Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid

Vernon, Andrew; Burman, William J.; Benator, Debra; Khan, Abdul Qadir; Bozeman, Lorna

doi:10.1016/s0140-6736(98)11467-8

Cited by 284 publications

(175 citation statements)

References 25 publications

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“…However, the onceweekly INH-RPT 10 mg/kg continuation phase regimen was less efficacious than twice-weekly RIF-INH in HIV-infected and other high-risk patients (3,5). In the final portion of our experiment we examined the sterilizing activity of improved once-weekly RPT-based continuation phase regimens by assessing the number of culture-positive mice 3 mo after completing 4, 5, and 6 mo of treatment.…”

Section: Discussionmentioning

confidence: 99%

“…However, treatment restrictions limit the use of INH-RPT to non-highrisk patients (HIV seronegative with noncavitary TB) and are based on higher rates of treatment failure or relapse with rifamycinmonoresistant bacilli in high-risk patients (3,5). Moreover, once-weekly INH-RPT has been shown to be less active than three times-or twice-weekly (3 of 7 or 2 of 7 d) therapy with rifampin (RIF) and INH (5)(6)(7).…”

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confidence: 99%

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Weekly Moxifloxacin and Rifapentine Is More Active Than the Denver Regimen in Murine Tuberculosis

Rosenthal

Williams

Tyagi

et al. 2005

Am J Respir Crit Care Med

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Rationale: Treatment of tuberculosis with an efficacious once-weekly regimen would be a significant achievement in improving patient adherence. Currently, the only recommended once-weekly continuation phase regimen of isoniazid plus rifapentine (10 mg/kg) is inferior to standard twice-weekly therapy with isoniazid plus rifampin and is, therefore, restricted to non-high-risk patients. The substitution of moxifloxacin, a new 8-methoxyfluoroquinolone, for isoniazid and an increase in the dose of rifapentine could augment the activity of once-weekly regimens. Methods: To test this hypothesis we evaluated the sterilizing activity of improved once-weekly rifapentine-based continuation phase regimens in a murine model that mimics the treatment of highrisk patients with tuberculosis. The bactericidal activity of standard daily therapy and standard intermittent therapy ("Denver" regimen) was also assessed to evaluate the effect of intermittent drug administration during the initial phase of therapy. Results: After 2 mo of treatment, lung colony-forming unit counts were 1 log 10 lower in mice treated with standard daily therapy than with the Denver regimen. During the continuation phase, the sterilizing activity of once-weekly moxifloxacin plus rifapentine (15 mg/kg) was significantly greater than that of the predominantly twice-weekly Denver regimen of isoniazid plus rifampin. No significant difference in sterilizing activity was detected between onceweekly isoniazid plus rifapentine (15 mg/kg) and the Denver regimen. Conclusions: These results suggest that the efficacy of the onceweekly isoniazid plus rifapentine continuation phase regimen can be increased by substituting moxifloxacin for isoniazid and by increasing the dose of rifapentine to a clinically acceptable level of 15 mg/kg. Keywords: antibiotics; intermittent therapy; mouse; treatment Effective control of tuberculosis (TB), especially in the setting of the HIV pandemic, requires the use of long and cumbersome chemotherapeutic regimens (1). Despite implementation of the World Health Organization directly observed therapy shortcourse strategy, nonadherence remains a serious threat to effective control of TB (2). Effective regimens employing drugs that could be administered once weekly (1 of 7 d) would be expected to facilitate supervised therapy by reducing the number of doses requiring supervision (3), leading to improved completion rates and raising prospects for expansion of DOTS coverage throughout the developing world.Rifapentine (RPT), a long-lasting rifamycin, is currently recommended for use at a dose of 10 mg/kg in combination with isoniazid (INH) during once-weekly continuation phase therapy (4). However, treatment restrictions limit the use of INH-RPT to non-highrisk patients (HIV seronegative with noncavitary TB) and are based on higher rates of treatment failure or relapse with rifamycinmonoresistant bacilli in high-risk patients (3, 5). Moreover, once-weekly INH-RPT has been shown to be less active than three times-or twice-weekly (3 of 7 or 2 of ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Weekly Moxifloxacin and Rifapentine Is More Active Than the Denver Regimen in Murine Tuberculosis

