Postantibiotic Effects of Antituberculosis Agents Alone and in Combination

Abstract

The postantibiotic effects (PAEs) of seven antimycobacterial agents, tested at their respective peak concentrations in serum alone and in different combinations, against Mycobacterium tuberculosis ATCC 27294 were studied with a radiometric culture system in parallel with the viable count method. Rifampin gave the longest PAE (67.8 h) among the drugs used alone, and combinations of first-line drugs generally gave PAEs longer than 120 h. The data obtained might help provide a better understanding of the scientific basis of intermittently administered antituberculosis chemotherapy.Postantibiotic effect (PAE) refers to the continued suppression of bacterial growth following limited exposure of organisms to an antimicrobial agent (1,15,21). A prolonged PAE may allow wider dosing intervals without the loss of therapeutic efficacy (3). For the treatment of tuberculosis, administration of drugs at wider intervals would reduce the costs and toxicities of drugs and facilitate directly observed antituberculosis chemotherapy, thus enhancing patient adherence (8) and leading to a favorable outcome. Earlier work on pulsed exposure to isoniazid, rifampin, and pyrazinamide for 6 to 96 h has provided hints about the suitability of intermittent administration of these drugs for the treatment of tuberculosis (4-7, 16). In an attempt to better understand the scientific basis of the efficacies of certain established intermittently administered antituberculosis regimens, as well as to gain pertinent knowledge about newer antimycobacterial agents, we embarked on a study that addresses the PAEs of various antituberculosis drugs in vitro.The standard strain of Mycobacterium tuberculosis chosen for the study, strain H37Rv (ATCC 27294), was susceptible to all drugs tested. The MICs of all single drugs except pyrazinamide were determined by the broth macrodilution method (25), while susceptibility testing with pyrazinamide was done by the absolute concentration method (12). Altogether, seven antituberculosis drugs were assessed by using concentrations equivalent to their respective peak concentrations in serum (C max ) in humans (17): amikacin (32 mg/liter), ethambutol (5 mg/ liter), isoniazid (4 mg/liter), ofloxacin (8 mg/liter), rifampin (16 mg/liter), streptomycin (40 mg/liter), and pyrazinamide (60 mg/liter). Stock solutions of the drugs (all drugs except ofloxacin were purchased from Sigma, St. Louis, Mo.; ofloxacin was a gift from Daiichi, Tokyo, Japan) were prepared in appropriate solvents, stored at Ϫ70°C in 1.0-ml aliquots, and used within 6 months. For each experiment, aliquots of the stock solutions were thawed and subsequently diluted in Middlebrook 7H9 broth supplemented with 2% glycerol and 10% oleic acid-dextrose-catalase (Difco Laboratories).To determine the PAE, a homogeneous suspension of cells whose turbidity matched that of a no. 1 McFarland standard was obtained from a 3-week-old culture and stored at Ϫ40°C in 1.0-ml aliquots. For each experiment, a single vial of cells was quickly thawed at 37°C and inoculated into 10...

Concentration-Dependent Mycobacterium tuberculosis Killing and Prevention of Resistance by Rifampin

“…In the past, other researchers have demonstrated that rifampin indeed has a long PAE. Chan et al exposed M. tuberculosis to a rifampin C max /MIC of 32 and demonstrated a PAE of 2.8 days (5). This harmonizes well with our own result, in which a C max /MIC of 64.1 (approximately double the value of 32) had a PAE double the one demonstrated by Chan et al (5).…”

In Vitro Postantibiotic Effects of Rifapentine, Isoniazid, and Moxifloxacin against Mycobacterium tuberculosis

“…Furthermore, the PAE at 20 mg/liter of the drug appeared longer than that at 10 mg/liter, perhaps reflecting concentration dependence. The PAEs of rifapentine at therapeutic concentrations thus appear (at least) equivalent and might even be superior to those of rifampin (6). Isoniazid only produced a detectable PAE (Ͻ24 h), which corroborated the result of our previous study (6).…”

“…The PAEs of rifapentine at therapeutic concentrations thus appear (at least) equivalent and might even be superior to those of rifampin (6). Isoniazid only produced a detectable PAE (Ͻ24 h), which corroborated the result of our previous study (6). Moxifloxacin was found to have insignificant PAE at the concentration of 1 and 2 mg/liter.…”

“…Moxifloxacin was found to have insignificant PAE at the concentration of 1 and 2 mg/liter. This also somewhat corroborated that found for ofloxacin (6). In combination, rifapentine and isoniazid produced the most impressive PAE (137 h), suggesting probable synergistic prolongation of PAE between the two drugs.…”

“…We have examined the PAEs of rifampin, isoniazid, amikacin, streptomycin, ethambutol, ofloxacin, and pyrazinamide against Mycobacterium tuberculosis in a previous study (6). We subsequently embarked on this study to assess the PAEs of rifapentine, moxifloxacin, and isoniazid.…”