Abstract
To compare the efficacy and safety of pharmacological regimens separately for Mycobacterium avium complex pulmonary disease (MAC-PD) and MAC bacteremia within a unified systematic-review framework while maintaining disease-specific treatment interpretations. We systematically searched PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure, Wanfang Data, and Google Scholar from inception to 13 August 2026. The protocol was prospectively registered in PROSPERO (CRD420251164280). Separate Bayesian random-effects network meta-analyses were performed for MAC-PD and MAC bacteremia, with no treatment effects pooled or compared across disease manifestations. Randomized controlled trials and cohort studies involving adults with MAC-PD or MAC bacteremia were eligible. Treatment regimens were categorized into clinically interpretable drug-treatment nodes according to antimicrobial composition and regimen components. The primary outcomes were treatment success and treatment-emergent adverse events (TEAEs) as reported in individual studies. Treatment effects were estimated as odds ratios (ORs) with 95% credible intervals (CrI), and treatment rankings were summarized using the surface under the cumulative ranking curve (SUCRA). Twenty-six studies, including 16 randomized controlled trials and 10 cohort studies involving 3,574 participants, were included. In MAC-PD, amikacin liposome inhalation suspension plus guideline-based therapy (ALIS_GBT) was associated with significantly higher odds of treatment success than guideline-based therapy alone (GBT; OR 5.74, 95% CrI 3.45-9.87) and ranked highest for efficacy (SUCRA=0.974). Several other regimens, including clofazimine-containing combinations, showed relatively favorable rankings but no statistically significant superiority over GBT in the principal comparisons. ALIS_GBT was associated with increased odds of TEAEs compared with GBT (OR 3.62, 95% CrI 1.63-8.77), and clofazimine plus aminoglycosides plus GBT also showed an increased TEAE signal (OR 4.60, 95% CrI 1.10-26.14). In MAC bacteremia, GBT ranked highest for treatment success (SUCRA=0.849). Clofazimine plus rifamycin, ethambutol, and fluoroquinolone was associated with lower odds of treatment success than GBT (OR 0.18, 95% CrI 0.09-0.33), as was clofazimine plus macrolide therapy (OR 0.52, 95% CrI 0.27-0.97). No regimen showed a statistically significant difference from GBT for TEAEs in MAC bacteremia. Substantial heterogeneity was observed for treatment success in both disease networks, whereas no heterogeneity was detected for TEAEs. No statistically significant local inconsistency or small-study effects were identified. In MAC-PD, ALIS added to GBT was associated with the ranked highest for treatment success probability but increased TEAE risk, supporting its role as a selective adjunctive option, particularly in patients with difficult-to-treat or refractory disease. In MAC bacteremia, GBT showed the most favorable treatment-success profile within the available evidence, whereas CLO_R_E_FQ and CLO_M were associated with lower odds of treatment success. These findings should be interpreted cautiously because of substantial heterogeneity, sparse evidence for several comparisons, imprecision, variable safety reporting, and limitations in transitivity. Further standardized head-to-head trials are needed to clarify optimal regimens, treatment duration, and safety-monitoring strategies for different MAC disease settings.