Rifalazil and Other Benzoxazinorifamycins in the Treatment of Chlamydia‐Based Persistent Infections

Rothstein, David M.; Duzer, John van; Sternlicht, Andrew; Gilman, Steven C.

doi:10.1002/ardp.200700080

Cited by 14 publications

(11 citation statements)

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“…Rifalazil plasma concentrations were detectable after more than 3 weeks in all subjects after a single 25-mg dose of rifalazil, as expected based on rifalazil's previously reported long elimination half-life of ϳ100 h (11). Treatment failures at visit 2 (day 8 to 12) tended to have lower rifalazil plasma concentrations than those diagnosed as cured at the same visit; however, the difference was not significant.…”

Section: Discussionsupporting

confidence: 74%

“…In vitro studies have shown that rifalazil has a significantly greater antimicrobial potency against C. trachomatis than azithromycin, with their MIC 90 s being 0.00025 and 0.125 g/ml, respectively (11)(12)(13). Rifalazil has a long elimination half-life of approximately 100 h and achieves high intracellular concentrations (11), which could reduce the likelihood of treatment failure and lessen the incidence of repeat infections. The clinical benefit of a single oral dose of 25 mg of rifalazil in treating C. trachomatis was demonstrated in a phase II clinical study which enrolled men with nongonococcal urethritis (NGU) (14).…”

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confidence: 99%

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Randomized, Double-Blind, Multicenter Safety and Efficacy Study of Rifalazil Compared with Azithromycin for Treatment of Uncomplicated Genital Chlamydia trachomatis Infection in Women

Geisler

Pascual²,

Mathew³

et al. 2014

Antimicrob Agents Chemother

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A randomized, double-blind study comparing single-dose chlamydia therapies of oral rifalazil (25 mg) and azithromycin (1 g) was conducted in 82 women with uncomplicated genital Chlamydia trachomatis infection. The microbiologic cure rate of C. trachomatis with rifalazil (n ‫؍‬ 33) was 84.8% at the visit on day 22 to 26 (test-of-cure visit), versus 92.1% with azithromycin (n ‫؍‬ 38), and the number of treatment failures in each group was 5 and 3, respectively. The difference in cure rate was ؊7.3%, with a lower limit of the 95% confidence interval (95% CI) of ؊22.5, and thus, noninferiority was not established at the prespecified margin (lower limit of CI of ؊15%). The overall treatment-emergent adverse event (TEAE) and treatment-related TEAE rates were lower in the rifalazil group (68% and 55%) than in the azithromycin group (71% and 62%), respectively. Subjects classified as treatment failures at day 22 to 26 had a lower mean plasma concentration of rifalazil at the visit on day 8 to 12 than those classified as treatment cures, but this difference was not significant; however, the levels were similar for both groups at the visit on day 22 to 26. A single 25-mg dose of rifalazil was well tolerated and eradicated C. trachomatis in most of these women with uncomplicated genital C. trachomatis infection. (The study was registered at clinicaltrials.gov under registration no. NCT01631201).

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Section: Discussionsupporting

confidence: 74%

mentioning

confidence: 99%

Randomized, Double-Blind, Multicenter Safety and Efficacy Study of Rifalazil Compared with Azithromycin for Treatment of Uncomplicated Genital Chlamydia trachomatis Infection in Women

Geisler

Pascual²,

Mathew³

et al. 2014

Antimicrob Agents Chemother

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“…At present, RIF continues to be a first-line drug for the treatment of tuberculosis (5). Through the years additional derivatives have been developed to treat a wider range of bacterial infections (3); for example, rifalazil serves as an effective antibiotic against Chlamydia-based persistent infections (6), and rifaximin is used to treat travelers' diarrhea and irritable bowel syndrome (7,8).…”