Rosenthal

Williams

Tyagi

et al. 2005

Am J Respir Crit Care Med

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“…For example, allowing drug concentrations to remain in the bottom portion of the selection window should rapidly enrich mutant subpopulations, because more mutant types are able to grow at low drug concentrations than at high concentrations [10,49]. Moreover, infrequent dosing with long-lived compounds that place concentrations inside the selection window for days at a time is expected to lead to drug resistance more rapidly than dosing that keeps concentrations above the window [50,51]. Third, if drug-resistance mutations confer such high levels of protection that antimicrobial concentrations cannot be maintained either above the MPC for bacteriostatic compounds or above a critical value of AUC 24 / MPC for lethal agents, restriction of mutant amplification may require dual-or triple-drug therapy with good pharmacodynamic overlap among the antimicrobial agents being used [2].…”

Section: Potential Applicationsmentioning

confidence: 99%

Mutant Selection Window Hypothesis Updated

Drlica¹,

Zhao²

2007

Clinical Infectious Diseases

349

338

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The mutant selection window hypothesis postulates that, for each antimicrobial-pathogen combination, an antimicrobial concentration range exists in which selective amplification of single-step, drug-resistant mutants occurs. This hypothesis suggests an antimutant dosing strategy that is keyed to the upper boundary of the selection window: the mutant prevention concentration. Correlations are described between the mutant prevention concentration-a static parameter that is measured with agar plates-and fluctuating drug concentrations that restrict mutant amplification in vitro and in animals. When drug resistance is acquired stepwise, the mutant selection window increases, making the suppression of each successive mutant increasingly more difficult. For agents that kill drug-resistant mutants in a drug concentration-dependent manner, the use of the area under the 24-h time-drug concentration curve value divided by the value of the mutant prevention concentration is suggested as an index for designing antimutant dosing regimens. The need for such regimens is emphasized by a clinical example in which acquisition of drug resistance occurs concurrently with eradication of susceptible bacterial cells. These data support using the mutant selection window to optimize antimicrobial dosing regimens.Antimicrobial resistance is a complex problem that is likely to require attention at many levels [1]. Issues concerning dosing are addressed by the mutant selection window hypothesis [2,3]. This hypothesis maintains that drug-resistant mutant subpopulations present prior to initiation of antimicrobial treatment are enriched and amplified during therapy when antimicrobial concentrations fall within a specific range (the mutant selection window). The upper boundary of the mutant selection window is the MIC of the least drugsusceptible mutant subpopulation, a value called the mutant prevention concentration (MPC) [4]. The lower boundary of the mutant selection window is the lowest concentration that exerts selective pressure, often approximated by the minimal concentration that inhibits colony formation by 99% (MIC 99 ). Two principles emerge from the hypothesis. First, traditional dos-

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“…Un nouveau schéma récemment mis au point consiste en un traitement associant l'INH et la rifapentine administrés une fois par semaine pendant 12 semaines (3HP). La rifapentine avait initialement été mise au point pour le traitement de la tuberculose active durant les années 1970 et au début des années 1980 (15), mais son utilisation chez les patients infectés par le VIH durant la phase de prolongation du traitement de la tuberculose active a révélé des taux de résistance au traitement supérieurs à ceux observés avec la rifampicine (16). C'est pourquoi la rifapentine n'est pas recommandée pour le traitement de la tuberculose active au Canada (17).…”

Section: Traitement De L'infection Tuberculeuse Latenteunclassified

Un schéma thérapeutique plus court qui s'annonce prometteur pour le traitement de l'infection tuberculeuse latente chez les Canadiens à risque

Pease¹,

Amaratunga²,

Alvarez³

2017

RMTC

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Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid

Cited by 284 publications

References 25 publications

Weekly Moxifloxacin and Rifapentine Is More Active Than the Denver Regimen in Murine Tuberculosis

Weekly Moxifloxacin and Rifapentine Is More Active Than the Denver Regimen in Murine Tuberculosis

Mutant Selection Window Hypothesis Updated

Un schéma thérapeutique plus court qui s'annonce prometteur pour le traitement de l'infection tuberculeuse latente chez les Canadiens à risque

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