rifampin and Long-QT-Syndrome

Multidrug resistant tuberculosis (MDR-TB) remains a major human health challenge. Bedaquiline was approved in 2012 by the US FDA, and listed by WHO as a treatment for multidrug-resistant tuberculosis (MDR-TB) in 2018. However, the side effects of bedaquiline including the risk of unexplained mortality, QTc prolongation and hepatotoxicity limit its wide clinical use. Based on bedaquiline, we describe herein discovery and development of a novel diarylpyridine series, which led to identification of WX-081 (sudapyridine, 21l). It displayed excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo and low cytotoxicity; additionally WX-081 had excellent pharmacokinetic parameters in animals, better lung exposure and lower QTc prolongation potential compared to bedaquiline. WX-081 is currently under clinical phase II development (NCT04608955).

Topics: Animals; Antitubercular Agents; Long QT Syndrome; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant

Drug-resistant tuberculosis (DR-TB) is a global health concern. QTc prolongation is a serious adverse effect in DR-TB patients receiving a shorter regimen. This study aimed to evaluate the correlation of moxifloxacin concentration, CRP, and inflammatory cytokines with QTc interval in DR-TB patients treated with a shorter regimen.. This study was performed in 2 groups of rifampicin-resistant (RR-TB) patients receiving shorter regimens. Correlation for all variables was analyzed.. CRP, IL-1β, and QTc baseline showed significant differences between 45 RR-TB patients on intensive phase and continuation phase with p-value of <0.001, 0.040, and <0.001, respectively. TNF-α and IL-6 between RR-TB patients on intensive phase and continuation phase showed no significant difference with p=0.530 and 0.477, respectively. CRP, TNF-α, IL-1 β, and IL-6 did not correlate with QTc interval in intensive phase (p=0.226, 0.281, 0.509, and 0.886, respectively), and also in continuation phase (0.805, 0.865, 0.406, 0.586, respectively). At 2 hours after taking the 48th-dose, moxifloxacin concentration did not correlate with QTc interval, both in intensive phase (p=0.576) and in continuation phase (p=0.691). At 1 hour before taking the 72nd-hour dose, moxifloxacin concentration also did not correlate with QTc interval in intensive phase (p=0.531) and continuation phase (p=0.209).. Moxifloxacin concentration, CRP, and inflammatory cytokines did not correlate with QTc interval in RR-TB patients treated with shorter regimens. The use of moxifloxacin is safe but should be routinely monitored and considered the presence of other risk factors for QTc prolongation in RR-TB patients who received shorter regimens.

Topics: Antitubercular Agents; C-Reactive Protein; Cytokines; Electrocardiography; Humans; Interleukin-6; Long QT Syndrome; Moxifloxacin; Rifampin; Tuberculosis, Multidrug-Resistant; Tumor Necrosis Factor-alpha

Latent tuberculosis infection is an important problem for solid organ transplant recipients because of the frequency of its occurrence and its potential for reactivation. Because of the high mortality rate associated with active tuberculosis infections in transplant recipients, guidelines from the American Thoracic Society recommend treatment for latent tuberculosis in this population. However, the choice of treatments is often difficult because liver transplant recipients may be more sensitive to isoniazid hepatotoxicity, and rifampin has significant drug interactions with the calcineurin inhibitors used for immunosuppression. Two prior case reports described success with the use of rifabutin, a rifampin alternative, as part of a multidrug treatment regimen for active tuberculosis in posttransplant patients; however, there is no prior literature describing any experience with rifabutin for the treatment of latent tuberculosis in the posttransplant setting. We present a summary of tacrolimus drug levels and corresponding dose requirements for a single posttransplant patient during the administration of 3 different latent tuberculosis drug regimens: rifampin alone, rifampin plus ketoconazole, and rifabutin. In this patient's case, rifabutin allowed the maintenance of adequate tacrolimus levels, although an approximate 2.5-fold increase in the dose was required. Rifampin alone was associated with inadequate immunosuppressant levels, and rifampin plus ketoconazole was associated with a problematically prolonged QT interval and concerns about inadequate tuberculosis treatment.

Topics: Adolescent; Antibiotics, Antitubercular; Drug Interactions; Drug Monitoring; Drug Substitution; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Ketoconazole; Kidney Transplantation; Latent Tuberculosis; Liver Transplantation; Long QT Syndrome; Male; Rifabutin; Rifampin; Tacrolimus; Treatment Outcome