In Vitro Activity of Oxazolidinone against Nontuberculous Mycobacteria, Including Macrolide-Resistant Clinical Isolates.
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ABSTRACT:
SUBMITTER: Kim DH
PROVIDER: S-EPMC8218642 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Bedaquiline (BDQ) has been proven to be effective in the treatment of multidrug-resistant tuberculosis. We hypothesized that BDQ could be a potential agent to treat nontuberculous mycobacterial (NTM) infection. The objective of this study was to evaluate the in vitro activity of BDQ against rapidly growing mycobacteria by assessing the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) against 18 NTM strains. For MIC determination we performed the resazurin microtitre assay broth dilution, and for the MBC the c.f.u. was determined. BDQ exhibited a strong inhibitory effect against most NTM tested; however, for some NTM strains the MBC was significantly higher than the MIC. A new finding is that Mycobacterium flavescens has a mutation in the gene atpE associated with natural resistance to BDQ. These preliminary promising results demonstrate that BDQ could be potentially useful for the treatment of NTM.
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Project description:The main goal of our study was to evaluate the in vitro bedaquiline susceptibility of six prevalent species of pathogenic nontuberculous mycobacteria (NTM) in China. In addition, we investigated the potential molecular mechanisms contributing to bedaquiline resistance in the different NTM species. Among slowly growing mycobacteria (SGM), bedaquiline exhibited the highest activity against Mycobacterium avium; the MIC50 and MIC90 values were 0.03 and 16 mg/liter, respectively. Among rapidly growing mycobacteria (RGM), Mycobacterium abscessus subsp. abscessus (M. abscessus) and Mycobacterium abscessus subsp. massiliense (M. massiliense) seemed more susceptible to bedaquiline than Mycobacterium fortuitum, with MIC50 and MIC90 values of 0.13 and >16 mg/liter, respectively, for both species. On the basis of bimodal distributions of bedaquiline MICs, we proposed the following epidemiological cutoff (ECOFF) values: 1.0 mg/liter for SGM and 2.0 mg/liter for RGM. Among M. avium, Mycobacterium intracellulare, Mycobacterium kansasii, M. abscessus, M. massiliense, and M. fortuitum isolates, 14 (29.8%), 41 (27.2%), 33 (39.3%), 44 (20.2%), 42 (25.8%), and 7 (31.8%), respectively, were resistant to bedaquiline. No significant differences in the proportions of bedaquiline resistance among these species were observed (P > 0.05). Genetic mutations were observed in 74 isolates (10.8%), with all nucleotide substitutions being synonymous. In conclusion, our data demonstrate that bedaquiline shows moderate in vitro activity against NTM species. Using the proposed ECOFF values, we could distinguish between bedaquiline-resistant and -susceptible strains with the broth dilution method. In addition, no nonsynonymous mutations in the atpE gene that conferred bedaquiline resistance in all six NTM species were identified.
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Project description:Due to the natural resistance of nontuberculous mycobacteria (NTM) to many antibiotics, the treatment of diseases caused by NTM is often long-term but unsuccessful. The main goal of this study was to evaluate the in vitro susceptibilities to clofazimine of 209 isolates consisting of different NTM species isolated in Beijing, China. Furthermore, 47 reference strains were also tested, including 30 rapidly growing mycobacterium (RGM) species and 17 slowly growing mycobacterium (SGM) species. The potential molecular mechanism contributing to clofazimine resistance of NTM was investigated as well. Clofazimine exhibited excellent activity against both reference strains and clinical isolates of different SGM species, and most of the strains had MICs far below 1 μg/ml. Although the majority of the clinical isolates of Mycobacterium abscessus and Mycobacterium fortuitum had MICs higher than 2 μg/ml, 17 out of the 30 reference strains of different RGM species had MICs below 1 μg/ml in vitro According to the MIC distributions, the tentative epidemiological cutoff (ECOFF) values for Mycobacterium kansasii, Mycobacterium avium, and Mycobacterium intracellulare were defined at 0.5 μg/ml, 1 μg/ml, and 2 μg/ml, respectively. Intriguingly, single-direction cross-resistance between bedaquiline- and clofazimine (Cfz)-resistant isolates was observed among the tested NTM species. This study demonstrates that clofazimine had strong activity against most SGM species in vitro, as well as some RGM species. The data provide important insights into the possible clinical application of Cfz to treat NTM infections.
