scholarly journals In Vitro Activity of Bedaquiline against Nontuberculous Mycobacteria in China

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Yu Pang ◽  
Huiwen Zheng ◽  
Yaoju Tan ◽  
Yuanyuan Song ◽  
Yanlin Zhao
Keyword(s):  
Molecular Mechanisms ◽  
Nontuberculous Mycobacteria ◽  
Mycobacterium Abscessus ◽  
Dilution Method ◽  
Mycobacterium Fortuitum ◽  
Nucleotide Substitutions ◽  
Content Type ◽  
Prevalent Species ◽  
Broth Dilution

ABSTRACT 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.

scholarly journals In VitroActivity of TP-271 against Mycobacterium abscessus, Mycobacterium fortuitum, and Nocardia Species

2012 ◽  
Vol 56 (7) ◽  
pp. 3986-3988 ◽  
Author(s):  
Michael Cynamon ◽  
Jeff Jureller ◽  
Balaji Desai ◽  
Krithika Ramachandran ◽  
Mary Sklaney ◽  
...  
Keyword(s):  
Mycobacterium Abscessus ◽  
Dilution Method ◽  
Mycobacterium Fortuitum ◽  
Nocardia Species ◽  
Content Type ◽  
Respective Control ◽  
Control Drug ◽  
Broth Dilution

ABSTRACTThein vitroactivities of TP-271, a novel fluorocycline antimicrobial, against 22 isolates ofMycobacterium abscessus, 22 isolates ofMycobacterium fortuitum, and 19 isolates ofNocardiaspp. were studied by a microtiter broth dilution method. The MIC90s forM. abscessus,M. fortuitum, andNocardiaspp. were 0.5 μg/ml, 0.03 μg/ml, and 8 μg/ml, respectively. TP-271 was significantly more active than the respective control drug in virtually all tests.

scholarly journals Effective Treatment of Mycobacterium avium subsp. hominissuis and Mycobacterium abscessus Species Infections in Macrophages, Biofilm, and Mice by Using Liposomal Ciprofloxacin

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
James D. Blanchard ◽  
Valerie Elias ◽  
David Cipolla ◽  
Igor Gonda ◽  
Luiz E. Bermudez
Keyword(s):  
Effective Treatment ◽  
Mouse Models ◽  
Mycobacterium Avium ◽  
Nontuberculous Mycobacteria ◽  
Mycobacterium Abscessus ◽  
Content Type ◽  
Number Of Individuals ◽  
Intranasal Instillation

ABSTRACT Nontuberculous mycobacteria (NTM) affect an increasing number of individuals worldwide. Infection with these organisms is more common in patients with chronic lung conditions, and treatment is challenging. Quinolones, such as ciprofloxacin, have been used to treat patients, but the results have not been encouraging. In this report, we evaluate novel formulations of liposome-encapsulated ciprofloxacin (liposomal ciprofloxacin) in vitro and in vivo. Its efficacy against Mycobacterium avium and Mycobacterium abscessus was examined in macrophages, in biofilms, and in vivo using intranasal instillation mouse models. Liposomal ciprofloxacin was significantly more active than free ciprofloxacin against both pathogens in macrophages and biofilms. When evaluated in vivo, treatment with the liposomal ciprofloxacin formulations was associated with significant decreases in the bacterial loads in the lungs of animals infected with M. avium and M. abscessus. In summary, topical delivery of liposomal ciprofloxacin in the lung at concentrations greater than those achieved in the serum can be effective in the treatment of NTM, and further evaluation is warranted.

scholarly journals In Vitro Activity of Bedaquiline and Delamanid against Nontuberculous Mycobacteria, Including Macrolide-Resistant Clinical Isolates

