rifampin and rifapentine

3 months of weekly rifapentine plus isoniazid (3HP) and 4 months of daily rifampicin (4R) are recommended for tuberculosis preventive treatment. As these regimens have not been compared directly, we used individual patient data and network meta-analysis methods to compare completion, safety, and efficacy between 3HP and 4R.. We conducted a network meta-analysis of individual patient data by searching PubMed for randomised controlled trials (RCTs) published between Jan 1, 2000, and Mar 1, 2019. Eligible studies compared 3HP or 4R to 6 months or 9 months of isoniazid and reported treatment completion, adverse events, or incidence of tuberculosis disease. Deidentified individual patient data from eligible studies were provided by study investigators and outcomes were harmonised. Methods for network meta-analysis were used to generate indirect adjusted risk ratios (aRRs) and risk differences (aRDs) with their 95% CIs.. We included 17 572 participants from 14 countries in six trials. In the network meta-analysis, treatment completion was higher for people on 3HP than for those on 4R (aRR 1·06 [95% CI 1·02-1·10]; aRD 0·05 [95% CI 0·02-0·07]). For treatment-related adverse events leading to drug discontinuation, risks were higher for 3HP than for 4R for adverse events of any severity (aRR 2·86 [2·12-4·21]; aRD 0·03 [0·02-0·05]) and for grade 3-4 adverse events (aRR 3·46 [2·09-6·17]; aRD 0·02 [0·01-0·03]). Similar increased risks with 3HP were observed with other definitions of adverse events and were consistent across age groups. No difference in the incidence of tuberculosis disease between 3HP and 4R was found.. In the absence of RCTs, our individual patient data network meta-analysis indicates that 3HP provided an increase in treatment completion over 4R, but was associated with a higher risk of adverse events. Although findings should be confirmed, the trade-off between completion and safety must be considered when selecting a regimen for tuberculosis preventive treatment.. None.. For the French and Spanish translations of the abstract see Supplementary Materials section.

Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Network Meta-Analysis; Rifampin; Tuberculosis

Rifapentine is a rifamycin with unique bactericidal activity against Mycobacterium tuberculosis. It is also a potent inducer of CYP3A activity. However, the duration of rifapentine-induced hepatic enzyme activity after withdrawal is unclear.. We report a case of a patient with Aspergillus meningitis treated with voriconazole after discontinuing rifapentine. Within ten days of rifapentine discontinuation, serum levels of voriconazole failed to reach the effective treatment range.. Rifapentine is a potent inducer of hepatic microsomal enzymes. The induction of hepatic enzymes may exceed ten days after rifapentine discontinuation. Clinicians should be reminded of residual enzyme induction by rifapentine, especially when treating critically ill patients.

Topics: Antitubercular Agents; Enzyme Induction; Humans; Mycobacterium tuberculosis; Rifampin; Voriconazole

The mainstay therapy for latent tuberculosis infection is a 9-month regimen of daily isoniazid (9H) and a 3-month regimen of 12 once-weekly doses of isoniazid and rifapentine (3HP). We performed this updated meta-analysis to compare hepatotoxicity, efficacy and completion rate between these two regimens.. We searched all literature in the major medical databases using the subject search terms "isoniazid" and "rifapentine", and performed a systemic review and meta-analysis.. A total of 14 studies were eligible for the meta-analysis, which included 5600 (49%) patients who received the 3HP regimen and 5919 (51%) patients who received the 9H regimen. A total of 202 (2%) patients had a drug-induced liver injury (DILI) and 11 317 (98%) did not. The pooled odds ratio (OR) of DILI in the 3HP regimen was 0.18 (95% confidence interval [CI], 0.12-0.26; p < 0.0001), compared with the 9H regimen. This result remained consistent in subgroup analyses of ethnicity and study design. The 3HP regimen was superior to the 9H regimen in the prevention of active tuberculosis (OR, 0.38, 95% CI, 0.18-0.80, p = 0.01). Furthermore, the 3HP regimen was associated with a better completion rate than the 9H regimen (OR: 2.30, 95% CI, 2.10-2.53, p < 0.0001).. The 3HP regimen is superior to the 9H regimen, with less hepatotoxicity, and better efficacy and completion rate in treating latent tuberculosis infection.

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Latent Tuberculosis; Medication Adherence; Middle Aged; Rifampin; Young Adult

Latent tuberculosis infection (LTBI) represents a major challenge to curing TB disease. Current guidelines for LTBI management include only three older drugs and their combinations-isoniazid and rifamycins (rifampicin and rifapentine). These available control strategies have little impact on latent TB elimination, and new specific therapeutics are urgently needed. In the present mini-review, we highlight some of the alternatives that may potentially be included in LTBI treatment recommendations and a list of early-stage prospective small molecules that act on drug targets specific for

Topics: Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Rifampin

Effective yet safe treatment of latent tuberculosis is important for preventing the spread of tuberculosis and the progression to active disease in pediatric patients. As of 2017, the short course combination regimen of weekly isoniazid and rifapentine (3HP) administered by directly observed therapy (DOT) has replaced 9 months of isoniazid as the standard of treatment for latent tuberculosis in pediatric patients. The literature, limited in size, has established the 3HP regimen's superior safety and adherence.. We completed a retrospective chart review (n = 22) of pediatric patients at our institution receiving the 3HP regimen via DOT between 2017 and 2019. Frequencies of selected outcomes were compared to previously published data collected in a literature review.. In this retrospective chart review, pediatric patients ages 2-20 years receiving 3HP with DOT for latent tuberculosis experienced frequent adverse events, more severe adverse events such as anaphylaxis, and higher treatment discontinuation than that which has been previously reported in the literature. Of note, our cohort's race/ethnicity differed from the cohorts described in the literature.. Our data suggests that the short course combination regimen for pediatric latent tuberculosis patients may have a higher adverse event rate than previously established. Although this sample size is small, this study urges further investigation of more diverse cohorts to better establish the 3HP regimen's safety and tolerability.

Topics: Adolescent; Adult; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Retrospective Studies; Rifampin; Young Adult

Topics: Adolescent; Adult; Antitubercular Agents; Child; Developing Countries; Drug Therapy, Combination; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Young Adult

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Dose-Response Relationship, Drug; Female; Humans; Latent Tuberculosis; Male; Middle Aged; Rifampin; Young Adult

Despite broad uptake of antiretroviral therapy (ART), tuberculosis (TB) incidence and mortality among people with HIV remain unacceptably high. Short-course regimens for TB, incorporating both novel and established drugs, offer the potential to enhance adherence and completion rates, thereby reducing the global TB burden. This review will outline short-course regimens for TB among patients with HIV.. After many years without new agents, there is now active testing of many novel drugs to treat TB, both for latent infection and active disease. Though not all studies have included patients with HIV, many have, and there are ongoing trials to address key implementation challenges such as potent drug-drug interactions with ART. The goal of short-course regimens for TB is to enhance treatment completion without compromising efficacy. Particularly among patients with HIV, studying these shortened regimens and integrating them into clinical care are of urgent importance. There are now multiple short-course regimens for latent infection and active disease that are safe and effective among patients with HIV.

