Combination therapy is a successful approach to treat tuberculosis in patients with susceptible strains of Mycobacterium tuberculosis. However, the emergence of resistant strains requires identification of new, effective therapies. Pretomanid (PA824) and moxifloxacin (MXF) are promising options currently under evaluation in clinical trials for the treatment of susceptible and resistant mycobacteria. We applied our recently described screening strategy to characterize the interaction between PA824 and MXF toward the killing of M. tuberculosis in logarithmic growth phase (log phase), acid phase, and nonreplicating-persister (NRP) phase. Respective in vitro data generated for the H37Rv and 18b strains were evaluated in a microdilution plate system containing both drugs in combination. The Universal Response Surface Approach model from Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol Rev 47:331–385, 1995) was used to characterize the nature of the interaction between both drugs; synergistic or additive combinations would prompt additional evaluation in the hollow-fiber infection model (HFIM) and in animal studies. The interaction between MXF and PA824 was additive against M. tuberculosis organisms in acid phase (interaction parameter [α] = 5.56e−8 [95% confidence interval {CI} = −0.278 to 0.278] and α = 0.408 [95% CI = 0.105 to 0.711], respectively), NRP phase (α = 0.625 [95% CI = −0.556 to 1.81] and α = 2.92 [95% CI = 0.215 to 5.63], respectively), and log phase (α = 1.57e−6 [95% CI = −0.930 to 0.930] and α = 1.83e−6 [95% CI = −0.929 and 0.929], respectively), prompting further testing of this promising combination for the treatment of tuberculosis in the HFIM and in animal studies.

The pharmacokinetics of CYC is enantioselective in patients with breast cancer concomitantly treated with epirubicin and ondansetron. Genotyping or phenotyping did not contribute to adjustment of the CYC dose regimen in patients included in this study.

Tuberculosis is the ninth-leading cause of death worldwide. Treatment success is approximately 80% for susceptible strains and decreases to 30% for extensively resistant strains. Shortening the therapy duration for is a major goal, which can be attained with the use of combination therapy. However, the identification of the most promising combination is a challenge given the quantity of older and newer agents available. Our objective was to identify promising 2-drug combinations using an strategy to ultimately be tested in an hollow fiber infection model (HFIM) and in animal models. We studied the effect of the combination of linezolid (LZD) and bedaquiline (BDQ) on strain H37Rv in log- and acid-phase growth and strain 18b in log- and nonreplicating-persister-phase growth in a plate system containing a 9-by-8 matrix of concentrations of both drugs alone and in combinations. A characterization of the interaction as antagonistic, additive, or synergistic was performed using the Greco universal response surface approach (URSA) model. Our results indicate that the interaction between LZD and BDQ is additive for bacterial killing in both strains for both of the metabolic states tested. This prescreen strategy was suitable to identify LZD and BDQ as a promising combination to be further tested in the HFIM. The presence of nonoverlapping mechanisms of drug action suggests each drug in the combination will likely be effective in suppressing the emergence of resistance by to the companion drug, which holds promise in improving treatment outcomes for tuberculosis.

To make advances in the treatment of cryptococcal meningitis, it is crucial to know a given drug's free fraction that reaches the biophase. In the present study, we applied microdialysis (D) as a tool to determine the free levels reached by voriconazole (VRC) in the brains of healthy and Cryptococcus neoformans-infected rats. The infection was induced by the intravenous (i.v.) administration of 1 ϫ 10 5 CFU of yeast. The dose administered was 5 mg/kg (of body weight) of VRC, given i.v. Plasma and microdialysate samples were analyzed by liquid chromatographytandem mass spectrometry (LC-MS/MS) and LC-UV methods. The free brain/free plasma ratio (fT) and population pharmacokinetic (popPK) analyses were performed to evaluate the impact of infection on PK parameters of the drug. The brain penetration ratio showed an increase on brain exposure in infected animals (fT healthy ϭ 0.85 versus fT infected ϭ 1.86). The structural PK model with two compartments and Michaelis-Menten (MM) elimination describes the VRC concentration-time profile in plasma and tissue simultaneously. The covariate infection was included in volume of distribution in the peripheral compartment in healthy animals (V 2 ) and maximum rate of metabolism (V M ). The levels reached in infected tissues were higher than the values described for MIC of VRC for Cryptococccus neoformans (0.03 to 0.5 g ml Ϫ1 ), indicating its great potential to treat meningitis associated with C. neoformans.

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