Modeling in vivo pharmacokinetics and pharmacodynamics of moxifloxacin therapy for Mycobacterium tuberculosis infection by using a novel cartridge system

Abstract

To study the efficacy of moxifloxacin treatment for tuberculosis, we utilized a novel cartridge system to simulate in vivo pharmacokinetics. We found this system to be a robust method for modeling in vivo pharmacokinetics and present data supporting the utility of intermittent moxifloxacin treatment as a component of antituberculosis chemotherapy.

FIG. 1.

(A) Schematic diagram of the PK-PD system used in this study. See the text for a complete description of the various components. (B) Capillary cartridge used for perfusion of the bacterial culture. Shown clamped at either end are tubes connected to the ICC, through which the culture medium is circulated. At the top of the cartridge are ports for inoculation and aspiration of the ECC, in which the bacteria reside.

FIG. 2.

Effects of different courses of MXF treatment on M. tuberculosis H37Ra as a function of time. An inoculum of 10⁵ CFU of H37Ra was placed into each of five cartridges and continuously perfused with medium. The cultures were exposed to no drug (A), one 100-μg pulse of MXF (B), two 100-μg doses 7 days apart (C), three 100-μg doses every 4 days (D), or three 33-μg doses every 4 days (E). Bacterial titers were determined by plate counts of samples taken from the cartridges at regular intervals. The calculated concentration of MXF in the cartridge is shown by dotted curves, which are scaled to the right vertical axes. Note that sampling from the cartridges whose data are shown in panels B and C was terminated at 300 h due to contamination observed in the central reservoir of the system.

FIG. 2.

Effects of different courses of MXF treatment on M. tuberculosis H37Ra as a function of time. An inoculum of 10⁵ CFU of H37Ra was placed into each of five cartridges and continuously perfused with medium. The cultures were exposed to no drug (A), one 100-μg pulse of MXF (B), two 100-μg doses 7 days apart (C), three 100-μg doses every 4 days (D), or three 33-μg doses every 4 days (E). Bacterial titers were determined by plate counts of samples taken from the cartridges at regular intervals. The calculated concentration of MXF in the cartridge is shown by dotted curves, which are scaled to the right vertical axes. Note that sampling from the cartridges whose data are shown in panels B and C was terminated at 300 h due to contamination observed in the central reservoir of the system.