Topics: Anti-HIV Agents; Antitubercular Agents; Drug Interactions; Extensively Drug-Resistant Tuberculosis; HIV Infections; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Tuberculosis (TB) remains a common cause of death globally. A regimen of 12 doses of isoniazid (INH) and rifapentine given once weekly (INH/RPT-3) has recently been recommended by the World Health Organization for the treatment of latent TB infection (LTBI). We aimed to determine whether the INH/RPT-3 regimen had similar or lesser rates of adverse events compared to other LTBI regimens, namely INH for 9 months, INH for 6 months, rifampin for 3 to 4 months, and rifampin plus INH for 3 to 4 months.. We searched MEDLINE, Embase, CENTRAL, PubMed, ICTRP, clinicaltrials.gov, and Canadian Agency for Drugs and Technologies in Health's Gray Matters Light for randomized, postmarketing, and comparative nonrandomized studies of patients with confirmed LTBI that reported the frequency of at least 1 adverse event of relevance for a regimen of interest. The search included studies published until March 2017. The frequencies of adverse events were extracted and are presented descriptively.. Data from 23 randomized and 55 nonrandomized studies were included. Although inconsistent event reporting and high heterogeneity limited comparisons, the adverse event profile of INH/RPT-3 appeared generally favorable. Flu-like reactions were reported with an increased frequency and hepatotoxicity with a lower frequency than standard treatment.. While INH/RPT-3 had an overall low frequency of adverse events compared to INH monotherapy, reporting of adverse events for many regimens was limited meaning results should be interpreted cautiously. Future studies of LTBI treatment would benefit from more complete collection and reporting of adverse events and more consistent definitions of hepatotoxicity.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Humans; Incidence; Isoniazid; Latent Tuberculosis; Respiratory Tract Diseases; Rifampin

Latent tuberculosis infection diagnosis and treatment is a strategic priority for eliminating tuberculosis in the U.S. The Centers for Disease Control and Prevention has recommended the short-course regimen of 3-month isoniazid-rifapentine administered by directly observed therapy. However, longer-duration regimens remain the most widely prescribed latent tuberculosis infection treatments. Limitation on adoption of 3-month isoniazid-rifapentine in the U.S. might be because of patients' preference for self-administered therapy, providers' lack of familiarity with 3-month isoniazid-rifapentine, or lack of resources to support directly observed therapy. This review examines the most recent evidence regarding 3-month isoniazid-rifapentine's effectiveness, safety, and treatment completion when directly compared with other latent tuberculosis infection regimens primarily comprising 9-month isoniazid treatment.. Using Community Guide methodology, reviewers identified, evaluated, and summarized available evidence published during January 2006-June 2017. Analysis of the data was completed in 2017.. The analysis included 15 unique studies. Three-month isoniazid-rifapentine was determined to be equal to other latent tuberculosis infection regimens in effectiveness (OR=0.89, 95% CI=0.46, 1.70), and has higher treatment completion (87.5%, 95% CI=83.2%, 91.3%) compared with other latent tuberculosis infection regimens (65.9%, 95% CI=53.5%, 77.3%). Three-month isoniazid-rifapentine was associated with similar risk to other latent tuberculosis infection regimens for adverse events (relative risk=0.59, 95% CI=0.23, 1.52); discontinuing treatment because of adverse events (relative risk=0.48, 95% CI=0.17, 1.34); and death (relative risk=0.79, 95% CI=0.56, 1.11).. The 3-month isoniazid-rifapentine regimen is as safe and effective as other recommended latent tuberculosis infection regimens and achieves significantly higher treatment completion rates.

Topics: Directly Observed Therapy; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Time Factors; United States

First-line therapy for active tuberculosis (TB) has remained unchanged for nearly 40 years. Isoniazid, rifampin, pyrazinamide, and ethambutol for the initial two-month phase followed by isoniazid and rifampin for 4 to 7 months is standard treatment for people at low risk for drug-resistant disease. Directly-observed therapy (DOT) remains the standard of care for pulmonary TB. Virtual treatment monitoring using digital technologies is becoming more common as a way to provide a more patient-centered approach to care. Attempts to shorten treatment duration have been unsuccessful based on recent clinical trials evaluating the role of fluoroquinolones. Treatment-shortening trials using higher doses of rifamycins are currently underway. Recently approved medications for TB treatment are recommended only for drug-resistant disease, but novel agents in varying stages of development are being evaluated. Rifamycin-based regimens for latent TB infection (LTBI) have been successful in preventing progression to TB disease. Once-weekly isoniazid and rifapentine for 12 weeks by DOT was shown to be safe and effective compared with 9 months of isoniazid. The same regimen was shown to have acceptable treatment completion when given self-administered. Newer studies are investigating even shorter LTBI treatment with durations of less than 2 months. Treatment of LTBI in people likely infected with multidrug resistant TB is very limited, but one observational study found that fluoroquinolones appear to be effective. The first randomized trials for treating LTBI in contacts to MDR-TB are currently enrolling.

Topics: Antitubercular Agents; Directly Observed Therapy; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Randomized Controlled Trials as Topic; Rifampin

Uptake of preventive treatment for tuberculosis (TB) remains poor. A 3-month regimen of rifapentine (RPT) plus isoniazid (INH) (3HP) could facilitate its scale-up. We conducted a systematic review to assess the effects of 3HP compared with daily 6- or 9-month INH monotherapy.. We searched the following databases to identify randomised controlled trials: PubMed, Embase, the Web of Science, Cochrane Central Register of Controlled Trials, three ongoing trial registers and conference abstracts up to 24 January 2017. Where possible, we pooled data using a random-effects model.. Four studies were included. Of those, we included two studies that compared 3HP with daily 6- or 9-month INH (6/9H) among adults with human immunodeficiency virus (HIV) co-infection, one among HIV-negative adults and one among predominantly HIV-negative children and adolescents. Risk of active TB was not significantly different between 3HP and 6/9H (risk ratio [RR] 0.73, 95%CI 0.23-2.29, in adults with HIV; RR 0.44, 95%CI 0.18-1.07, in adults without HIV; RR 0.13, 95%CI 0.01-2.54, in children and adolescents). Risk of hepatotoxicity was significantly lower in the 3HP group among adults with HIV (RR 0.26, 95%CI 0.12-0.55) and those without HIV (RR 0.16, 95%CI 0.10-0.27). 3HP was also associated with a higher completion rate in all subgroups.. HP was shown to have a preventive effect similar to that of INH monotherapy, with fewer adverse events and higher completion rates. 3HP can contribute significantly to the scale-up of preventive treatment.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Child; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; HIV Seronegativity; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Tuberculosis, Pulmonary