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confidence: 99%

Structural basis of rifampin inactivation by rifampin phosphotransferase

Lin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Rifampin (RIF) is a first-line drug used for the treatment of tuberculosis and other bacterial infections. Various RIF resistance mechanisms have been reported, and recently an RIF-inactivation enzyme, RIF phosphotransferase (RPH), was reported to phosphorylate RIF at its C21 hydroxyl at the cost of ATP. However, the underlying molecular mechanism remained unknown. Here, we solve the structures of RPH from Listeria monocytogenes (LmRPH) in different conformations. LmRPH comprises three domains: an ATP-binding domain (AD), an RIF-binding domain (RD), and a catalytic His-containing domain (HD). Structural analyses reveal that the C-terminal HD can swing between the AD and RD, like a toggle switch, to transfer phosphate. In addition to its catalytic role, the HD can bind to the AD and induce conformational changes that stabilize ATP binding, and the binding of the HD to the RD is required for the formation of the RIF-binding pocket. A line of hydrophobic residues forms the RIF-binding pocket and interacts with the 1-amino, 2-naphthol, 4-sulfonic acid and naphthol moieties of RIF. The R group of RIF points toward the outside of the pocket, explaining the low substrate selectivity of RPH. Four residues near the C21 hydroxyl of RIF, His825, Arg666, Lys670, and Gln337, were found to play essential roles in the phosphorylation of RIF; among these the His825 residue may function as the phosphate acceptor and donor. Our study reveals the molecular mechanism of RIF phosphorylation catalyzed by RPH and will guide the development of a new generation of rifamycins.antibiotic resistance | rifampin | phosphotransferase | molecular mechanism | toggle switch

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“…6 Because vascular infection with C pneumoniae is likely to require prolonged courses of therapy, the ability of rifalazil to promote long-term eradication of infection may be beneficial in the treatment of patients with PAD. 7 Accordingly, the goal of this study was to determine whether rifalazil would be effective in patients with symptomatic PAD. The Prospective Evaluation of Rifalazil Effect on Vascular Symptoms of Intermittent Claudication and Other Endpoints in Chlamydia pneumoniae Seropositive Patients (PROVIDENCE-1) study was designed to test the hypothesis that this potent anti-Chlamydial agent would improve peak walking time (PWT) relative to placebo in PAD patients with intermittent claudication.…”

Section: Clinical Perspective P 458mentioning

confidence: 99%

Anti-Chlamydial Antibiotic Therapy for Symptom Improvement in Peripheral Artery Disease

Jaff

Dale²,

Creager

et al. 2009

Circulation

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Background-A potentially strong association exists between Chlamydia pneumoniae and atherosclerosis, but the clinical benefits of antibiotic therapy have not been demonstrated. Preliminary studies of antibiotic therapy in peripheral artery disease have shown a decreased need for revascularization and improved walking ability. The objective of this phase-III trial was to assess the effect of a potent anti-Chlamydial agent, rifalazil, on peak walking time in patients with symptomatic peripheral artery disease. Methods and Results-Patients with intermittent claudication secondary to peripheral artery disease who were seropositive for C pneumoniae were randomized to 25 mg rifalazil once weekly for 8 weeks or matching placebo. Two hundred ninety-seven patients were enrolled from 3 countries and were followed up for 1 year. The meanϮSD ankle brachial index at baseline was 0.63Ϯ0.16. The primary end point, change from baseline in log peak walking time on a graded treadmill, was assessed 180 days after randomization. Secondary end points included changes in claudication onset time and quality of life, assessed with the Walking Impairment Questionnaire and the Short Form Medical Outcomes 36. No benefit of rifalazil therapy was found in the primary or any secondary end point among this cohort of patients with peripheral artery disease. The group treated with rifalazil improved their peak walking times by 23% (95% confidence interval, 15 to 31) from baseline to day 180, whereas the placebo group improved by 18% (95% confidence interval, 11 to 26; Pϭ0.38). Peak walking time, claudication onset time, Walking Impairment Questionnaire, and Short Form Medical Outcomes 36 showed no treatment-by-time interaction during the 360-day study period. Thirty-two adjudicated cardiovascular events occurred, 16 in each treatment group. Conclusions-Rifalazil did not improve exercise performance or quality of life in patients with intermittent claudication.No safety concerns were identified. Given the very small effect size, it is unlikely that larger studies would demonstrate a symptomatic benefit of this therapy in peripheral artery disease. (Circulation. 2009;119:452-458.)

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Rifalazil and Other Benzoxazinorifamycins in the Treatment of Chlamydia‐Based Persistent Infections

Cited by 14 publications

References 100 publications

Randomized, Double-Blind, Multicenter Safety and Efficacy Study of Rifalazil Compared with Azithromycin for Treatment of Uncomplicated Genital Chlamydia trachomatis Infection in Women

Randomized, Double-Blind, Multicenter Safety and Efficacy Study of Rifalazil Compared with Azithromycin for Treatment of Uncomplicated Genital Chlamydia trachomatis Infection in Women

Structural basis of rifampin inactivation by rifampin phosphotransferase

Anti-Chlamydial Antibiotic Therapy for Symptom Improvement in Peripheral Artery Disease

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