Dataset Information

Preliminary Results of Bedaquiline as Salvage Therapy for Patients With Nontuberculous Mycobacterial Lung Disease.

ABSTRACT:

Background

Bedaquiline is an oral antimycobacterial agent belonging to a new class of drugs called diarylquinolines. It has low equivalent minimal inhibitory concentrations for Mycobacterium tuberculosis and nontuberculous mycobacterial (NTM) lung disease, especially Mycobacterium avium complex (MAC) and Mycobacterium abscessus (Mab). Bedaquiline appears to be effective for the treatment of multidrug-resistant TB but has not been tested clinically for NTM disease.

Methods

We describe a case series of off-label use of bedaquiline for treatment failure lung disease caused by MAC or Mab. Only patients whose insurance would pay for the drug were included. Fifteen adult patients were selected, but only 10 (six MAC, four Mab) could obtain bedaquiline. The 10 patients had been treated for 1 to 8 years, and all were on treatment at the start of bedaquiline therapy. Eighty percent had macrolide-resistant isolates (eight of 10). The patients were treated with the same bedaquiline dosage as that used in TB trials and received the best available companion drugs (mean, 5.0 drugs). All patients completed 6 months of therapy and remain on bedaquiline.

Results

Common side effects included nausea (60%), arthralgias (40%), and anorexia and subjective fever (30%). No abnormal ECG findings were observed with a mean corrected QT interval lengthening of 2.4 milliseconds at 6 months. After 6 months of therapy, 60% of patients (six of 10) had a microbiologic response, with 50% (five of 10) having one or more negative cultures.

Conclusions

This small preliminary report demonstrates potential clinical and microbiologic activity of bedaquiline in patients with advanced MAC or Mab lung disease but the findings require confirmation with larger studies.

SUBMITTER: Philley JV

PROVIDER: S-EPMC4694173 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Publications

Preliminary Results of Bedaquiline as Salvage Therapy for Patients With Nontuberculous Mycobacterial Lung Disease.

Philley Julie V JV Wallace Richard J RJ Benwill Jeana L JL Taskar Varsha V Brown-Elliott Barbara A BA Thakkar Foram F Aksamit Timothy R TR Griffith David E DE

Chest 20150801 2

<h4>Background</h4>Bedaquiline is an oral antimycobacterial agent belonging to a new class of drugs called diarylquinolines. It has low equivalent minimal inhibitory concentrations for Mycobacterium tuberculosis and nontuberculous mycobacterial (NTM) lung disease, especially Mycobacterium avium complex (MAC) and Mycobacterium abscessus (Mab). Bedaquiline appears to be effective for the treatment of multidrug-resistant TB but has not been tested clinically for NTM disease.<h4>Methods</h4>We descr ...[more]

PMID: 25675393

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Project description:Nontuberculous mycobacteria (NTM) cause pulmonary disease in individuals without obvious immunodeficiency. This study was initiated to gain insight into the immunological factors that predispose persons to NTM pulmonary disease (NTMPD). Blood was obtained from 15 pairs of NTMPD patients and their healthy household contacts. Peripheral blood mononuclear cells (PBMCs) were stimulated with the Mycobacterium avium complex (MAC). A total of 34 cytokines and chemokines were evaluated in plasma and PBMC culture supernatants using multiplex immunoassays, and gene expression in the PBMCs was determined using real-time PCR. PBMCs from NTMPD patients produced significantly less interleukin-1β (IL-1β), IL-18, IL-1α, and IL-10 than PBMCs from their healthy household contacts in response to MAC. Although plasma RANTES levels were high in NTMPD patients, they had no effect on IL-1β production by macrophages infected with MAC. Toll-like receptor 2 (TLR2) and TWIK2 (a two-pore domain K+ channel) were impaired in response to MAC in PBMCs of NTMPD patients. A TLR2 inhibitor decreased all four cytokines, whereas a two-pore domain K+ channel inhibitor decreased the production of IL-1β, IL-18, and IL-1α, but not IL-10, by MAC-stimulated PBMCs and monocytes. The ratio of monocytes was reduced in whole blood of NTMPD patients compared with that of healthy household contacts. A reduced monocyte ratio might contribute to the attenuated production of IL-1 family cytokines by PBMCs of NTMPD patients in response to MAC stimulations. Collectively, our findings suggest that the attenuated IL-1 response may increase susceptibility to NTM pulmonary infection through multiple factors, including impaired expression of the TLR2 and TWIK2 and reduced monocyte ratio. IMPORTANCE Upon MAC stimulation, the production of IL-1 family cytokines and IL-10 by PBMCs of NTMPD patients was attenuated compared with that of healthy household contacts. Upon MAC stimulation, the expression of TLR2 and TWIK2 (one of the two-pore domain K+ channels) was attenuated in PBMCs of NTMPD patients compared with that of healthy household contacts. The production of IL-1 family cytokines by MAC-stimulated PBMCs and MAC-infected monocytes of healthy donors was reduced by a TLR2 inhibitor and two-pore domain K+ channel inhibitor. The ratio of monocytes was reduced in whole blood of NTMPD patients compared with that of healthy household contacts. Collectively, our data suggest that defects in the expression of TLR2 and TWIK2 in human PBMCs or monocytes and reduced monocyte ratio are involved in the reduced production of IL-1 family cytokines, and it may increase susceptibility to NTM pulmonary infection.

Dataset Information

Preliminary Results of Bedaquiline as Salvage Therapy for Patients With Nontuberculous Mycobacterial Lung Disease.

Background

Methods

Results

Conclusions

Publications

Preliminary Results of Bedaquiline as Salvage Therapy for Patients With Nontuberculous Mycobacterial Lung Disease.

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