Purpose: The emergence of clarithromycin resistance is a challenge in treating Mycobacterium abscessus  infections. Known mechanisms that contribute to intrinsic clarithromycin resistance focus on rrl  gene-related mutations, but resistant clinical isolates often exhibit an inconsistent rrl  genotype.
Patients and Methods: In this study, 194 clinical Mycobacterium abscessus  isolates were collected from patients with lung infections and the whole genome of each isolate was sequenced. A comprehensive examination of the molecular mechanisms underlying intrinsic clarithromycin resistance was performed, combining MIC determination, comparative genome sequence analysis and qRT-PCR.
Results: Of the 194 isolates, 13 (6.7%) were clarithromycin resistant; only seven of these harbored a rrl  2270/2271 mutation. The remaining six resistant isolates did not exhibit a specific resistance-associated mutation in the clarithromycin target-site genes, rrl, rplC, rplD  and rplV , or in the rrl  modification gene erm(41). qRT-PCR analysis showed that the increased expression of the efflux pump genes, MAB_2355c, MAB_1409c and MAB_1846, as well as their positive regulatory gene whiB7 , consistently correlated with increased clarithromycin resistance. The presence of efflux pump inhibitors significantly decreased the MIC of clarithromycin for nonsusceptible isolates, especially the intrinsic resistant isolates that exhibited no rrl  2270/2271 mutation.
Conclusion: These findings indicate that efflux pumps play a prominent role in the intrinsic resistance of M. abscessus  to clarithromycin, complementing other known resistance mechanisms.
Keywords: Mycobacterium abscessus , clarithromycin resistance, efflux pumps