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Dae Hun Kim ◽  
Byung Woo Jhun ◽  
Seong Mi Moon ◽  
Su-Young Kim ◽  
Kyeongman Jeon ◽  
...  
Keyword(s):  
Mycobacterium Avium ◽  
Nontuberculous Mycobacteria ◽  
Mycobacterium Abscessus ◽  
Vitro Activity ◽  
Clinical Isolates ◽  
In Vitro Activity ◽  
Mycobacterium Kansasii ◽  
Antimicrobial Drugs ◽  
Content Type

ABSTRACT We evaluated the in vitro activities of the antimicrobial drugs bedaquiline and delamanid against the major pathogenic nontuberculous mycobacteria (NTM). Delamanid showed high MIC values for all NTM except Mycobacterium kansasii. However, bedaquiline showed low MIC values for the major pathogenic NTM, including Mycobacterium avium complex, Mycobacterium abscessus subsp. abscessus, M. abscessus subsp. massiliense, and M. kansasii. Bedaquiline also had low MIC values with macrolide-resistant NTM strains and warrants further investigation as a potential antibiotic for NTM treatment.

scholarly journals Molecular Mechanisms of Intrinsic Streptomycin Resistance in Mycobacterium abscessus

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Michael Dal Molin ◽  
Myriam Gut ◽  
Anna Rominski ◽  
Klara Haldimann ◽  
Katja Becker ◽  
...  
Keyword(s):  
Deletion Mutant ◽  
Molecular Mechanisms ◽  
Gene Deletion ◽  
Opportunistic Pathogen ◽  
Mycobacterium Abscessus ◽  
Streptomycin Resistance ◽  
Resistance Determinant ◽  
Mycobacterium Fortuitum ◽  
Content Type ◽  
Targeted Deletion

ABSTRACTStreptomycin, the first drug used for the treatment of tuberculosis, shows limited activity against the highly resistant pathogenMycobacterium abscessus. We recently identified two aminoglycoside-acetylating genes [aac(2′)andeis2] which, however, do not affect susceptibility to streptomycin. This suggests the existence of a discrete mechanism of streptomycin resistance.M. abscessusBLASTP analysis identified MAB_2385 as a close homologue of the 3″-O-phosphotransferase [APH(3″)] from the opportunistic pathogenMycobacterium fortuitumas a putative streptomycin resistance determinant. Heterologous expression ofMAB_2385inMycobacterium smegmatisincreased the streptomycin MIC, while the gene deletion mutantM. abscessusΔMAB_2385 showed increased streptomycin susceptibility. The MICs of other aminoglycosides were not altered inM. abscessusΔMAB_2385. This demonstrates thatMAB_2385encodes a specific and prime innate streptomycin resistance determinant inM. abscessus. We further explored the feasibility of applyingrpsL-based streptomycin counterselection to generate gene deletion mutants inM. abscessus. Spontaneous streptomycin-resistant mutants ofM. abscessusΔMAB_2385 were selected, and we demonstrated that the wild-typerpsLis dominant over the mutatedrpsLK43Rin merodiploid strains. In a proof of concept study, we exploited this phenotype for construction of a targeted deletion mutant, thereby establishing anrpsL-based counterselection method inM. abscessus.

scholarly journals In Vitro Activity of Clofazimine against Nontuberculous Mycobacteria Isolated in Beijing, China

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Jingjing Luo ◽  
Xia Yu ◽  
Guanglu Jiang ◽  
Yuhong Fu ◽  
Fengmin Huo ◽  
...  
Keyword(s):  
Nontuberculous Mycobacteria ◽  
Clinical Isolates ◽  
Natural Resistance ◽  
Cross Resistance ◽  
Mycobacterium Fortuitum ◽  
Strong Activity ◽  
Content Type ◽  
Beijing China ◽  
Reference Strains

ABSTRACT 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.

scholarly journals In VitroSusceptibility Testing of a Novel Benzimidazole, SPR719, against Nontuberculous Mycobacteria

