An overview of drugs for the treatment of Mycobacterium kansasii pulmonary disease.

OBJECTIVES: The aim of this study was to determine and compare the efficacy of drugs to treat Mycobacterium kansasii (Mkn) pulmonary disease by performing minimum inhibitory concentration (MIC) determination and time-kill studies. METHODS: We determined the MICs to 13 drugs against the Mkn standard laboratory strain ATCC 12478 and 20 clinical isolates and performed time-kill studies with 18 drugs from different classes using the standard laboratory strain of Mkn. The ß-lactam antibiotics were tested with or without the combination of the ß-lactamase inhibitor avibactam. An inhibitory sigmoid Emax model was used to describe the relationship between drug concentrations and bacterial burden. RESULTS: Among the 13 tested drugs in the MIC experiments, the lowest MIC was recorded for bedaquiline. Among the 18 drugs used in the time-kill studies, maximum kill with cefdinir, tebipenem, clarithromycin, azithromycin, moxifloxacin, levofloxacin, tedizolid, bedaquiline, pretomanid and telacebac was greater than that for some of the drugs (isoniazid, rifampicin and ethambutol) used in standard combination therapy. CONCLUSION: We report preclinical data on the efficacy and potency of drugs that can potentially be repurposed to create a safe, effective and likely shorter-duration regimen for the treatment of Mkn pulmonary disease.

Emergence of mmpT5 Variants during Bedaquiline Treatment of Mycobacterium intracellulare Lung Disease.

Bedaquiline (BDQ), a diarylquinoline antibiotic that targets ATP synthase, is effective for the treatment of Mycobacterium tuberculosis infections that no longer respond to conventional drugs. While investigating the off-label use of BDQ as salvage therapy, seven of 13 patients with Mycobacterium intracellulare lung disease had an initial microbiological response and then relapsed. Whole-genome comparison of pretreatment and relapse isolates of M. intracellulare uncovered mutations in a previously uncharacterized locus, mmpT5 Preliminary analysis suggested similarities between mmpT5 and the mmpR5 locus, which is associated with low-level BDQ resistance in M. tuberculosis Both genes encode transcriptional regulators and are adjacent to orthologs of the mmpS5-mmpL5 drug efflux operon. However, MmpT5 belongs to the TetR superfamily, whereas MmpR5 is a MarR family protein. Targeted sequencing uncovered nonsynonymous mmpT5 mutations in isolates from all seven relapse cases, including two pretreatment isolates. In contrast, only two relapse patient isolates had nonsynonymous changes in ATP synthase subunit c (atpE), the primary target of BDQ. Susceptibility testing indicated that mmpT5 mutations are associated with modest 2- to 8-fold increases in MICs for BDQ and clofazimine, whereas one atpE mutant exhibited a 50-fold increase in MIC for BDQ. Bedaquiline shows potential for the treatment of M. intracellulare lung disease, but optimization of treatment regimens is required to prevent the emergence of mmpT5 variants and microbiological relapse.