Efflux Pumps Contribute to Intrinsic Clarithromycin Resistance in Clinical, Isolates.

PURPOSE

The emergence of clarithromycin resistance is a challenge in treating infections. Known mechanisms that contribute to intrinsic clarithromycin resistance focus on gene-related mutations, but resistant clinical isolates often exhibit an inconsistent genotype.

PATIENTS AND METHODS

In this study, 194 clinical 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 2270/2271 mutation. The remaining six resistant isolates did not exhibit a specific resistance-associated mutation in the clarithromycin target-site genes, and , or in the modification gene (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 , 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 2270/2271 mutation.

CONCLUSION

These findings indicate that efflux pumps play a prominent role in the intrinsic resistance of to clarithromycin, complementing other known resistance mechanisms.