Postantibiotic Effects of Antituberculosis Agents Alone and in Combination

Chan, C. Y.; Au-Yeang, Carrie; Yew, Wing‐Wai; Hui, Mamie; Cheng, A. F. B.

doi:10.1128/aac.45.12.3631-3634.2001

Cited by 31 publications

(30 citation statements)

References 22 publications

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“…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).…”

Section: Discussionsupporting

confidence: 80%

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

Gumbo

Louie

Deziel

et al. 2007

Antimicrob Agents Chemother

315

303

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Rifampin is a cornerstone of modern antituberculosis therapy. However, rifampin's half-life of 3 h is believed to limit its utility for intermittent therapy, so new congeners with long half-lives are being developed. Using an in vitro pharmacokinetic-pharmacodynamic model of tuberculosis, we examined the relationships between rifampin exposure, microbial killing of log-phase-growth Mycobacterium tuberculosis, and suppression of resistance. Rifampin's microbial killing was linked to the area under the concentration-time curve-to-MIC ratio. The suppression of resistance was associated with the free peak concentration (C max )-to-MIC ratio and not the duration that the rifampin concentration was above MIC. Rifampin prevented resistance to itself at a free C max /MIC ratio of >175. The postantibiotic effect duration was >5.2 days and was most closely related to the C max /MIC ratio (r 2 ‫؍‬ 0.96). To explain rifampin's concentration-dependent effect, we examined the kinetics of rifampin entry into M. tuberculosis. Rifampin achieved concentration-dependent intracellular steady-state concentrations within 15 min. Our results suggest that doses of rifampin higher than those currently employed would optimize the effect of rifampin, if patients could tolerate them. Another major implication is that in the design of new rifampin congeners for intermittent therapy, the important properties may include (i) the efficient entry of the rifamycin into M. tuberculosis, (ii) the achievement of a free C max /MIC of >175 that can be tolerated by patients, and (iii) a long postantibiotic effect duration.Tuberculosis (TB) is arguably the most important infectious disease to have confronted humankind. Currently, Mycobacterium tuberculosis infects 2 billion of the 6 billion people worldwide (50). The discovery of rifampin 40 years ago (31) was revolutionary in allowing the creation of potent combination drug regimens against this ancient nemesis. Rifampin is the backbone of modern anti-TB chemotherapy by virtue of being active against M. tuberculosis in exponential growth phase as well as possessing activity against nonreplicating persistent bacilli. Major limitations to rifampin use are believed to include its short half-life (t 1/2 ), which allows cycles of M. tuberculosis regrowth and resistance emergence.It has been the belief for almost half a century that if a drug such as rifampin was given once a week in the initial phase of therapy, its short serum t 1/2 of 3 h would allow short periods of microbial killing followed by regrowth between doses (33, 37). The inference is that the length of time that rifampin is above a certain threshold concentration is the most important index associated with M. tuberculosis killing and the prevention of resistance. Thus, one of the strategic goals of the World Health Organization, the pharmaceutical industry, and research scientists has been to develop rifampin congeners with long t 1/2 s, such as rifapentine, which would make intermittent dosing more effective (3,9,24,26).It is widely believed...

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Section: Discussionsupporting

confidence: 80%

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

Gumbo

Louie

Deziel

et al. 2007

Antimicrob Agents Chemother

315

303

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“…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).…”

supporting

confidence: 80%

“…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.…”

supporting

confidence: 79%

“…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.…”

supporting

confidence: 77%

“…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.…”

mentioning

confidence: 99%

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

Chan

Au-Yeang

Yew

et al. 2004

Antimicrob Agents Chemother

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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...

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Antitubercular Agents

Aldrich

Boshoff

2010

Burger's Medicinal Chemistry and Drug Discovery

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Postantibiotic Effects of Antituberculosis Agents Alone and in Combination

Cited by 31 publications

References 22 publications

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

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

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

Antitubercular Agents

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