Treatment Of Nontuberculous Mycobacteria Lung Disease Research Articles

In Vitro Evaluation of Drug-Drug Interaction Potential of Epetraborole, a Novel Bacterial Leucyl-tRNA Synthetase Inhibitor.

Epetraborole (EBO) is a boron-containing inhibitor of bacterial leucyl-tRNA synthetase, with potent activity against nontuberculous mycobacteria (NTM) and Gram-negative bacteria, including Burkholderia pseudomallei. EBO is being developed for the treatment of NTM lung disease and melioidosis, administered in combination with other therapeutic agents in both diseases. Therefore, EBO and its major circulating metabolite M3 were evaluated in comprehensive drug-drug interaction (DDI) in vitro studies. The CYP inhibitory and substrate potential of EBO and M3 were assessed using hepatic microsomes. Stably transfected cells that expressed individual efflux or uptake transporters were used to determine whether EBO or M3 were substrates or inhibitors for these receptors. Stability studies indicated that EBO is a poor substrate for major CYP enzymes. Neither EBO nor M3 was a potent reversible or time-dependent inhibitor of major CYP enzymes. EBO was not an inducer of CYP1A2 mRNA, while it was a weak inducer of CYP2B6 and CYP3A4. EBO was a substrate only for OCT2. At clinically relevant concentrations, neither EBO nor M3 inhibited major human efflux or uptake transporters. Based on these data, at clinically relevant concentrations of EBO and M3, there is a low risk of victim or perpetrator DDI.

The value of gene chip detection of bronchoalveolar lavage fluid in the diagnosis of nontuberculous mycobacterial lung disease.

Nontuberculous mycobacteria (NTM) are mycobacteria other than mycobacterium tuberculosis complex (MTBC) and mycobacterium leprae. NTM can cause infection in many human tissues and organs and is most commonly seen in the lungs. Clinically, the symptoms and signs of nontuberculous mycobacteria lung disease (NMLD) are very similar to those of tuberculosis (TB). Because most NTMs are resistant to conventional anti-TB drugs, the rapid diagnosis of NMLD is the key to treatment. This study aimed to use gene chip technology to examine bronchoalveolar lavage fluid (BALF) from NMLD patients to explore the value of this technique for the rapid diagnosis of NMLD in BALF. A retrospective analysis of 308 patients with NMLD treated at Fuzhou Pulmonary Hospital from January 2018 to June 2020 was performed. BALF was collected from the patients. Gene chip detection (Capital Bio Corporation, Chengdu, China) and BACTEC MGIT960 (Becton, Dickinson and Company, MD, USA) liquid culture were performed to compare the NTM positive detection rates between the two methods. The NTM strain isolated from liquid culture were identified by rDNA sequencing and the results of identification were compared with those of gene chip detection using BALF specimens. A total of 221 cases of NTM were detected in 308 BALF specimens by the gene chip method; the positive rate was 71.75% (221/308). A total of 218 cases of NTM were detected by the liquid culture method, and the positive rate was 70.78% (218/308). There was no significant difference in the positive rate of NTM detected in BALF specimens between the two methods (χ2=0.138 P=0.804>0.05); 187 cases were detected with both sequencing and gene chip detection, and the coincidence rate of strain identification with the two methods reached 96.79% (181/187). Sequencing of 218 strains of NTM was carried out; eight species were identified, and the top four species were M. intracellulare (131/218, 60.09%), M. avium (48/218, 22.02%), M. abscessus (27/218, 12.38%), and M. kansasii (5/218, 2.29%). Gene chip technology can rapidly detect NTM in BALF and accurately identify bacterial species. It has important clinical value in the early diagnosis and treatment of NMLD.

A Leucyl-tRNA Synthetase Inhibitor with Broad-Spectrum Anti-Mycobacterial Activity.

Global infections by non-tuberculous mycobacteria (NTM) are steadily rising. New drugs are needed to treat NTM infections, but the NTM drug pipeline remains poorly populated and focused on repurposing or reformulating approved antibiotics. We sought to accelerate de novo NTM drug discovery by testing advanced compounds with established activity against Mycobacterium tuberculosis 3-aminomethyl 4-halogen benzoxaboroles, a novel class of leucyl-tRNA synthetase inhibitors, were recently discovered as active against M. tuberculosis Here, we report that the benzoxaborole EC/11770 is not only a potent anti-tubercular agent but is active against the M. abscessus and M. avium complexes. Focusing on M. abscessus, which causes the most difficult-to-cure NTM disease, we show that EC/11770 retained potency against drug-tolerant biofilms in vitro and was effective in a mouse lung infection model. Resistant mutant selection experiments showed a low frequency of resistance and confirmed leucyl-tRNA synthetase as the target. This work establishes the benzoxaborole EC/11770 as a novel preclinical candidate for the treatment of NTM lung disease and tuberculosis and validates leucyl-tRNA synthetase as an attractive target for the development of broad-spectrum anti-mycobacterials.

Recent advances in nontuberculous mycobacterial lung infections.

Nontuberculous mycobacteria (NTM) are members of the Mycobacterium genus other than Mycobacterium tuberculosis complex and Mycobacterium leprae. NTM are widely distributed in the environment and are increasingly recognized as causes of chronic lung disease that can be challenging to treat. In this brief review, we consider recent developments in the ecology, epidemiology, natural history, and treatment of NTM lung disease with a focus on Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex .

