Combining lefamulin with rifampin provides in vitro synergistic antimicrobial effects against Rhodococcus equi isolates susceptible to macrolides and rifampin

Objective: Because of lefamulin's antimicrobial spectrum and intrapulmonary disposition, the objective of this study was to estimate MICs for macrolide- and rifampin-susceptible (MRS) and macrolide- and rifampin-resistant (MRR) isolates of Rhodococcus equi to lefamulin either alone or in combination with rifampin. Methods: Gradient diffusion and broth microdilution were performed to determine MICs for lefamulin alone using MRS (n = 43) and MRR isolates (61) of R equi. Twenty MRR and 20 MRS isolates were tested for synergistic effects using a checkerboard assay and the fractional inhibitory concentration index as an outcome measure. Results: For both MRR and MRS isolates, MIC values were significantly higher using broth microdilution (median MIC, 32 µg/mL; range, 8 to 64 µg/mL) than gradient diffusion (median MIC, 12 µg/mL; range, 5 to 28 µg/mL) testing. The fractional inhibitory concentration values of MRR isolates (median, 0.562; range, 0.250 to 1.000) were significantly higher than those of MRS isolates (median, 0.280; range, 0.039 to 1.038). In addition, the proportion of isolates exhibiting synergistic interaction was significantly greater among MRS isolates (16 of 20 [80%]) than among MRR isolates (6 of 20 [30%]). Conclusions: Overall, the MIC values for lefamulin against R equi were high relative to concentrations considered therapeutic in humans. When combined with rifampin, lefamulin exhibited synergistic effects for MRS but not MRR isolates. Clinical Relevance: Need exists for alternative antimicrobials to treat rhodococcal foal pneumonia. Results indicate that studies in foals of the pharmacokinetics and pulmonary disposition of lefamulin in combination with rifampin are warranted.