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Barbara A. Brown-Elliott ◽  
Aileen Rubio ◽  
Richard J. Wallace
Keyword(s):  
Nontuberculous Mycobacteria ◽  
Treatment Options ◽  
Active Form ◽  
Mycobacterium Abscessus ◽  
Nontuberculous Mycobacterium ◽  
Content Type ◽  
Clinical Laboratories ◽  
Mueller Hinton ◽  
Mueller Hinton Broth

ABSTRACTNontuberculous mycobacterium (NTM) infections are increasing globally. TheMycobacterium aviumcomplex (MAC) andMycobacterium abscessusare the most frequently encountered NTM among clinical laboratories, and treatment options are extremely limited. In this study, thein vitropotency of a novel benzimidazole, SPR719, the microbiologically active form of the orally available prodrug SPR720, was tested against several species of NTM. MICs were determined for 161 isolates of NTM of 13 taxa (seven species, three subspecies, and three groups/complexes) in cation-adjusted Mueller-Hinton Broth, as described and recommended by the Clinical and Laboratory Standards Institute (CLSI M24-A2). Comparator antimicrobials included amikacin, cefoxitin, ciprofloxacin, clarithromycin, doxycycline, imipenem, linezolid, minocycline, moxifloxacin, tigecycline, and trimethoprim-sulfamethoxazole (TMP-SMX) for the rapidly growing mycobacteria (RGM), amikacin and clarithromycin for the MAC, and amikacin, ciprofloxacin, clarithromycin, doxycycline, linezolid, moxifloxacin, rifabutin, rifampin, and TMP-SMX for the other slowly growing NTM. SPR719 was found to be potent against multiple clinical strains of NTM with an MIC50range of 0.25 to 4 μg/ml for several species of NTM. These findings support the further advancement of SPR720 for the treatment of NTM disease.

scholarly journals Determination of MIC Distribution and Mechanisms of Decreased Susceptibility to Bedaquiline among Clinical Isolates of Mycobacterium abscessus

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Bing Li ◽  
Meiping Ye ◽  
Qi Guo ◽  
Zhemin Zhang ◽  
Shiyi Yang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Efflux Pump ◽  
Mycobacterium Abscessus ◽  
Clinical Isolates ◽  
Whole Genome Sequencing Data ◽  
Pcr Analysis ◽  
Sequencing Data ◽  
Gene Encoding ◽  
Content Type

ABSTRACT Chemotherapeutic options against Mycobacterium abscessus infections are very limited. Bedaquiline, a new antituberculosis (anti-TB) drug, is effective for the treatment of multidrug-resistant TB. However, few data are available on bedaquiline for treatment of M. abscessus infections. In this study, we determined the profile for in vitro susceptibility of M. abscessus clinical isolates to bedaquiline and investigated the potential molecular mechanisms of decreased susceptibility. A total of 197 M. abscessus clinical isolates were collected from sputum and bronchoalveolar fluid of patients with lung infections. Standard broth microdilution test revealed that bedaquiline exhibited high in vitro killing activity against M. abscessus isolates, with a MIC 50 of 0.062 and a MIC 90 of 0.125 mg/liter. Whole-genome sequencing data showed that no nonsynonymous mutation occurred in atpE , the gene encoding the bedaquiline-targeted protein. However, of 6 strains with decreased susceptibility of bedaquiline (MIC = 0.5 to 1 mg/liter), 3 strains had nonsynonymous mutations in mab_4384 , the gene encoding the repressor of efflux pump MmpS5/MmpL5. Quantitative reverse transcription-PCR (qRT-PCR) analysis showed that the expression of MmpS5/MmpL5 in the group with decreased susceptibility to bedaquiline was significantly higher than in those with medium MICs (MIC = 0.125 to 0.5 mg/liter) or in the low-MIC group (MIC ≤ 0.062 mg/liter). Two isolates with increased MICs did not show overexpression of MmpS5/MmpL5, which could not be explained by known molecular mechanisms. This is the first report showing the association of MmpS5/MmpL5 with decreased bedaquiline susceptibility in M. abscessus clinical isolates and suggesting the presence of other, yet-to-be identified mechanisms for decreased bedaquiline susceptibility in M. abscessus .