We conducted a systematic review and network meta-analysis (NMA) to examine the efficacy and completion rates of treatments for latent tuberculosis infection (LTBI). While a previous review found newer, short-duration regimens to be effective, several included studies did not confirm LTBI, and analyses did not account for variable follow-up or assess completion.. We searched MEDLINE, Embase, CENTRAL, PubMed, and additional sources to identify RCTs in patients with confirmed LTBI that involved a regimen of interest and reported on efficacy or completion. Regimens of interest included isoniazid (INH) with rifapentine once weekly for 12 weeks (INH/RPT-3), 6 and 9 months of daily INH (INH-6; INH-9), 3-4 months daily INH plus rifampicin (INH/RFMP 3-4), and 4 months daily rifampicin alone (RFMP-4). NMAs were performed to compare regimens for both endpoints.. Sixteen RCTs (n = 44,149) and 14 RCTs (n = 44,128) were included in analyses of efficacy and completion. Studies were published between 1968 and 2015, and there was diversity in patient age and comorbidities. All regimens of interest except INH-9 showed significant benefits in preventing active TB compared to placebo. Comparisons between active regimens did not reveal significant differences. While definitions of regimen completion varied across studies, regimens of 3-4 months were associated with a greater likelihood of adequate completion.. Most of the active regimens showed an ability to reduce the risk of active TB relative to no treatment, however important differences between active regimens were not found. Shorter rifamycin-based regimens may offer comparable benefits to longer INH regimens. Regimens of 3-4 months duration are more likely to be completed than longer regimens.

Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Male; Network Meta-Analysis; Rifampin; Time Factors

Moxifloxacin, an 8-methoxy quinolone, is an important drug in the treatment of multidrug-resistant tuberculosis and is being investigated in novel drug regimens with pretomanid, bedaquiline, and pyrazinamide, or rifapentine, for the treatment of drug-susceptible tuberculosis. Early results of these studies are promising. Although current evidence does not support the use of moxifloxacin in treatment-shortening regimens for drug-susceptible tuberculosis, it may be recommended in patients unable to tolerate standard first-line drug regimens or for isoniazid monoresistance. Evidence suggests that the standard 400-mg dose of moxifloxacin used in the treatment of tuberculosis may be suboptimal in some patients, leading to worse tuberculosis treatment outcomes and emergence of drug resistance. Furthermore, a drug interaction with the rifamycins results in up to 31% reduced plasma concentrations of moxifloxacin when these are combined for treatment of drug-susceptible tuberculosis, although the clinical relevance of this interaction is unclear. Moxifloxacin exhibits extensive interindividual pharmacokinetic variability. Higher doses of moxifloxacin may be needed to achieve drug exposures required for improved clinical outcomes. Further study is, however, needed to determine the safety of proposed higher doses and clinically validated targets for drug exposure to moxifloxacin associated with improved tuberculosis treatment outcomes. We discuss in this review the evidence for the use of moxifloxacin in drug-susceptible tuberculosis and explore the role of moxifloxacin pharmacokinetics, pharmacodynamics, and drug interactions with rifamycins, on tuberculosis treatment outcomes when used in first-line tuberculosis drug regimens.

Topics: Animals; Antitubercular Agents; Drug Interactions; Fluoroquinolones; Humans; Moxifloxacin; Rifampin; Tuberculosis

One-third of the world's population is infected with Mycobacterium tuberculosis (M.tb.). Latent tuberculosis infection (LTBI) can progress to tuberculosis disease, the leading cause of death by infection. Rifamycin antibiotics, like rifampin and rifapentine, have unique sterilizing activity against M.tb. What are the advantages of each for LTBI or tuberculosis treatment? Areas covered: We review studies assessing the pharmacokinetics (PK), pharmacodynamics (PD), drug interaction risk, safety, and efficacy of rifampin and rifapentine and provide basis for comparing them. Expert commentary: Rifampin has shorter half-life, higher MIC against M.tb, lower protein binding, and better distribution into cavitary contents than rifapentine. Drug interactions for the two drugs maybe similar in magnitude. For LTBI, rifapentine is effective as convenient, once-weekly, 12-week course of treatment. Rifampin is also effective for LTBI, but must be given daily for four months, therefore, drug interactions are more problematic. For drug-sensitive tuberculosis disease, rifampin remains the standard of care. Safety profile of rifampin is better-described; adverse events differ somewhat for the two drugs. The registered once-weekly rifapentine regimen is inadequate, but higher doses of either drugs may shorten the treatment duration required for effective management of TB. Results of clinical trials evaluating high-dose rifamycin regimens are eagerly awaited.

Topics: Animals; Antibiotics, Antitubercular; Dose-Response Relationship, Drug; Half-Life; Humans; Latent Tuberculosis; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