Implication of species change of Nontuberculous Mycobacteria during or after treatment

BackgroundCo-existence or subsequent isolation of multiple nontuberculous mycobacteria (NTM) species in same patient has been reported. However, clinical significance of these observations is unclear. The aim of this study was to determine clinical implications of changes of NTM species during or after treatment in patients with NTM lung disease.MethodsPatients with NTM lung disease, who experienced changes of NTM species during treatment or within 2 years of treatment completion between January 1, 2009 and December 31, 2015, were included in the analysis. Demographic, clinical, microbiological, and radiographic data were reviewed and analyzed.ResultsDuring the study period, 473 patients were newly diagnosed with NTM lung disease. Treatment was started in 164 patients (34.6%). Among these 164 patients, 16 experienced changes of NTM species during or within 2 years of treatment completion. Seven showed changes from M. avium complex (MAC) to M. abscessus subspecies abscessus (MAA) and five patients displayed changes from M. abscessus subspecies massiliense (MAM) to MAC. With isolation of new NTM species, 6 out of 7 patients with change from MAC to MAA reported worsening of symptoms, whereas none of the five patients with change from MAM to MAC reported worsening of symptoms. All MAA isolated during or after treatment for MAC lung diseases showed inducible resistance to clarithromycin.ConclusionsChange of NTM species may occur during or after treatment for NTM lung disease. Especially, changes from MAC to MAA is accompanied by symptomatic and radiographic worsening as well as inducible resistance to clarithromycin.

Diagnosis and Treatment of Nontuberculous Mycobacterial Lung Disease: Clinicians' Perspectives.

Nontuberculous mycobacteria (NTM) are emerging pathogens that affect both immunocompromised and immunocompetent patients. The incidence and prevalence of NTM lung disease are increasing worldwide and rapidly becoming a major public health problem. For the diagnosis of NTM lung disease, patients suspected to have NTM lung disease are required to meet all clinical and microbiologic criteria. The development of molecular methods allows the characterization of new species and NTM identification at a subspecies level. Even after the identification of NTM species from respiratory specimens, clinicians should consider the clinical significance of such findings. Besides the limited options, treatment is lengthy and varies by species, and therefore a challenge. Treatment may be complicated by potential toxicity with discouraging outcomes. The decision to start treatment for NTM lung disease is not easy and requires careful individualized analysis of risks and benefits. Clinicians should be alert to those unique aspects of NTM lung disease concerning diagnosis with advanced molecular methods and treatment with limited options. Current recommendations and recent advances for diagnosis and treatment of NTM lung disease are summarized in this article.

In Vitro Synergy between Clofazimine and Amikacin in Treatment of Nontuberculous Mycobacterial Disease

Disease caused by nontuberculous mycobacteria (NTM) is increasing in frequency. The outcome of treatment for NTM lung disease is poor, particularly lung disease caused by Mycobacterium simiae and M. abscessus. Exploring synergy between active available drugs is a sensible way forward given the lack of new active drugs. We tested for synergy between amikacin and clofazimine, using standardized methods, in 564 consecutive clinical isolates identified as 21 species of rapidly growing mycobacteria, 16 clinical M. avium complex isolates, and 10 M. simiae isolates. Clofazimine and amikacin are each active in vitro against NTM; 97% (n = 548) of the rapid growers revealed MICs of clofazimine of ≤1 μg/ml, and 93% (n = 524) proved susceptible to amikacin. The combination showed significant synergistic activity in 56 of 68 (82%) eligible M. abscessus isolates, 4 of 5 M. chelonae isolates, and 1 M. fortuitum and 1 M. cosmeticum isolate, with 4- to 8-fold decreases in MICs to both drugs. Significant synergy could also be demonstrated against all M. avium complex and M. simiae isolates, with fractional inhibitory concentrations of <0.5. Clofazimine and amikacin show significant synergistic activity against both rapidly and slowly growing nontuberculous mycobacteria. The safety and tolerability of adding clofazimine to amikacin-containing regimens should be tested in clinical trials, and the results of susceptibility tests for these two compounds and their combination merit clinical validation. Synergy between clofazimine and other antibiotics with intracellular targets should be explored.

Nontuberculous Mycobacteria Isolated from Respiratory Specimens during Recent Two Years: Distribution and Clinical Significance

Background: The isolation of nontuberculous mycobacteria (NTM) has been increasing worldwide as well as its clinical importance. The aim of this study was to investigate the distribution and clinical significance of NTM that has been isolated from respiratory specimens during a recent two-year period at a tertiary hospital. Methods: We analyzed respiratory samples that were obtained between January 2009 and December 2010 for AFB culture. We retrospectively reviewed the electronic medical records of these patients to obtain both clinical and radiologic information. NTM pulmonary disease was defined by using the guidelines provided by the America Thoracic Society/Infectious Diseases Society of America. Results: Among the 1,601 specimens that resulted in a positive AFB culture, 310 (19.4%) were NTM. In 189 patients, the most common isolate was M. aviumintracellulare complex (MAC) (127, 67.2%), which was then followed by M. abscessus (31, 16.4%), M. fortuitum (10, 5.3%), M. kansasii (9, 4.8%), and other NTM species. Of these, 93 (49.2%) patients were diagnosed with NTM pulmonary disease. MAC, M. abscessus, and M. kansasii were more virulent than the other species. None of the cases of NTM pulmonary disease were caused by M. fortuitum, M. chelonae, M. peregrinum, M. terrae complex, or M. gordonae. Conclusion: In Korea, the prevalence of NTM isolates is increasing, as are the cases of pulmonary disease. The pathogenic potential of NTM differs enormously by species and as a result the treatment of NTM lung disease depends on which species has caused the infection. The isolation and identification of NTM isolated from respiratory specimens are mandatory in order for clinical microbiology laboratories to make an accurate diagnosis and suggest the proper treatment of the NTM disease. (Korean J Clin Microbiol 2012;15:98-103)