Impact of different clarithromycin resistance in Mycobacterium abscessus lung disease: a multicenter cohort study

Macrolides remained cornerstone of Mycobacterium abscessus treatment, but emerging resistance patterns compromised therapeutic efficacies. Clarithromycin resistance can manifest as either mutational or inducible, while the clinical impacts of different resistance mechanisms in M. abscessus pulmonary disease (MAB-PD) had been poorly characterized. We conducted a multicenter retrospective cohort study from 2011 to 2023 across four tertiary centers in Taiwan. Adults with clarithromycin-resistant MAB-PD were included and stratified by resistance type: mutational vs inducible. Outcomes included all-cause 3-year mortality, microbiological clearance, and radiographic progression. Among 108 enrolled patients, 16 (14.7%) had mutational resistance and the remaining 92 had inducible type. Isolates comprised 103 M. abscessus, three M. massiliense, and two M. bolletii. Mutational resistance was associated with significantly higher 3-year mortality (18.8% vs 4.3%, P = 0.03) and lower acid-fast smear conversion rates in treated patients (18.2% vs 67.6%, P = 0.004). Multivariable analysis identified mutational clarithromycin resistance as an independent predictor of mortality (adjusted hazard ratio 5.21, 95% confidence interval 1.10-24.6, P = 0.04). Strains with mutational resistance demonstrated higher median minimal inhibitory concentrations to linezolid (24 vs 16 mg/L), cefoxitin (64 vs 32 mg/L), and amikacin (16 vs 8 mg/L). Mutational clarithromycin resistance in MAB-PD is associated with substantially worse clinical outcomes compared to inducible resistance, including higher mortality and poorer treatment responses. These findings suggested that more intensive treatment strategies might be needed for mutational clarithromycin resistance in MAB-PD.

Macrolide resistance critically undermines treatment outcomes in Mycobacterium abscessus lung disease, yet the prognostic impact of distinct resistance mechanisms has remained unclear. This multicenter study demonstrates that mutational clarithromycin resistance, although less common than inducible resistance, is associated with markedly higher mortality, poorer microbiological response, and broader multidrug resistance. These findings provide clinically actionable evidence that not all macrolide resistance is equivalent. Recognizing mutational resistance as a high-risk phenotype has important implications for risk stratification, prognostication, and treatment intensification, supporting a more personalized approach to managing MAB-LD in routine clinical practice.