Testing for and treating latent tuberculosis infection (LTBI) is among the main strategies to achieve TB elimination in the United States. The best approach to testing among non-US born residents, particularly those with comorbid conditions, is uncertain.. To estimate health outcomes, costs, and cost-effectiveness of LTBI testing and treatment among non-US born residents with and without medical comorbidities.. Decision analytic tree and Markov cohort simulation model among non-US born residents with no comorbidities, with diabetes, with HIV infection, or with end-stage renal disease (ESRD) using a health care sector perspective with 3% annual discounting. Strategies compared included no testing, tuberculin skin test (TST), interferon gamma release assay (IGRA), confirm positive (initial TST, IGRA only for TST-positive results; both tests positive indicates LTBI), and confirm negative (initial IGRA, then TST for IGRA-negative; any test positive indicates LTBI). All strategies were coupled to treatment with 3 months of self-administered rifapentine and isoniazid.. Number needed to test and treat to prevent 1 case of TB reactivation, discounted quality-adjusted life-years (QALYs), discounted lifetime medical costs, and incremental cost-effectiveness ratios (ICERs).. Improving health outcomes increased costs, with choice of test dependent on willingness to pay. Strategies ranked by ascending costs and benefits: no testing, confirm positive, TST, IGRA, and confirm negative. The ICERs varied by non-US born patient risk group: patients with no comorbidities, IGRA was likely cost-effective at $83 000/QALY; patients with diabetes, both confirm positive ($53 000/QALY) and IGRA ($120 000/QALY) were likely cost-effective; patients with HIV, confirm negative was clearly preferred ($63 000/QALY); and patients with ESRD, no testing was cost-effective. Increased LTBI prevalence and reduced return for TST reading improved IGRA's relative performance. In 10 000 probabilistic simulations among non-US born patients with no comorbidities, with diabetes, and with HIV, some form of testing was virtually always cost-effective. These simulations highlight the uncertainty of test choice for non-US born patients with no comorbidities and non-US born patients with diabetes, but strategies including IGRA were preferred in over 60% of simulations for all non-US born populations except those with ESRD.. Testing for and treating LTBI among non-US born residents with and without selected comorbidities is likely cost-effective except among those with ESRD in whom competing risks of death limit benefits. Strategies including IGRA fell below a $100 000/QALY willingness-to-pay threshold for non-US born patients with no comorbidities, patients with diabetes, and patients with HIV.

Topics: Antitubercular Agents; Bayes Theorem; Comorbidity; Cost-Benefit Analysis; Decision Trees; Emigrants and Immigrants; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Markov Chains; Quality-Adjusted Life Years; Rifampin; Tuberculin Test; United States

Rifapentine is a rifamycin derivate approved by the US Food and Drug Administration in 1998 for the treatment of active, drug-susceptible tuberculosis (TB). In 2014, rifapentine was approved for the treatment of latent TB infection in patients at high risk of progression to active disease and is currently under evaluation by the European Medicines Agency. Expanding indications of rifapentine largely affect diabetes patients, since about one-third of them harbor latent TB. Clinical consequences of rifapentine use in this population and potentially harmful interactions with hypoglycemic agents are widely underexplored and generally considered similar to the ones of rifampicin. Indeed, rifapentine too may decrease blood levels of many oral antidiabetics and compete with them for protein-binding sites and/or transporters. However, the two drugs differ in protein-binding degree, the magnitude of cytochrome P450 induction and auto-induction, the degree of renal elimination, and so on. Rifapentine seems to be more suitable for use in diabetes patients with renal impairment, owing to the fact that it does not cause renal toxicity, and it is eliminated via kidneys in smaller proportions than rifampicin. On the other hand, there are no data related to rifapentine use in patients >65 years, and hypoalbuminemia associated with diabetic kidney disease may affect a free fraction of rifapentine to a greater extent than that of rifampicin. Until more pharmacokinetic information and information on the safety of rifapentine use in diabetic patients and drug-drug interactions are available, diabetes in TB patients treated with rifapentine should be managed with insulin analogs, and glucose and rifapentine plasma levels should be closely monitored.

Topics: Antibiotics, Antitubercular; Diabetes Mellitus; Drug Interactions; Humans; Hypoglycemic Agents; Latent Tuberculosis; Rifampin; Tuberculosis

Rifamycins inhibit RNA polymerase of most bacterial genera. Rifampicin remains part of combination therapy for treating tuberculosis (TB), and for treating Gram-positive prosthetic joint and valve infections, in which biofilms are prominent. Rifabutin has use for AIDS patients in treating mycobacterial infections TB and Mycobacterium avium complex (MAC), having fewer drug-drug interactions that interfere with AIDS medications. Rifabutin is occasionally used in combination to eradicate Helicobacter pylori (peptic ulcer disease). Rifapentine has yet to fulfill its potential in reducing time of treatment for TB. Rifaximin is a monotherapeutic agent to treat gastrointestinal (GI) disorders, such as hepatic encephalopathy, irritable bowel syndrome, and travelers' diarrhea. Rifaximin is confined to the GI tract because it is not systemically absorbed on oral dosing, achieving high local concentrations, and showing anti-inflammatory properties in addition to its antibacterial activity. Resistance issues are unavoidable with all the rifamycins when the bioburden is high, because of mutations that modify RNA polymerase.

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Drug Therapy, Combination; Gastrointestinal Diseases; Humans; Rifabutin; Rifampin; Rifamycins; Rifaximin; Tuberculosis

Tuberculosis (TB), a dreadful disease is one of the most important health problems worldwide, and is responsible for approximately 1.3 million death tolls in 2012. DOTS is the currently used drug therapy in TB and the long term drug regimens and patients' poor compliance lead to emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB, which invigorates the research efforts to address the urgent need for the quick diagnosis and for newer antitubercular agents and vaccines to completely eradicate TB. Today we have at least 20 new diagnostic test platforms, 14 TB vaccine candidates in clinical trials and over 35 candidates in preclinical development, and among the antitubercular agents under clinical investigation, 4 anti-TB agents are in Phase III (efficacy) trials and 7 anti-TB agents are in Phase II, early bactericidal activity and sputum culture conversion trials (rifapentine is in a Phase II and a Phase III trial), 5 anti-TB agents in preclinical development and 3 anti-TB agents in Good Laboratory Practice toxicity evaluation. Recently US FDA has approved TMC207 as a part of combination therapy to treat adults with MDR pulmonary TB in the absence of other alternatives. We provide here the concise review on the chemical entities currently in the clinical trials, the new vaccines in the developmental pipeline, and the new diagnostic test.

Topics: Adult; Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Directly Observed Therapy; Drug Discovery; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis Vaccines

Children were often the forgotten victims of the global tuberculosis (TB) epidemic, neglected by traditional TB services as well as maternal and child health initiatives. Luckily this is changing with a greater focus on children and the issues regarding their optimal management. A common misconception is that children with TB are always difficult to diagnose and treat. New diagnostic tools are urgently needed, but most children with TB in high-burden settings can be diagnosed with available approaches and treatment outcomes are generally excellent. Increased TB awareness, appropriate training of health care workers and inclusion in integrated management of childhood illness strategies will improve the access and quality of care that children receive. This review highlights what needs to be done to ensure that no child unnecessarily dies from TB and provides a brief overview of new advances in the field.

Topics: Antitubercular Agents; BCG Vaccine; Child; Global Health; Health Knowledge, Attitudes, Practice; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Vaccination

Topics: Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Practice Guidelines as Topic; Rifampin; Risk Factors

Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3-4 month isoniazid plus rifampicin; or 3-4 month rifampicin alone.