scholarly journals In Vitro Activities of Omadacycline against Rapidly Growing Mycobacteria

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Carolyn Shoen ◽  
David Benaroch ◽  
Mary Sklaney ◽  
Michael Cynamon
Keyword(s):  
Mycobacterium Abscessus ◽  
Mycobacterium Fortuitum ◽  
Mycobacterium Chelonae ◽  
Content Type ◽  
Rapidly Growing Mycobacteria ◽  
Dilution Assay ◽  
Tetracycline Derivative

ABSTRACT The in vitro activity of omadacycline, a new tetracycline derivative, was evaluated against isolates of Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum using a broth microtiter dilution assay. Omadacycline had MIC90 values of 2 μg/ml, 0.25 μg/ml, and 0.5 μg/ml, respectively. The in vitro activity of omadacycline against rapidly growing mycobacteria indicates that it may have the potential to improve therapy for infections caused by these organisms.

scholarly journals In Vitro Antimycobacterial Activity of 5-Chloropyrazinamide

1998 ◽  
Vol 42 (2) ◽  
pp. 462-463 ◽  
Author(s):  
Michael H. Cynamon ◽  
Robert J. Speirs ◽  
John T. Welch
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Bovis ◽  
Mechanism Of Action ◽  
Nontuberculous Mycobacteria ◽  
Antimycobacterial Activity ◽  
Vitro Activity ◽  
Dilution Method ◽  
In Vitro Activity ◽  
Broth Dilution

ABSTRACT 5-Chloropyrazinamide and 5-chloropyrazinoic acid were evaluated for in vitro activity against Mycobacterium tuberculosis,Mycobacterium bovis, and several nontuberculous mycobacteria by a broth dilution method. 5-Chloropyrazinamide was more active than pyrazinamide against all organisms tested. It is likely that this agent has a different mechanism of action than pyrazinamide.

scholarly journals DAP12 Inhibits Pulmonary Immune Responses to Cryptococcus neoformans

2016 ◽  
Vol 84 (6) ◽  
pp. 1879-1886 ◽  
Author(s):  
Lena J. Heung ◽  
Tobias M. Hohl
Keyword(s):  
Immune Response ◽  
Nk Cells ◽  
Cryptococcus Neoformans ◽  
Molecular Mechanisms ◽  
Content Type ◽  
Effector Cells ◽  
Opportunistic Fungal Pathogen ◽  
Efficient Uptake ◽  
Bacteria And Fungi

Cryptococcus neoformansis an opportunistic fungal pathogen that is inhaled into the lungs and can lead to life-threatening meningoencephalitis in immunocompromised patients. Currently, the molecular mechanisms that regulate the mammalian immune response to respiratory cryptococcal challenge remain poorly defined. DAP12, a signaling adapter for multiple pattern recognition receptors in myeloid and natural killer (NK) cells, has been shown to play both activating and inhibitory roles during lung infections by different bacteria and fungi. In this study, we demonstrate that DAP12 plays an important inhibitory role in the immune response toC. neoformans. Infectious outcomes in DAP12−/−mice, including survival and lung fungal burden, are significantly improved compared to those in C57BL/6 wild-type (WT) mice. We find that eosinophils and macrophages are decreased while NK cells are increased in the lungs of infected DAP12−/−mice. In contrast to WT NK cells, DAP12−/−NK cells are able to repressC. neoformansgrowthin vitro. Additionally, DAP12−/−macrophages are more highly activated than WT macrophages, with increased production of tumor necrosis factor (TNF) and CCL5/RANTES and more efficient uptake and killing ofC. neoformans. These findings suggest that DAP12 acts as a brake on the pulmonary immune response toC. neoformansby promoting pulmonary eosinophilia and by inhibiting the activation and antifungal activities of effector cells, including NK cells and macrophages.

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