In vitro susceptibility study of clarithromycin combined with antifungal agents against Talaromyces marneffei

Objective To evaluate the in vitro combined effects of clarithromycin (CLA) with 4 antifungal agents against Talaromyces marneffei (TM), and to compare the impacts of different interpretive criteria on the combined susceptibility results, thereby providing a theoretical basis for the clinical treatment of co-infection caused by TM and nontuberculous mycobacteria (NTM).

Methods The checkerboard microdilution method was adopted to perform the combination susceptibility testing of CLA with amphotericin B (AmB), fluconazole (FLC), itraconazole (ITC) and voriconazole (VOC) against 20 TM strains (19 clinical isolates+1 reference strain). For azoles, 2 interpretive criteria were respectively adopted: half-maximal inhibitory concentration (IC₅₀) and complete-inhibitory concentration (IC₁₀₀), and the combined effects were assessed using fractional inhibitory concentration index (FICI).

Results The combination of AmB and CLA showed the highest synergy rate (18/20, 90%), and the geometric mean of , IC₁₀₀of AmB decreased from 2.297 μg/mL to 0.536 μg/mL after the combination (P＜0.001). The combination of ITC and CLA showed consistent activity under both interpretive criteria, with synergy rates of 45%–65% and additive rates of 35%–55%. The synergistic effects of the FLC-CLA and VOC-CLA combinations were highly dependent on the interpretive criteria: indifferent interactions predominated at IC₅₀ (100% and 85%, respectively), whereas additive interactions predominated at , IC₁₀₀ (85% and 75%, respectively). No antagonism was observed for any combination.

Conclusion The combination of AmB and CLA exhibits the strongest synergistic effect, suggesting its potential as a preferred option for combined therapy in severe co-infections. The combination of ITC and CLA exhibits a stable synergistic effect, suggesting its potential for oral sequential therapy. The synergistic effects of the FLC-CLA and VOC-CLA combinations can only be observed at IC₁₀₀. The choice of interpretive criteria significantly affects the qualitative outcomes of azole-combination susceptibility testing.