Topics: Antirheumatic Agents; Antitubercular Agents; Coinfection; Comorbidity; Disease Management; Drug Users; Emigrants and Immigrants; Evidence-Based Medicine; Health Personnel; HIV Infections; Humans; Ill-Housed Persons; Interferon-gamma Release Tests; Isoniazid; Kidney Failure, Chronic; Latent Tuberculosis; Mass Screening; Practice Guidelines as Topic; Prisoners; Public Health; Radiography, Thoracic; Renal Dialysis; Rifampin; Risk Assessment; Silicosis; Substance-Related Disorders; Transplant Recipients; Tuberculin Test; Tumor Necrosis Factor-alpha; World Health Organization

Prophylactic treatment of latent tuberculosis infection (LTBI) is necessary for controlling TB in low-incidence settings. However, treatment is often limited by poor completion rates.. At a community health center serving low-income Hispanics, treatment completion among patients accepting 12 weekly doses of isoniazid (INH) plus rifapentine (RPT) administered as directly observed therapy (DOT) was compared with that among patients accepting nine months of daily self-administered INH during 2012 and 2013 (n=139).. Among patients who agreed to treatment, INH-RPT combination therapy was associated with higher completion rates (OR 3.06; 95% CI, 1.23-7.62; p=.016) when compared to INH only. Overall completion rates were 77.8% (35/45) for INH-RPT combination therapy and 52.1% (49/94) for INH monotherapy.. High completion rates for LTBI treatment can be achieved at a community health center using INH-RPT administered via DOT. Greater success treating with INH-RPT may be attributed to DOT strategy and a shorter treatment regimen.

Topics: Community Health Centers; Directly Observed Therapy; Drug Therapy, Combination; Hispanic or Latino; Humans; Isoniazid; Latent Tuberculosis; Medication Adherence; Poverty; Rifampin; Wisconsin

Tuberculosis (TB) remains rampant throughout the world, in large part due to the lengthy treatment times of current therapeutic options. Rifapentine, a rifamycin antibiotic, is currently approved for intermittent dosing in the treatment of TB. Recent animal studies have shown that more frequent administration of rifapentine could shorten treatment times, for both latent and active TB infection. However, these results were not replicated in a subsequent human clinical trial.. This review analyses the evidence for more frequent administration of rifapentine and the reasons for the apparent lack of efficacy in shortening treatment times in human patients. Inhaled delivery is discussed as a potential option to achieve the therapeutic effect of rifapentine by overcoming the barriers associated with oral administration of this drug. Avenues for developing an inhalable form of rifapentine are also presented.. Rifapentine is a promising active pharmaceutical ingredient with potential to accelerate treatment of TB if delivered by inhaled administration. Progression of current fundamental work on inhaled anti-tubercular therapies to human clinical trials is essential for determining their role in future treatment regimens. While the ultimate goal for global TB control is a vaccine, a short and effective treatment option is equally crucial.

Topics: Administration, Inhalation; Animals; Antitubercular Agents; Drug Administration Schedule; Humans; Rifampin; Tuberculosis, Pulmonary

Effective treatment of latent tuberculosis infection (LTBI) is an important component of TB elimination programs. Promising new regimens that may be more effective are being introduced. Because few regimens can be directly compared, network meta-analyses, which allow indirect comparisons to be made, strengthen conclusions.. To determine the most efficacious regimen for preventing active TB with the lowest likelihood of adverse events to inform LTBI treatment policies.. PubMed, EMBASE, and Web of Science up to 29 January 2014; clinical trial registries; and conference abstracts.. Randomized, controlled trials that evaluated LTBI treatment in humans and recorded at least 1 of 2 prespecified end points (preventing active TB or hepatotoxicity), without language or date restrictions.. Data from eligible studies were independently extracted by 2 investigators according to a standard protocol.. Of the 1516 articles identified, 53 studies met the inclusion criteria. Data on 15 regimens were available; of 105 possible comparisons, 42 (40%) were compared directly. Compared with placebo, isoniazid for 6 months (odds ratio [OR], 0.64 [95% credible interval {CrI}, 0.48 to 0.83]) or 12 months or longer (OR, 0.52 [CrI, 0.41 to 0.66]), rifampicin for 3 to 4 months (OR, 0.41 [CrI, 0.18 to 0.86]), and rifampicin-isoniazid regimens for 3 to 4 months (OR, 0.52 [CrI, 0.34 to 0.79]) were efficacious within the network.. The risk of bias was unclear for many studies across various domains. Evidence was sparse for some comparisons, particularly hepatotoxicity.. Comparison of different LTBI treatment regimens showed that various therapies containing rifamycins for 3 months or more were efficacious at preventing active TB, potentially more so than isoniazid alone. Regimens containing rifamycins may be effective alternatives to isoniazid monotherapy.. None.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Pyrazinamide; Rifampin

Resistance to rifampicin (RIF) is a broad subject covering not just the mechanism of clinical resistance, nearly always due to a genetic change in the β subunit of bacterial RNA polymerase (RNAP), but also how studies of resistant polymerases have helped us understand the structure of the enzyme, the intricacies of the transcription process and its role in complex physiological pathways. This review can only scratch the surface of these phenomena. The identification, in strains of Escherichia coli, of the positions within β of the mutations determining resistance is discussed in some detail, as are mutations in organisms that are therapeutic targets of RIF, in particular Mycobacterium tuberculosis. Interestingly, changes in the same three codons of the consensus sequence occur repeatedly in unrelated RIF-resistant (RIF(r)) clinical isolates of several different bacterial species, and a single mutation predominates in mycobacteria. The utilization of our knowledge of these mutations to develop rapid screening tests for detecting resistance is briefly discussed. Cross-resistance among rifamycins has been a topic of controversy; current thinking is that there is no difference in the susceptibility of RNAP mutants to RIF, rifapentine and rifabutin. Also summarized are intrinsic RIF resistance and other resistance mechanisms.

Topics: Animals; Anti-Bacterial Agents; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Escherichia coli; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifabutin; Rifampin

Latent tuberculosis infection (LTBI) refers to a circumstance in which viable Mycobacterium tuberculosis (MTB) bacilli are present in an individual but symptoms and signs of active disease are lacking, and the bacilli are relatively inactive metabolically. In favorable circumstances, some of these inactive bacilli resume greater metabolic activity and replication, leading to the development of active tuberculosis disease. Treatment of this condition (TLTBI) is designed to prevent (soon, or in the distant future) this progression from asymptomatic infection to symptomatic, potentially lethal, active disease. This narrative review draws upon recent reviews of LTBI and seeks particularly to include recently published or presented data that are not included in those prior reviews. Adverse effects of treatment are considered, as are the special circumstances of human immunodeficiency virus-related LTBI, drug resistance, and use of TLTBI in the context of tumor necrosis factor alpha (TNF-α) inhibition. The review describes the main studies underpinning Centers for Disease Control and Prevention recommendations on use of the new 3-month isoniazid-rifapentine regimen and points to evolving data that may support future modification of those recommendations.

