Effect of administration of moxifloxacin plus rifampin against Mycobacterium tuberculosis for 7 of 7 days versus 5 of 7 days in an in vitro pharmacodynamic system

Abstract

Some trials administered antituberculosis agents for 5 of 7 days (5/7-day regimen) to optimize adherence. Since moxifloxacin has a longer half-life than rifampin, rifampin concentrations are <1% of the maximum concentration in serum (C(max)) on day 6 and nondetectable on day 7, while concentrations of moxifloxacin remain and are able to induce error-prone replication. We determined if functional moxifloxacin monotherapy for 24 h/week caused resistance. In in vitro pharmacodynamic experiments, Mycobacterium tuberculosis was treated with mean area under the concentration-time curve (AUC) exposures for moxifloxacin and rifampin of 400 and 600 mg/kg/day and exposures equal to 1 standard deviation (SD) above and below the mean values. The drugs were administered on schedules of 7/7 days and 5/7 days. Over the 28-day experiments, bacteria were plated onto antibiotic-free agar to determine the effects of exposure and schedule on the total population. MICs were checked for emergence of resistance. At days 7 and 14, there was a 0.56- to 1.22-log(10)-CFU/ml greater cell kill with the 7/7-day regimen versus the 5/7-day regimen (low exposure). This difference was not seen for the larger exposures at day 21. At day 23, the low-exposure 5/7-day arm had breakthrough resistance, with the total count increasing to >2 log(10) CFU/ml above the low-exposure 7/7-day arm. Pharmacokinetic mismatching of drugs in the therapy of tuberculosis may result in emergence of resistance when a drug holiday is imposed during which there is functional monotherapy and where the remaining agent induces error-prone replication. This is particularly true for the portion of the population where the clearance is higher (1 SD above the mean).

Importance: Directly observed therapy is a cornerstone of treatment of Mycobacterium tuberculosis. Patients are often given a drug holiday to facilitate the direct observation of therapy. With rifampin and moxifloxacin, there is a discordance between the half-lives of these agents (1.9 versus 6.5 h when employed in combination). In addition, moxifloxacin induces error-prone replication in Mycobacterium tuberculosis. In this experiment, we demonstrate that the drug holiday (5 of 7 days of therapy [5/7-day regimen]) allows the emergence of resistance to moxifloxacin, which was not seen with 7/7-day therapy. If drug holidays are used, it is imperative to better match pharmacokinetics to minimize the risk of emergence of resistance.

FIG 1

Hollow fiber infection model system.

FIG 2

(A) First trial of moxifloxacin-plus-rifampin 7/7-day versus 5/7-day regimens. The AUC exposures in the symbol keys are the free AUC_{24 hs} that were infused into that particular hollow fiber system experimental arm on the days that the drugs were administered. (B) Second trial of moxifloxacin-plus-rifampin 7/7-day versus 5/7-day regimens. The AUC exposures in the figure legends are the free AUC_{24 hs} that were infused into that particular hollow fiber system experimental arm on the days that the drugs were administered. There is re-growth between day 23 and day 28, specifically in the lowest exposure group (arm E) in the experimental arm where the drugs were administered 5/7days. There was a 2.25 Log₁₀ (CFU/ml) difference between arms B and E, attributable to difference in administration schedule and weekly drug exposures. In arm E colonies recovered had a wild-type MIC for rifampin (0.03 mg/L), but increased 4-fold for moxifloxacin (0.25 to 1.0 mg/L).

FIG 3

Moxifloxacin and rifampin concentrations (μg/ml) for the successful arm (A; arm B) versus failure arm (B; arm E). Solid curves are the targeted concentration-time profiles to be simulated in the hollow fiber systems. The red triangles are the measured concentrations of the respective drugs over the first 72 h of each experiment.