e Multidrug therapy is a standard practice when treating infections by nontuberculous mycobacteria (NTM), but few treatment options exist. We conducted this study to define the drug-drug interaction between clofazimine and both amikacin and clarithromycin and its contribution to NTM treatment. Mycobacterium abscessus and Mycobacterium avium type strains were used. Time-kill assays for clofazimine alone and combined with amikacin or clarithromycin were performed at concentrations of 0.25؋ to 2؋ MIC. Phar- Multidrug therapy is a standard practice when treating mycobacterial infections. However, the pharmacodynamic (PD) interactions among the combined drugs are largely unknown. Understanding these interactions will help to identify synergistic combinations with increased antibacterial killing, which ultimately can result in a better treatment outcome.One of the promising combinations is amikacin and clofazimine, given the key role of amikacin in the treatment of NTM infections (2, 3) and the unique characteristics of clofazimine, like its prolonged half-life, its preferential accumulation inside macrophages (4), and the recently found bactericidal activity only after 2 weeks of treatment in the mouse model of tuberculosis (5).Clarithromycin, on the other hand, has substantial in vitro and clinical activity against Mycobacterium avium complex (MAC), and it has been long considered the cornerstone for Mycobacterium abscessus treatment (3).Hence, the examination of its interaction with clofazimine is interesting.Previous studies showed in vitro synergy between clofazimine and amikacin against both rapidly and slowly growing NTM (1, 6). The combination clarithromycin-clofazimine also showed synergy against MAC strains in checkerboard evaluation (7). These checkerboard titrations offer no information on the mechanism of synergistic activity, the exact killing activity of these combinations, or its concentration dependence. We therefore investigated the pharmacodynamic interactions between clofazimine and amikacin, and clofazimine and clarithromycin, against two key NTM species, using time-kill assays analyzed with two pharmacodynamic drug interaction models: the response surface model of Bliss independence (RSBI) and isobolographic analysis of Loewe additivity (ISLA) (8, 9). MATERIALS AND METHODS Bacterial

In pharmacokinetic/pharmacodynamic models of pulmonary Mycobacterium abscessus complex, the recommended macrolide-containing combination therapy has poor kill rates. However, clinical outcomes are unknown. We searched the literature for studies published between 1990 and 2017 that reported microbial outcomes in patients treated for pulmonary M. abscessus disease. A good outcome was defined as sustained sputum culture conversion (SSCC) without relapse. Random effects models were used to pool studies and estimate proportions of patients with good outcomes. Odds ratios (OR) and 95% confidence intervals (CI) were computed. Sensitivity analyses and metaregression were used to assess the robustness of findings. In 19 studies of 1,533 patients, combination therapy was administered to 508 patients with M. abscessus subsp. abscessus, 204 with M. abscessus subsp. massiliense, and 301 with M. abscessus with no subspecies specified. Macrolide-containing regimens achieved SSCC in only 77/233 (34%) new M. abscessus subsp. abscessus patients versus 117/141 (54%) M. abscessus subsp. massiliense patients (OR, 0.108 [95% CI, 0.066 to 0.181]). In refractory disease, SSCC was achieved in 20% (95% CI, 7 to 36%) of patients, which was not significantly different across subspecies. The estimated recurrent rates per month were 1.835% (range, 1.667 to 3.196%) for M. abscessus subsp. abscessus versus 0.683% (range, 0.229 to 1.136%) for M. abscessus subsp. massiliense (OR, 6.189 [95% CI, 2.896 to 13.650]). The proportion of patients with good outcomes was 52/223 (23%) with M. abscessus subsp. abscessus versus 118/141 (84%) with M. abscessus subsp. massiliense disease (OR, 0.059 [95% CI, 0.034 to 0.101]). M. abscessus subsp. abscessus pulmonary disease outcomes with the currently recommended regimens are atrocious, with outcomes similar to those for extensively drug-resistant tuberculosis. Therapeutically, the concept of nontuberculous mycobacteria is misguided. There is an urgent need to craft entirely new treatment regimens.