Topics: Antitubercular Agents; Disease Progression; Drug Resistance, Bacterial; Drug Therapy, Combination; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Rifampin; Tumor Necrosis Factor-alpha

Topics: Antitubercular Agents; Aza Compounds; Cross-Sectional Studies; Diagnosis, Differential; Diarylquinolines; Fluoroquinolones; Germany; Humans; Moxifloxacin; Nitroimidazoles; Oxazoles; Prognosis; Quinolines; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

Preventing active tuberculosis (TB) from developing in people with latent tuberculosis infection (LTBI) is important for global TB control. Isoniazid (INH) for six to nine months has 60% to 90% protective efficacy, but the treatment period is long, liver toxicity is a problem, and completion rates outside trials are only around 50%. Rifampicin or rifamycin-combination treatments are shorter and may result in higher completion rates.. To compare the effects of rifampicin monotherapy or rifamycin-combination therapy versus INH monotherapy for preventing active TB in HIV-negative people at risk of developing active TB.. We searched the Cochrane Infectious Disease Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; clinical trials registries; regional databases; conference proceedings; and references, without language restrictions to December 2012; and contacted experts for relevant published, unpublished and ongoing trials.. Randomized controlled trials (RCTs) of HIV-negative adults and children at risk of active TB treated with rifampicin, or rifamycin-combination therapy with or without INH (any dose or duration), compared with INH for six to nine months.. At least two authors independently screened and selected trials, assessed risk of bias, and extracted data. We sought clarifications from trial authors. We pooled relative risks (RRs) with their 95% confidence intervals (CIs), using a random-effects model if heterogeneity was significant. We assessed overall evidence quality using the GRADE approach.. Ten trials are included, enrolling 10,717 adults and children, mostly HIV-negative (2% HIV-positive), with a follow-up period ranging from two to five years. Rifampicin (three/four months) vs. INH (six months)Five trials published between 1992 to 2012 compared these regimens, and one small 1992 trial in adults with silicosis did not detect a difference in the occurrence of TB over five years of follow up (one trial, 312 participants; very low quality evidence). However, more people in these trials completed the shorter course (RR 1.19, 95% CI 1.01 to 1.30; five trials, 1768 participants; moderate quality evidence). Treatment-limiting adverse events were not significantly different (four trials, 1674 participants; very low quality evidence), but rifampicin caused less hepatotoxicity (RR 0.12, 95% CI 0.05 to 0.30; four trials, 1674 participants; moderate quality evidence). Rifampicin plus INH (three months) vs. INH (six months)The 1992 silicosis trial did not detect a difference between people receiving rifampicin plus INH compared to INH alone for occurrence of active TB (one trial, 328 participants; very low quality evidence). Adherence was similar in this and a 1998 trial in people without silicosis (two trials, 524 participants; high quality evidence). No difference was detected for treatment-limiting adverse events (two trials, 536 participants; low quality evidence), or hepatotoxicity (two trials, 536 participants; low quality evidence). Rifampicin plus pyrazinamide (two months) vs. INH (six months)Three small trials published in 1994, 2003, and 2005 compared these two regimens, and two reported a low occurrence of active TB, with no statistically significant differences between treatment regimens (two trials, 176 participants; very low quality evidence) though, apart from one child from the 1994 trial, these data on active TB were from the 2003 trial in adults with silicosis. Adherence with both regimens was low with no statistically significant differences (four trials, 700 participants; very low quality evidence). However, people receiving rifampicin plus pyrazinamide had more treatment-limiting adverse events (RR 3.61, 95% CI 1.82 to 7.19; two trials, 368 participants; high quality evidence), and hepatotoxicity (RR 4.59, 95% 2.14 to 9.85; three trials, 540 participants; moderate quality evidence). Weekly, directly-observed rifapentine plus INH (three months) vs. daily, self-administered INH (nine months)A large trial conducted from 2001 to 2008 am. Trials to date of shortened prophylactic regimens using rifampicin alone have not demonstrated higher rates of active TB when compared to longer regimens with INH. Treatment completion is probably higher and adverse events may be fewer with shorter rifampicin regimens. Shortened regimens of rifampicin with INH may offer no advantage over longer INH regimens. Rifampicin combined with pyrazinamide is associated with more adverse events. A weekly regimen of rifapentine plus INH has higher completion rates, and less liver toxicity, though treatment discontinuation due to adverse events is probably more likely than with INH.

Topics: Adult; Antibiotics, Antitubercular; Child; Directly Observed Therapy; Drug Administration Schedule; HIV Seronegativity; Humans; Isoniazid; Latent Tuberculosis; Randomized Controlled Trials as Topic; Rifabutin; Rifampin; Tuberculosis, Pulmonary

Treatment of latent tuberculosis (TB) infection is an important component of TB control programs in both high- and low-prevalence countries. Clinical trials of treatment of latent TB conducted over several decades have demonstrated that preventive treatment can reduce the risk of developing active TB up to 90%. Although 9 months of daily, self-administered isoniazid has been the most widely used and recommended regimen for the treatment of latent infection, other regimens such as 3 months of daily isoniazid and rifampin, or 4 months of daily rifampin alone have also been recommended and used. Most recently, a 12-dose regimen of once-weekly isoniazid and rifapentine has been shown to be noninferior to 9 months of daily isoniazid in a large and well conducted clinical trial. Adoption of such a regimen on a large scale could have significant implications for TB elimination efforts.

Topics: Animals; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Time Factors; Tuberculosis

Rifampin is a potent inducer of both cytochrome P-450 oxidative enzymes and the P-glycoprotein transport system. Among numerous well documented, clinically significant interactions, examples include warfarin, oral contraceptives, itraconazole, digoxin, verapamil, simvastatin, and human immunodeficiency virus-related protease inhibitors. Rifabutin reduces serum concentrations of antiretroviral agents, but less so than rifampin. Rifapentine is also an inducer of drug metabolism.. A literature search of English language journals from 2008 to March 2012 was completed using several databases, including PubMed, EMBASE, and SCOPUS. Search terms included rifampin, rifabutin, rifapentine AND drug interactions.. Examples of clinically relevant interactions with rifampin demonstrated by recent reports include posaconazole, voriconazole, oxycodone, risperidone, mirodenafil, and ebastine.. To avoid a reduced therapeutic response, therapeutic failure, or toxic reactions when rifampin, rifabutin, or rifapentine are added to or discontinued from medication regimens, clinicians need to be aware of these interactions. Recent studies have indicated that other transporter systems play a role in these drug interactions. As reports of rifampin drug interactions continue to grow, this review is a reminder to clinicians to be vigilant.

