The therapy of Mycobacterium tuberculosis (MTB) infection is long and arduous. It has been hypothesized that the therapy duration is driven primarily by populations of organisms in different metabolic states that replicate slowly or not at all (Acid-phase and NRP-phase organisms). Linezolid is an oxazolidinone antimicrobial with substantial activity against Log-phase MTB. Here, we examined organisms in Acid-phase growth and Non-Replicative Persister phenotype growth and determined the effect of differing clinically-relevant exposures to linezolid in a Hollow Fiber Infection Model (HFIM). The endpoints measured were bacterial kill over 29 days and whether organisms less-susceptible to linezolid could be recovered during this period. In addition, we evaluated the effect of administration schedule on linezolid activity, contrasting daily administration with twice the daily dose administered every other day. Linezolid demonstrated robust activity when administered daily against both Acid-phase and NRP-phase organisms. We demonstrated a clear dose response, with 900 mg of linezolid daily generating ≥ 3 Log(CFU/ml) killing of Acid-phase and NRP-phase MTB bacterial kill over 29 days. Amplification of a population less susceptible to linezolid was not seen. Activity was reduced with every 48-hour dosing, indicating that Cmin/MIC ratio drove microbiological effect. We conclude that once-daily linezolid has substantial activity against MTB in Acid-phase and NRP-phase metabolic states. Other studies have shown activity versus Log-phase MTB. Linezolid is a valuable addition to the therapeutic armamentarium for MTB and has the potential for substantially shortening therapy duration.
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