Pulmonary disease (PD) caused by nontuberculous mycobacteria is an emerging infection mainly in countries where the incidence of tuberculosis is in decline. It affects an elderly population, often with underlying chronic lung diseases, but its epidemiology shows significant regional variation. Guidelines and recommendations for treatment of these infections exist, but build strongly on expert opinion, as very few good quality clinical trials have been performed in this field. Only for the most frequent causative agents, the Mycobacterium avium complex, Mycobacterium kansasii and Mycobacterium abscessus, a reasonable number of trials and case series is now available. For the less frequent causative agents of pulmonary nontuberculous mycobacterial (NTM) disease (Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium fortuitum, Mycobacterium chelonae) data is mostly limited to a few very small case series. Within this review, we have collected and combined evidence from all available trials and case series. From the data of these trials and case series, we reconstruct a more evidence-based overview of possible drug treatment regimens and their outcomes.

The total effect observed for all antibiotics was low and primarily determined by the Emax and not by the Hill's slope. The limited activity detected fits well with the poor outcome of antibiotic treatment for disease caused by RGM, particularly for M. abscessus. An evaluation of drug combinations will be the next step in understanding and improving current treatment standards.

d Ethionamide (ETH) is an antibiotic used for the treatment of multidrug-resistant (MDR) tuberculosis (TB) (MDR-TB), and its use may be limited with the emergence of resistance in the Mycobacterium tuberculosis population. ETH resistance in M. tuberculosis is phenomenon independent or cross related when accompanied with isoniazid (INH) resistance. In most cases, resistance to INH and ETH is explained by mutations in the inhA promoter and in the following genes: katG, ethA, ethR, mshA, ndh, and inhA. We sequenced the above genes in 64 M. tuberculosis isolates (n ‫؍‬ 57 ETH-resistant MDR-TB isolates; n ‫؍‬ 3 ETH-susceptible MDR-TB isolates; and n ‫؍‬ 4 fully susceptible isolates). Each isolate was tested for susceptibility to first-and second-line drugs using the agar proportion method. Mutations were observed in ETH-resistant MDR-TB isolates at the following rates: 100% in katG, 72% in ethA, 45.6% in mshA, 8.7% in ndh, and 33.3% in inhA or its promoter. Of the three ETH-susceptible MDR-TB isolates, all showed mutations in katG; one had a mutation in ethA, and another, in mshA and inhA. Finally, of the four fully susceptible isolates, two showed no detectable mutation in the studied genes, and two had mutations in mshA gene unrelated to the resistance. Mutations not previously reported were found in the ethA, mshA, katG, and ndh genes. The concordance between the phenotypic susceptibility testing to INH and ETH and the sequencing was 1 and 0.45, respectively. Among isolates exhibiting INH resistance, the high frequency of independent resistance and cross-resistance with ETH in the M. tuberculosis isolates suggests the need to confirm the susceptibility to ETH before considering it in the treatment of patients with MDR-TB. E thionamide (ETH), a structural analog of isoniazid (INH), is a second-line drug used in the treatment of multidrug-resistant tuberculosis (MDR-TB) (1). Both ETH and INH are classified as prodrugs that are activated by different mycobacterial enzymes. INH is activated by the katG-encoded catalase-peroxidase, and ETH is activated by the ethA-encoded monooxygenase (2, 3). The activated INH and ETH drugs share the same molecular target, i.e., the NADH-dependent enoyl-acyl carrier protein reductase InhA, which is involved in the long-chain mycolic acid biosynthesis pathway (4). Therefore, the cross-resistance between INH and ETH can be detected in Mycobacterium tuberculosis clinical isolates in the case of mutations affecting the common target, which may occur when patients have previously been treated with INH and not with ETH (5). The frequency of cross-resistance differs between countries: 100% in Korea (6), 95.12% in Argentina (7), 94% in Brazil (8), 62% in France (9), and 13.8% in Thailand (10).Resistance to INH and ETH is mainly due to the chromosomal mutations. The mutation-carrying genes, such as those encoding the enzymes KatG (11,12) and EthA (13,14), are associated with individual resistance to INH and ETH, respectively. Mutations at the inhA promoter region or inhA gene result in the ove...