Topics: Anti-Arrhythmia Agents; Antibiotics, Antitubercular; Anticholesteremic Agents; Antifungal Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Contraceptives, Oral; Cytochrome P-450 Enzyme System; Digoxin; Drug Interactions; HIV Protease Inhibitors; Humans; Itraconazole; Rifabutin; Rifampin; Simvastatin; Verapamil

Nine months of daily isoniazid is efficacious in treating latent M. tuberculosis infection, but completion rates are low, limiting treatment effectiveness. In 2011, three important studies were published involving novel regimens for the treatment of latent M. tuberculosis infection. At least 36 months of isoniazid was more effective than 6 months of isoniazid in one study, but not in another-both of which were conducted among tuberculin skin test positive HIV-infected adults living in high tuberculosis incidence settings. Three months of once-weekly isoniazid plus rifapentine or twice-weekly isoniazid plus rifampin (both given under direct observation) resulted in tuberculosis rates similar to those seen with 6 months of isoniazid among HIV-infected persons in high tuberculosis incidence settings. Three months of once-weekly, directly-observed isoniazid plus rifapentine was at least as effective as 9 months of daily isoniazid among predominantly HIV-uninfected persons living in low and medium tuberculosis incidence countries. The 3-month once-weekly isoniazid plus rifapentine regimen demonstrates promise for treatment of latent M. tuberculosis infection in HIV-infected persons.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Rifampin; Time Factors; Treatment Outcome; Tuberculin Test; Tuberculosis, Multidrug-Resistant

Much remains unknown about latent infection with Mycobacterium tuberculosis. Existing immunodiagnostic tools for this condition have various limitations, most importantly in their ability to predict disease. Randomised controlled trials have established protective efficacy of isoniazid therapy for 6-12 months among non-HIV-infected and HIV-infected subjects. While efficacy may reach 90%, acceptance and adherence to prolonged therapy are less than desired. Rifampicin plus pyrazinamide for 2 months, though efficacious, has been associated with excess hepatotoxicity in non-HIV-infected persons. Isoniazid plus rifampicin for 3 months has proven efficacy, but adverse effects may be more frequent than isoniazid or rifampicin monotherapy. Rifampicin monotherapy for 3-4 months is well tolerated, but efficacy data are currently limited, and concerns remain over possible selection of rifampicin-resistant mutants. For contacts of patients with multidrug-resistant tuberculosis, expert opinions differ on whether to treat with at least two drugs or just a fluoroquinolone, and for how long. With the existing diagnostic and treatment tools, efficacy of preventive therapy does not necessarily translate into field effectiveness. A targeted approach is required to maximise cost-effectiveness. Each geographic region needs to set its own priority after taking into account available scientific data and local circumstances.

Topics: Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Communicable Disease Control; Drug Design; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Mycobacterium tuberculosis; Patient Compliance; Pyrazinamide; Rifampin; Treatment Outcome

Available data on anti-tuberculosis drug research reveal different properties of the agents and provoke speculation about future directions. Higher doses of the rifamycins are promising and are currently being evaluated in regimens of shorter duration that the isoniazid plus rifampin-based, six-to-nine month-course therapy. Moxifloxacin and gatifloxacin might shorten tuberculosis treatment as well, possibly in combination with rifapentine, while SQ109 could enhance the activity of rifampin-containing regimens. On the other hand, co-administration of moxifloxacin and PA-824 could be active against latent tuberculosis, whereas linezolid, PA-824 and TMC207 are candidates for a rifampin-free regimen in multidrug-resistant and extensively-resistant tuberculosis. Unfortunately, shorter than existent treatment regimens based on the new agents discussed here are likely to take at least another decade to be fully developed and implemented in clinical practice.

Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Therapy, Combination; Forecasting; Guinea Pigs; Humans; Mice; Primates; Rabbits; Rifampin; Tuberculosis

Topics: Acetamides; Animals; Antitubercular Agents; Aza Compounds; Diarylquinolines; Fluoroquinolones; Humans; Linezolid; Mice; Moxifloxacin; Oxazolidinones; Quinolines; Rifampin; Tuberculosis; Tuberculosis Vaccines; Vitamin D; Vitamins

Post-operative reactivation of Mycobacterium tuberculosis (TB) is a recognized complication of surgery. We report a case of reactivation TB involving pacemaker wires and review the literature on surgical site TB infections following cardiac surgery to examine the clinical features and outcomes of this rare but important presentation of TB.

Topics: Aged, 80 and over; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Mycobacterium tuberculosis; Pacemaker, Artificial; Recurrence; Rifampin; Surgical Wound Infection; Tomography, X-Ray Computed; Tuberculosis

To evaluate the efficacy and safety of rifapentine (RPT) vs. rifampicin (RMP) for the treatment of pulmonary tuberculosis (PTB).. Systematic review of randomised controlled trials (RCTs) that compared combination drug regimens containing RPT with those containing RMP for the treatment of drug-susceptible or previously untreated PTB.. Nine RCTs were identified. Statistically significant differences were not found in the cure rates, severe adverse effects, severe hepatotoxicity or bacteriological relapse rates between the regimens containing once- or twice-weekly RPT and those containing daily RMP for human immunodeficiency virus (HIV) negative patients, but were found in the bacteriological relapse rates between regimens containing once-weekly or less frequent RPT and those containing twice- or thrice-weekly RMP: the pooled relative risks in the two subgroups were respectively 1.71 (95%CI 1.13-2.58, P = 0.01) and 2.44 (95%CI 1.15-5.18, P = 0.02). The trial for HIV-positive patients did not show significant differences in the sputum conversion rate, severe adverse effects or bacteriological relapse rate between the RPT- and RMP-containing regimens; four of the five relapses were associated with the RPT-containing regimen, but none of the three relapses with the RMP-containing regimen produced monoresistance to rifamycin (RIF).. Once- or twice-weekly RPT and daily RMP have similar efficacy and safety for the treatment of HIV-negative PTB, but once-weekly or less frequent use of RPT, in comparison with twice- or thrice-weekly RMP, increases the risk of bacteriological relapse. RPT might increase the risk of resistance to RIF in HIV-positive patients.

