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

Abstract

Postantibiotic effects (PAEs) of rifapentine, isoniazid, and moxifloxacin against Mycobacterium tuberculosis ATCC 27294 were studied using a radiometric culture system. Rifapentine at 20 mg/liter gave the longest PAE (104 h) among the drugs used alone. The combinations of rifapentine plus isoniazid, rifapentine plus moxifloxacin, and isoniazid plus moxifloxacin gave PAEs of 136.5, 59.0, and 8.3 h, respectively.Postantibiotic effect (PAE) refers to the continued suppression of bacterial growth following limited exposure of organisms to an antimicrobial agent (3,24). The significant PAE of a single drug or a combination of drugs may allow wider dosing intervals without the loss of therapeutic efficacy (8). In managing patients with tuberculosis, administration of drugs at intermittent intervals would reduce cost and possibly toxicity of drugs, as well as enhance adherence through greater feasibility of directly observed therapy (13). Earlier work a few decades ago on pulsed exposure of rifampin and isoniazid for 6 to 96 h provided some therapeutic hints on such issues (9-12).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. The former two agents could be regarded as new antituberculosis drugs.The standard strain of Mycobacterium tuberculosis H37Rv (ATCC 27294) chosen for this study was susceptible to all three drugs tested. The MICs of rifapentine, isoniazid, and moxifloxacin against the standard strain of M. tuberculosis were 0.125, 0.06, and 0.25 mg/liter, respectively, as determined by the broth macrodilution method. The PAEs of the three antituberculosis agents were assessed using drug concentrations falling into the likely therapeutic ranges in humans (7,17,(19)(20)(21): rifapentine (10 to 20 mg/liter), isoniazid (2 mg/liter), and moxifloxacin (1 to 2 mg/liter). Rifapentine and moxifloxacin drug powders for testing were gifts from d'Aventis Pharmaceutical International (Romainville, France) and Bayer Pharmaceutical (Wuppertal, Germany), respectively. Isoniazid drug powder for testing was purchased from Sigma (St. Louis, Mo.). The stock solutions 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 aciddextrose catalase (Difco Laboratories).The PAEs of the three drugs alone and in combination were determined using a previously established radiometric culture method (14). A homogenous suspension of bacterial cells matching that of McFarland standard 1 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 thawed quickly at 37°C and inoculated into 10 ml of BACTEC 12B medium supplemented with 2.5% Panta reconstituti...

New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development

“…The MIC of rifapentine ranges from 0.02 to 0.125 mg/liter, i.e., two to four times lower than that of rifampin (8,18,31,32,101). When adjusted for protein binding, the AUC/MIC ratio for rifapentine in standard dose is 76.6 (AUC/MIC ratio for rifampin, 70.8) (108).…”

Lewofloksacyna i moksyfloksacyna w leczeniu zakażeń bakteryjnych

“…Interesującym wynikiem badań porównawczych było wykazanie zróżnicowanego czasowo efektu poantybiotykowego w odniesieniu do leczenia zakażenia prątkiem gruźlicy. Ryfapentyna z izoniazydem powodowała trwający 136,5 godziny PAE, ryfapentyna z moksyfloksacyną -59-godzinny, a izoniazyd z moksyfloksacyną -jedynie 8,3-godzinny efekt poantybiotykowy [18]. Artyku jest dost pny na zasadzie dozwolonego u ytku osobistego.…”

Antitubercular In Vitro Drug Discovery: Tools for Begin the Search

“…The post antibiotic effect (PAE) is defined as persistent suppression of bacterial growth after a brief exposure (1 or 2 h) of bacteria to an antibiotic (Chan et al, 2004). Factors that affect the duration of the post antibiotic effect include duration of antibiotic exposure, bacterial species, culture medium and class of antibiotic.…”