPMC3698754 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Rifampicin reduces susceptibility to ofloxacin in rifampicin-resistant Mycobacterium tuberculosis through efflux.

Louw Gail E GE Warren Robin M RM Gey van Pittius Nicolaas C NC Leon Rosalba R Jimenez Adelina A Hernandez-Pando Rogelio R McEvoy Christopher R E CR Grobbelaar Melanie M Murray Megan M van Helden Paul D PD Victor Thomas C TC

American journal of respiratory and critical care medicine 20110421 2

<h4>Rationale</h4>Central dogma suggests that rifampicin resistance in Mycobacterium tuberculosis develops solely through rpoB gene mutations.<h4>Objective</h4>To determine whether rifampicin induces efflux pumps activation in rifampicin resistant M. tuberculosis strains thereby defining rifampicin resistance levels and reducing ofloxacin susceptibility.<h4>Methods</h4>Rifampicin and/or ofloxacin minimum inhibitory concentrations (MICs) were determined in rifampicin resistant strains by culture ...[more]

PMID: 21512166

Similar Datasets

Project description:BackgroundMulti-drug resistant Mycobacterium tuberculosis is a growing public health problem in developing countries including Somalia. Although, the prevalence of multi-drug resistant tuberculosis among new and retreated cases is high, data on GeneXpert- Mycobacterium tuberculosis/rifampicin-resistant assay, which is a surrogate marker for multidrug resistance, is not well explored in Mogadishu.ObjectivesTo determine the prevalence of rifampicin-resistant Mycobacterium tuberculosis and its associated factors among presumptive pulmonary tuberculosis patients visiting tuberculosis centers in Mogadishu, Somalia.MethodsA multicenter cross-sectional study was conducted in three tuberculosis treatment centers from March 12 to April 30, 2021. Laboratory professionals collected sputum sample consecutively from presumptive pulmonary tuberculosis participants and performed a GeneXpert assay to determine the rifampicin resistance. Socio-demographic and clinical data were collected using structured questionnaire. Logistic regression analyses were performed to assess factors associated with rifampicin resistance using an adjusted odds ratio at a 95% confidence interval. Statistical significance was considered at a p-value of less than 0.05.ResultsA total of 370 presumptive tuberculosis suspects were included; of whom 58.4% were females and the mean age of the participants was 44.3 ± 14 years. Mycobacterium tuberculosis was detected in 63 (17%) (95% confidence interval = 13.2-20.8) suspects. Of these the prevalence of rifampicin-resistant Mycobacterium tuberculosis was 35% (95% confidence interval = 30.2-39.8). Anti-tuberculosis treatment history (adjusted odds ratio = 4.1; 95% confidence interval = 1.91-6.75), monthly income less than $100 USD (adjusted odds ratio = 2.2; 95% confidence interval = 1.77-5.98) and being diagnosed with Asthma (adjusted odds ratio = 2.63; 95% confidence interval = 1.3-7.3) were significantly associated with rifampicin-resistant tuberculosis.ConclusionA considerable proportion of rifampicin-resistant tuberculosis is reported in these study settings. The strong association between multidrug resistance tuberculosis and patients' retreatment history of tuberculosis, low income, and co-morbidity with asthma highlights the need for more efforts in tuberculosis treatment and monitoring programs to limit the emergence of multi-drug resistant strain in the study areas.

Dataset Information

Rifampicin reduces susceptibility to ofloxacin in rifampicin-resistant Mycobacterium tuberculosis through efflux.

Rationale

Objective

Methods

Measurements and main findings

Conclusion

Publications

Rifampicin reduces susceptibility to ofloxacin in rifampicin-resistant Mycobacterium tuberculosis through efflux.

Similar Datasets

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