In pharmacokinetic/pharmacodynamic models of pulmonaryMycobacterium abscessuscomplex, 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 pulmonaryM. abscessusdisease. 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 withM. abscessussubsp.abscessus, 204 withM. abscessussubsp.massiliense, and 301 withM. abscessuswith no subspecies specified. Macrolide-containing regimens achieved SSCC in only 77/233 (34%) newM. abscessussubsp.abscessuspatients versus 117/141 (54%)M. abscessussubsp.massiliensepatients (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%) forM. abscessussubsp.abscessusversus 0.683% (range, 0.229 to 1.136%) forM. abscessussubsp.massiliense(OR, 6.189 [95% CI, 2.896 to 13.650]). The proportion of patients with good outcomes was 52/223 (23%) withM. abscessussubsp.abscessusversus 118/141 (84%) withM. abscessussubsp.massiliensedisease (OR, 0.059 [95% CI, 0.034 to 0.101]).M. abscessussubsp.abscessuspulmonary 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.

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. Pharmacodynamic interactions were assessed by response surface model of Bliss independence (RSBI) and isobolographic analysis of Loewe additivity (ISLA), calculating the percentage of statistically significant Bliss interactions and interaction indices (I), respectively. Monte Carlo simulations with predicted human lung concentrations were used to calculate target attainment rates for combination and monotherapy regimens. Clofazimine alone was bacteriostatic for both NTM. Clofazimine-amikacin was synergistic against M. abscessus (I = 0.41; 95% confidence interval [CI], 0.29 to 0.55) and M. avium (I = 0.027; 95% CI, 0.007 to 0.048). Based on RSBI analysis, synergistic interactions of 28.4 to 29.0% and 23.2 to 56.7% were observed at 1× to 2× MIC and 0.25× to 2× MIC for M. abscessus and M. avium , respectively. Clofazimine-clarithromycin was also synergistic against M. abscessus (I = 0.53; 95% CI, 0.35 to 0.72) and M. avium (I = 0.16; 95% CI, 0.04 to 0.35), RSBI analysis showed 23.5% and 23.3 to 53.3% at 2× MIC and 0.25× to 0.5× MIC for M. abscessus and M. avium , respectively. Clofazimine prevented the regrowth observed with amikacin or clarithromycin alone. Target attainment rates of combination regimens were >60% higher than those of monotherapy regimens for M. abscessus and M. avium . The combination of clofazimine with amikacin or clarithromycin was synergistic in vitro . This suggests a potential role for clofazimine in treatment regimens that warrants further evaluation.

This study was conducted to generate basic pharmacodynamic information on the relationship between antibiotic concentrations and the growth of rapidly growing mycobacteria (RGM), and thereby contribute to a better understanding of current and future drug regimens for diseases caused by RGM. Type strains of Mycobacterium abscessus and Mycobacterium fortuitum were used; the MICs of cefoxitin, amikacin, moxifloxacin, linezolid and clarithromycin were determined by broth microdilution. Time–kill assays were performed, exposing the bacteria to 2-fold concentrations from 0.25 to 32 times the MIC at 30°C for 120 h. The sigmoid maximum effect (E_max) model was fitted to the time–kill curves data. The highest killing of M. abscessus was observed between 24 and 72 h; amikacin had the highest E_max (0.0427 h⁻¹), followed by clarithromycin (0.0231 h⁻¹) and cefoxitin (0.0142 h⁻¹). For M. fortuitum, between 3 and 24 h, amikacin also showed the highest E_max (0.1933 h⁻¹). There were no significant differences between the Hill's slopes determined for all the antibiotics tested against M. abscessus or M. fortuitum (P = 0.2213 and P = 0.2696, respectively). The total effect observed for all antibiotics was low and primarily determined by the E_max 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.

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.

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.

Mycobacterium abscessus causes chronic pulmonary infections that are extremely difficult to cure. The currently recommended combination therapy is associated with high failure rates and relapse. Tigecycline has been explored in salvage regimens, with a response rate of 43% in those who received at least a month of therapy. We performed a dose-response study in a hollow-fiber system model of pulmonary M. abscessus infection in which we recapitulated tigecycline human pulmonary concentration-time profiles of 8 different doses for 21 days. We identified the maximal kill or efficacy in CFU per milliliter and the ratio of the 0- to 24-h area under the concentration-time curve to MIC (AUC/MIC) associated with 80% efficacy (EC ₈₀ ). The tigecycline efficacy was 5.38 ± 2.35 log ₁₀ CFU/ml, and the drug achieved the unprecedented feat of a bacterial level of 1.0 log ₁₀ CFU/ml below the pretreatment inoculum (1-log kill) of M. abscessus in the hollow-fiber system. The EC ₈₀ AUC/MIC ratio was 36.65, while that for a 1-log kill was 44.6. Monte Carlo experiments with 10,000 patients were used to identify the clinical dose best able to achieve the EC ₈₀ or 1-log kill. The standard dose of 100 mg/day had a cumulative fraction of response of 51% for the EC ₈₀ and 46% for 1-log kill. For both the EC ₈₀ target and 1-log kill, the optimal tigecycline clinical dose was identified as 200 mg/day. The susceptibility breakpoint was ≤0.5 mg/liter. Tigecycline is the most active single agent evaluated to date, and we propose that 200 mg/day be examined as the backbone of new combination therapy regimens to replace current treatment.