Systematic Review and Meta-analyses of the Effect of Chemotherapy on Pulmonary Mycobacterium abscessus Outcomes and Disease Recurrence

Abstract

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.

Keywords: Mycobacterium abscessus; hollow-fiber model; macrolides; medical outcomes; pulmonary infection.

FIG 1

Study enrollment.

FIG 2

Sustained sputum culture conversion (SSCC) with initial macrolide-containing regimens. The forest plot depicts 13 studies comprising 16 macrolide-containing regimens that were examined as initial therapy in 223 treatment-naive patients with M. abscessus subsp. abscessus (designated Maa), 141 treatment-naive patients with M. abscessus subsp. massiliense (designated Mam), and 213 treatment-naive patients with M. abscessus with no subspecies specified (designated MaNSS). Risk of bias assessed for each effect size (ES) estimate is shown in the extreme right column. Despite the marked heterogeneity between these regimens (overall I² value of >90%), patients with M. abscessus subsp. abscessus were significantly less likely to have SSCC than patients with M. abscessus subsp. massiliense, as shown by noninterloping confidence intervals between the two subspecies.

FIG 3

Sustained sputum conversion (SSCC) with macrolide-containing regimens in refractory patients. The forest plot depicts 5 studies comprising 6 macrolide-containing regimens that were examined in 52 refractory patients with M. abscessus subsp. abscessus, 20 refractory patients with M. abscessus subsp. massiliense, and 66 treatment-naive patients with M. abscessus with no subspecies specified. Risk of bias assessed for each effect estimate is shown in the extreme right column. There was no significant difference in SSCC between the subspecies. There was also marked heterogeneity in SSCC estimate across the different regimens (overall I² value of 72%; P < 0.001).

FIG 4

Recurrent pulmonary disease with confirmed M. abscessus complex. The forest plot depicts 10 studies comprising 14 macrolide-containing regimens that were examined after follow-up of 30 patients with M. abscessus subsp. abscessus, 11 patients with M. abscessus subsp. massiliense, and 32 patients with M. abscessus with no subspecies specified. Three hundred sixty-six patients were followed up and were at risk of recurrence; 73 suffered a recurrence. The median follow-up duration for each regimen is shown in the extreme right column in panel A, while the risk of bias is shown in the extreme right column in panel B. Panel A shows that, despite the marked heterogeneity between these regimens (overall I² value of >77%), patients with M. abscessus subsp. abscessus were significantly more likely to have recurrent disease on follow-up, 40% (95% CI, 15 to 67%) compared to 7% (95% CI, 2 to 14%) in patients with M. abscessus subsp. massiliense, as shown by noninterloping confidence intervals between the two subspecies. The findings remain the same when the different follow-up durations are adjusted for, as shown in panel B. Panel C gives the average recurrence rate per month of follow-up, while panel D gives the same estimate per year of follow-up. Panels C and D also show that disease recurrences were significantly higher in studies with low/moderate risk of bias than those with some serious risk across the M. abscessus species.