Omadacycline as a drug candidate for Mycobacterium avium infections: in vitro insights on single and combination therapies.

OBJECTIVES

The current antibiotic arsenal for the treatment of Mycobacterium avium infections is limited and new treatment options are needed. This exploratory study assessed the in vitro activity of omadacycline against M. avium alone and combined with current guideline-recommended antibiotics and the ability of omadacycline to prevent the emergence of antibiotic resistance.

METHODS

The activity of omadacycline and comparator antibiotics against M. avium was studied by minimum inhibitory concentration (MIC) assays and time-kill kinetics assays to investigate time- and concentration-dependent activity patterns. Omadacycline's ability to prevent clarithromycin and amikacin resistance was investigated by phenotypic and molecular assays.

RESULTS

The MIC of omadacycline was impacted by medium composition: a higher MIC was found in CAMHB (128 mg/L) versus Middlebrook broth (8 mg/L). MIC values were also impacted by omadacycline instability in solution over time and daily drug supplementation reduced the MIC to 1 mg/L. In time-kill assays, omadacycline demonstrated time- and concentration-dependent activity. Omadacycline-containing drug combinations resulted in varying degrees of enhanced activity, which was most apparent for omadacycline plus amikacin. Omadacycline prevented amikacin MICs from increasing and impeded the emergence of rrs mutations observed with amikacin alone. While enhanced activity of omadacycline plus clarithromycin was less pronounced, rrl mutations were not detected in the presence of omadacycline.

CONCLUSIONS

Omadacycline demonstrated in vitro activity against M. avium, particularly in combination with amikacin. Emergence of clarithromycin and amikacin resistance seemed to be prevented by co-exposure to omadacycline. Further research is warranted to assess omadacycline's role in treating M. avium disease.