Comparison of activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human macrophages

Abstract

The activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human monocytederived macrophages were determined. The MICs and MBCs of rifapentine for intracellular bacteria were twoto fourfold lower than those of rifampin. For extracellular bacteria, this difference was less noticeable. Nevertheless, the more favorable pharmacokinetics of rifapentine over rifampin was addressed in other experimental models. These models showed substantial differences after short pulsed exposures of the infected macrophages to the drugs and when the infected macrophages were exposed to changing drug concentrations that imitated the pharmacokinetic curves observed in blood. Once-a-week exposures to rifapentine concentrations equivalent to those attained in blood after one 600-mg dose resulted during the first week in a dramatic decline in the number of bacteria, and this decline was maintained at a minimal level for a period of four weeks. The results of this study have shown the suitability of rifapentine for intermittent-treatment regimens. The prolonged effect of rifapentine found in this study may be associated with high ratios of intracellular accumulation, which were four-to fivefold higher than those found for rifampin. Further studies on the intracellular distribution of rifamycins and on the sites of actual interaction between the drugs and bacteria residing in macrophages are necessary.The combined use of isoniazid, rifampin, and pyrazinamide provided the basis for a successful short course of tuberculosis therapy. The discovery of long-lasting rifamycins, particularly of rifapentine (RPT), created the possibility for intermittent drug regimens (5,7,18). In the early studies, RPT was reported to have an in vitro activity the same as or higher than that of rifampin (RMP) (19,20). Subsequent studies have shown that the broth-determined MICs of RPT were two-to threefold lower than those of RMP (8, 10). The elimination half-life of RPT in animals and humans was about five times longer than that of RMP, and the levels of RPT in plasma substantially exceeded the MICs for a period of up to 72 h after a single oral dose (1)(2)(3)12). The advantage of RPT over RMP has been shown in murine models (1,5,11,18). Besides its more favorable pharmacokinetic parameters in blood, RPT accumulates to higher concentrations than does RMP in polymorphonuclear leukocytes and macrophages (6,9,16).In anticipation of a controlled clinical trial for the comparison of RPT and RMP in the therapy of tuberculosis, the present study compares the potential activities of these rifamycins against extracellular and intracellular Mycobacterium tuberculosis. Inhibitory and bactericidal activities (MICs and MBCs) against intracellular bacteria in human monocyte-derived macrophages were determined and compared with MICs and MBCs against extracellular bacteria. The actual accumulation of these drugs in human monocytes was also determined. Special attention was given to the evaluation of the long-lasting effect of RPT after pulsed expo...

Single-Dose Intrapulmonary Pharmacokinetics of Rifapentine in Normal Subjects

“…These data provide a pharmacokinetic rationale for extended-interval dosing. The optimum dosing regimen for rifapentine will have to be determined by controlled clinical trials.Rifapentine is an orally administered rifamycin derivative that has antituberculous activity and that is similar to rifampin (11,12,16,27). The MICs for sensitive strains are usually in the range of 0.03 to 0.12 mg/liter, and MICs for resistant strains are Ն8 mg/liter (15).…”

Evaluation of macrolides for possible use against multidrug-resistantMycobacterium tuberculosis

“…However, some studies reported promising results that might contribute to clinical activity in the sense of macrolides exerting bacteriostatic effects in vitro [39,45,48,49] and in vivo [39,47,59]. Furthermore, a decrease in mortality in murine infection models [39,60] and synergistic effects when CLR was combined in vitro with second-line anti-TB drugs [36,37,40,57,73] were seen. Also, an interaction was reported in a clinical study [61], suggesting an increase of LZD serum concentration when combined with CLR.…”

Genetics and pulmonary medicine bullet 5: Genetics of drug resistant tuberculosis

“…Other strategies for manipulation of permeability barriers using inhibitors of eZux pumps (reserpine, calcium channel blockers, cycloserine A, and other compounds) remain poorly investigated in bacteriology. A therapeutic role for compounds such as clarithromycin 58 and even immunomodulators such as interferon [59][60][61] has not been defined (table 2). Finally, drug development is being streamlined by detailed analysis of the molecular targets.…”