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Project description:IntroductionMultidrug resistant tuberculosis (MDR-TB) presents a great challenge to public health, especially for developing countries. Some nontuberculous mycobacteria (NTM) cause the similar clinical and radiological characteristics with tuberculosis. We aimed to identify the frequency of NTM infections among subjects who were suspected to have MDR-TB due to lack of response to anti-TB treatment.MethodsThis retrospective study evaluated patients with suspected MDR-TB due to lack of sputum conversion after 2-3 month therapy with first line anti-TB treatment from 2009 through 2014. Cultures for mycobacteria were performed and identification was done to species level by phenotypic and molecular tests. The outcome of the patients with NTM disease and related risk factors for poor outcome were evaluated.ResultsOut of 117 consecutive strains isolated from suspected MDR-TB subjects, 35 (30%) strains were identified as NTM by using conventional and molecular approaches. Of these patients with positive NTM cultures, 32 (27%) patients met ATS/IDSA diagnostic criteria. Out of 32, 29 (90%) individuals with confirmed NTM diseases had underlying disorders including 8 subjects with malignancy, 5 with organ transplantations, and 4 with the human immunodeficiency virus. No known underlying disorder was found in 3 (9%) subjects. Treatment outcomes were available for 27 subjects, 17 (63%) of whom were cured and 10 (37%) had poor outcome including 6 (60%) who failed and 4 (40%) who died during treatment.ConclusionThe high costs to the patient and society should lead health care providers to consider NTM in all patients suspected of having TB.
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Project description:Nontuberculous mycobacteria Metagenome
| PRJNA779755 | ENA
Project description:The NTM Project at the Children's Hospital of Philadelphia
| PRJNA532547 | ENA
Project description:Limited data are available regarding the in vitro activity of clofazimine against nontuberculous mycobacteria (NTM) or on outcomes of clofazimine-containing regimens in NTM-pulmonary disease (PD). Therefore, we evaluated the in vitro activity of clofazimine and the clinical outcomes of clofazimine-containing regimens. We evaluated clofazimine in vitro activity for 303 NTM isolates from NTM-PD patients. Fifty-seven clarithromycin-resistant and 35 amikacin-resistant isolates were also analyzed. Culture conversion after a 12-month treatment regimen containing clofazimine was evaluated in 58 NTM-PD patients, including 20 patients with drug-resistant isolates. Most of the 303 isolates (238/303) had minimum inhibitory concentrations (MICs) ≤ 0.25 µg/mL for clofazimine (57/63 Mycobacterium avium, 53/57 M. intracellulare, 49/52 M. kansasii, 22/64 M. abscessus, and 57/67 M. massiliense). For the 57 clarithromycin-resistant and 35 amikacin-resistant isolates, most had MICs ≤ 0.25 µg/mL (47/57 and 32/35, respectively). Among the 38 NTM-PD patients without resistance to clarithromycin or amikacin, 47% achieved culture conversion (8/27 M. abscessus, 9/9 M. massiliense, 0/1 M. avium, and 1/1 M. intracellulare). The conversion rate was higher in the MIC ≤ 0.25 µg/mL group than in the MIC = 0.5 µg/mL group (13/18 vs. 5/20, p = 0.004), and an MIC ≤ 0.25 µg/mL remained a significant factor in multivariable analysis. Culture conversion was achieved in 20% of 20 patients with clarithromycin- or amikacin-resistant isolates. However, a clofazimine MIC ≤ 0.25 µg/mL was not significant for culture conversion in the 58 NTM-PD patients, regardless of the drug resistance pattern. Clofazimine was effective in vitro against NTM species. Some patients on clofazimine-containing regimens achieved culture conversion.
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Project description:Due to the natural resistance of nontuberculous mycobacteria (NTM) against multiple antibiotics, treatment of infections caused by them is often long-course and less successful. The main objective of our study was the evaluation of in vitro susceptibility of 209 isolates consisting of different NTM species against bedaquiline and delamanid. Furthermore, reference strains of 33 rapidly growing mycobacterium (RGM) species and 19 slowly growing mycobacterium (SGM) species were also tested. Bedaquiline exhibited strong in vitro activity against both reference strains and clinical isolates of different SGM species, as the majority of the strains demonstrated MICs far below 1 μg/ml. Bedaquiline (Bdq) also exhibited potent activity against the recruited RGM species. A total of 29 out of 33 reference RGM strains had MICs lower than 1 μg/ml. According to the MIC distributions, the tentative epidemiological cutoff (ECOFF) values, and the pharmacokinetic data, a uniform breakpoint of 2 μg/ml was temporarily proposed for NTM's Bdq susceptibility testing. Although delamanid (Dlm) was not active against most of the tested reference strains and clinical isolates of RGM species, it exhibited highly variable antimicrobial activities against the 19 tested SGM species. Eleven species had MICs lower than 0.25 μg/ml, and 7 species had MICs greater than 32 μg/ml. Large numbers of M. kansasii (39/45) and M. gordonae (6/10) clinical isolates had MICs of ≤0.125 μg/ml. This study demonstrated that bedaquiline had potent activity against different NTM species in vitro, and delamanid had moderate activity against certain species of SGM. The data provided important insights on the possible clinical application of Bdq and Dlm to treat NTM infections.
| S-EPMC6658755 | biostudies-literature