Limited information exists on the pharmacokinetic (PK)-pharmacodynamic (PD) relationships of drugs against Mycobacterium tuberculosis. Our aim was to identify the PK-PD parameter that best describes the efficacy of rifampin on the basis of in vitro and PK properties. Consistent with 83.8% protein binding by equilibrium dialysis, the rifampin MIC for M. tuberculosis strain H37Rv rose from 0.1 in a serum-free system to 1.0 mg/ml when it was tested in the presence of 50% serum. In time-kill studies, rifampin exhibited area under the concentration-time curve (AUC)-dependent killing in vitro, with maximal killing seen on all days and with the potency increasing steadily over a 9-day exposure period. MIC and time-kill studies performed with intracellular organisms in a macrophage monolayer model yielded similar results. By use of a murine aerosol infection model with dose ranging and dose fractionation over 6 days, the PD parameter that best correlated with a reduction in bacterial counts was found to be AUC/MIC (r 2 ‫؍‬ 0.95), whereas the maximum concentration in serum/MIC (r 2 ‫؍‬ 0.86) and the time that the concentration remained above the MIC (r 2 ‫؍‬ 0.44) showed lesser degrees of correlation.

, and 38 to 100,000 mg/kg (CIP) were performed with a murine aerosol infection model. MXF was the most efficacious agent (3.0 ؎ 0.2 log 10 CFU/lung reduction), followed by SPX (1.4 ؎ 0.1) and OFX (1.5 ؎ 0.1). CIP showed no effect. The ratio of the AUC to the MIC was the pharmacodynamic parameter that best described the in vivo efficacy. In summary, a lack of intracellular killing predicted the lack of in vivo activity of CIP. The in vivo rank order for maximal efficacy of the three active fluoroquinolones was not clearly predicted by the in vitro assays, however.

Limited data exist on the pharmacokinetic-pharmacodynamic (PK-PD) parameters of the bactericidal activities of the available antimycobacterial drugs. We report on the PK-PD relationships for isoniazid. Isoniazid exhibited concentration (C)-dependent killing of Mycobacterium tuberculosis H37Rv in vitro, with a maximum reduction of 4 log 10 CFU/ml. In these studies, 50% of the maximum effect was achieved at a C/MIC ratio of 0.5, and the maximum effect did not increase with exposure times of up to 21 days. Conversely, isoniazid produced less than a 0.5-log 10 CFU/ml reduction in two different intracellular infection models (J774A.1 murine macrophages and whole human blood). In a murine model of aerosol infection, isoniazid therapy for 6 days produced a reduction of 1.4 log 10 CFU/lung. Dose fractionation studies demonstrated that the 24-h area under the concentration-time curve/MIC (r 2 ‫؍‬ 0.83) correlated best with the bactericidal efficacy, followed by the maximum concentration of drug in serum/MIC (r 2 ‫؍‬ 0.73).No new drugs for the treatment of tuberculosis have been registered in the last 40 years. Discovery of new antimycobacterial agents is in part limited by the laborious and slow nature of the in vitro and in vivo studies required. Knowledge of the pharmacokinetic (PK)-pharmacodynamic (PD) properties of candidate drugs could be used to facilitate drug discovery and evaluation of the effects of combinations of agents. As a step toward such a strategy, we have recently identified the PK-PD parameter that correlated with the in vivo efficacy of rifampin in a murine aerosol model of tuberculosis (7). In the present study, we have extended this work to include isoniazid. MATERIALS AND METHODSReagents. Isoniazid (lot 36H1179) and carboxymethyl cellulose (lot 77H1077) were purchased from Sigma, St. Louis, Mo. Isoniazid stock solutions were prepared in 100% dimethyl sulfoxide (DMSO; Sigma) and diluted in normal saline prior to final use. ETDA (lot 5-4514) was purchased from Hi-Media Labs, Mumbai, India. Acetonitrile (high-pressure liquid chromatography [HPLC] grade) and trichloroacetic acid (TCA) were obtained from Spectrochem Pvt. Ltd., Mumbai, India. Cinnamaldehyde (lot 96320) was obtained from Fluka Biochemika, Bucks, Switzerland.Microbial cultures and cell lines. Mycobacterium tuberculosis H37Rv (ATCC 27294) and J774A.1 macrophages were prepared for in vitro, macrophage, and animal infection studies by previously described methods (7).Blood from healthy volunteers. Group O-positive blood from healthy volunteers collected in citrate phosphate dextrose adenine anticoagulant was obtained from a registered blood bank (TTK Blood Bank, Bangalore, India). It was stored at 4°C and was used for assays up to 1 month from the date of collection.Animals. The Institutional Animal Ethics Committee, registered with the Government of India (registration no. CPCSEA 1999/5), approved all experimental protocols with animals and the use of animals. Ethical practices recommend the use of equal numbers of animals of both sexes w...

No abstract