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...
The combined effect of clarithromycin and rifabutin against Mycobacterium avium multiplying either within human monocyte-derived macrophages or extracellularly in a liquid medium was additive: both MICs and MBCs were twofold lower for the combination than they were for each drug alone. Prolonged exposure for 4 weeks of M. avium-infected macrophages to combined concentrations that were only twofold greater than the MICs resulted in a 100-fold decrease in the number of viable bacteria, while in the drug-free controls a 100-fold or greater increase in comparison with the initial viable counts took place. Comparison of this effect with the results of the prolonged exposure to each drug alone suggested that under these experimental conditions rifabutin enhanced the antimicrobial activity of clarithromycin against intracellular bacteria. At the same time, inhibition of intracellular growth by a 2-h pulsed exposure of the infected macrophages to the combination of the two drugs was not different from the effect induced by clarithromycin alone. In conclusion, clarithromycin played the major role in the antimicrobial activity of the tested combination, while rifabutin may have enhanced this effect during a prolonged exposure of the intracellular bacteria to these two agents.Combinations of clarithromycin with a variety of other drugs have been investigated in vitro in cell-free culture media and macrophages (3,7,9,10,16,17). The overall analyses of these data indicated that the interaction in these combinations tested against Mycobacterium avium was additive rather than synergistic (2). The effect of this combination for the treatment and prevention of disseminated M. avium infection in patients with AIDS is under investigation. The aim of the present study was to evaluate the activity of clarithromycin in combination with rifabutin against M. avium in a cell-free culture medium and human monocyte-derived macrophages. The study included an evaluation of the antimicrobial activity during prolonged exposure and the effect of a drug combination given to infected macrophages by pulsed exposure.MATERUILS AND METHODS Antimicrobial agents. Rifabutin (Adria Laboratories, Pharmacia, Columbus, Ohio) was dissolved first in methanol (640 jig/ml) and was then diluted further in distilled water to make appropriate working solutions. Clarithromycin (Abbott Laboratories, Abbott Park, Ill.) was first dissolved in dimethyl sulfoxide (1,280 jig/ml) and was then diluted further in phosphate buffer (pH 6.5).Test strains. Three strains identified as M. avium by the Gen-Probe (San Diego, Calif.) technique were used for the studies. These strains, isolated from blood samples obtained from patients with AIDS, were used in our previous studies (8,12,13). They were preserved in frozen 7H9 broth culture aliquots at -70°C. For each experiment, a subculture in 7H9 broth was made from a frozen aliquot.Antimicrobial activity against extracellular bacteria. The MIC was defined as the lowest drug concentration that inhibited more than 99% of the bacteria...
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