Macrolide-resistant Mycobacterium avium complex pulmonary disease: A narrative review

Mycobacterium avium complex pulmonary disease (MAC-PD) is on the rise across the world, where only about two-thirds are cured by current treatment strategies. Treatment of MAC-PD includes macrolides as the key drug in a three-drug regimen, making the emergence of macrolide resistance particularly concerning, as treatment success is reduced to about 21%. Macrolide-resistant (MR) MAC is typically caused by a mutation in the 23S rRNA gene and usually develops after inappropriate treatment, such as macrolide monotherapy or omission of ethambutol from the regimen. However, treatment options for MR-MAC-PD are highly limited. The combination of lung resection surgery with or without amikacin, along with continued ethambutol use, has been associated with improved outcomes relative to regimens without these. Although limited, clinical observational data suggest that isoniazid, fluoroquinolones, and macrolides should not be used for MR-MAC-PD. Repurposing and development of novel drugs may hold promise for improving the treatment of MAC disease in the future. For instance, clofazimine and minocycline have both been proposed as a replacement for rifampicin. Bedaquiline has also been suggested as rescue therapy. This narrative clinical review describes the prevalence of MR-MAC-PD, resistance mechanisms, clinical management strategies, and provides a brief overview of the drug pipeline for MAC-PD, aiming to inform clinical practice and guide evidence-based management.