Topics: Antitubercular Agents; Humans; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Pulmonary

It is estimated that one third of the global population is infected with MYCOBACTERIUM TUBERCULOSIS. Treatment of M. TUBERCULOSIS infection is an important strategy for tuberculosis elimination, but the effectiveness of this strategy is limited by poor adherence to therapy, which is due at least in part to the long duration of treatment. A 9-month course of isoniazid is the currently preferred treatment regimen for M. TUBERCULOSIS infection, due to the extensive data regarding the effectiveness and tolerability of isoniazid, and limited data on the effectiveness and tolerability of alternative shorter-course regimens. This review covers all currently available regimens, including less established alternative treatment regimens (e.g., rifampin for 4 months and isoniazid + rifampin for 3 months), as well as regimens that are currently under investigation (e.g., isoniazid + rifapentine for 3 months). Potential future regimens and experimental approaches are also discussed.

Topics: Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Mycobacterium tuberculosis; Patient Compliance; Rifampin; Treatment Outcome; Tuberculosis

Topics: Animals; Antibiotics, Antitubercular; Humans; Rifampin; Treatment Outcome; Tuberculosis

The World Health Organization estimates that up to 50 million persons worldwide may be infected with drug resistant strains of TB. The fatality rate of MDR-TB is 20-80%. Drug resistant tuberculosis cases are on the rise in Pakistan. The reasons for this menace are multiple including improper prescription, compliance and over the counter sale of anti-TB drugs. The treatment cost of drug-resistant TB is high, both to the individual patient and society. This article is written to create awareness about the available second line drugs and those in the pipeline. Considering the fact that resistant tuberculosis is difficult to manage, it is suggested that these drugs should only be used after consultation with a physician experienced in the treatment of drug resistant TB. The most frequent mistake made by treating physicians is addition of one drug in the failing regimen. At present, 27 potential anti-TB drugs are at various stages of development. The aim is that by 2010 at least one of these molecules completes the journey and should come in the market.

Topics: Antitubercular Agents; Fluoroquinolones; Humans; Rifabutin; Rifampin; Treatment Failure; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Rifapentine is a recently approved antituberculosis drug that has not yet been widely used in clinical settings. Clinical data support intermittent use of rifapentine with isoniazid during the continuation phase of tuberculosis treatment. Patients with culture-positive, noncavitary, pulmonary tuberculosis whose sputum smear is negative for acid-fast bacilli at the end of the 2-month intensive treatment phase are eligible for rifapentine therapy. Rifapentine should not be used in human immunodeficiency virus-infected patients, given their increased risk of developing rifampin resistance with currently recommended dosages. Rifapentine is not currently recommended for children aged <12 years, pregnant or lactating women, or individuals with culture-negative or extrapulmonary tuberculosis. Rifapentine (600 mg) is administered once weekly with isoniazid (900 mg) during the continuation phase of treatment. This combination should only be given under direct observation. As with rifampin, drug-drug interactions are common, and regular patient monitoring is required. Ease of administration makes this regimen attractive both for tuberculosis-control programs and for patients.

Topics: Antitubercular Agents; Humans; Rifampin; Tuberculosis, Pulmonary

Topics: Antibiotics, Antitubercular; Drug Therapy, Combination; Humans; Mycobacterium avium-intracellulare Infection; Rifabutin; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

To review the pharmacokinetics, efficacy, adverse effects, and cost of the newest antitubercular drug, rifapentine.. A MEDLINE search using key terms such as rifapentine, rifampin, isoniazid, Mycobacterium tuberculosis, and pyrazinamide was conducted for the time period 1966-November 1998.. Animal data were used for basic information and human studies were selected for inclusion if they were randomized, controlled studies assessing efficacy, or if they were single- or multiple-dose studies assessing the pharmacokinetics of rifapentine. Background articles on the pathophysiology of tuberculosis and cost of care and noncontrolled studies assessing drug interactions were also included.. Compared with an oral solution, the relative bioavailability of rifapentine is 70% following oral admninistration of tablets. Food increased bioavailability by 55%. Rifapentine accumulated significantly in human macrophages and its elimination half-life was longer than that of rifampin. Comparative studies of rifapentine and rifampin in humans during intensive- and continuation-phase treatment of tuberculosis suggest that at currently accepted doses, rifapentine was slightly less effective than rifampin. The most significant drug interaction with rifapentine involves indinavir: the maximum concentration and AUC of indinavir are reduced by 55% and 70%, respectively, when rifapentine is coadministered with indinavir. Adverse events of rifapentine may occur less frequently at the currently recommended 600-mg dose as compared with rifampin; however, the difference was not statistically significant. If only drug costs were evaluated during the six-month treatment of tuberculosis, rifapentine is more expensive than rifampin.. Rifapentine can be administered twice weekly during the intensive phase of tuberculosis treatment and then once weekly during the continuation phase of treatment. This may improve patient adherence over some other treatments and possibly reduce costs of treatment by preventing development of resistant tubercular strains due to nonadherence. Rifapentine is well tolerated, with most patients experiencing adverse effects at a similar rate as rifampin. Rifapentine induces cytochrome P450 somewhat less than rifampin, although few drug interaction studies have been done with rifapentine. Its efficacy at the currently approved dosage of 600 mg may be slightly lower than that of rifampin. Studies are needed to determine if equal or greater efficacy can be achieved with higher doses of rifapentine. Rifampin is less expensive than rifapentine. Further pharmacoeconomic studies are needed to evaluate costs of relapse and failure in patients receiving these agents.

Topics: Abnormalities, Drug-Induced; Animals; Antibiotics, Antitubercular; Drug Interactions; Female; Humans; Lactation; Mycobacterium tuberculosis; Pregnancy; Pregnancy Complications; Rifampin; Tuberculosis

Rifapentine is a rifamycin antibiotic with antimycobacterial activity. Rifapentine is generally more active against Mycobacterium tuberculosis than rifampicin (rifampin), although strains resistant to rifampicin are usually cross-resistant to rifapentine. Sputum culture conversion rates were slightly higher after 6 months of rifapentine- versus rifampicin-based therapy in patients with pulmonary tuberculosis in a Western study; however, relapse rates were higher in rifapentine recipients during follow-up. The excess relapses in the rifapentine group appeared to be related to poor compliance with nonrifamycin antituberculosis drugs during the intensive phase (first 2 months) of therapy. Rifapentine- and rifampicin-containing regimens produced similar sputum culture conversion rates with low rates of relapse in 2 randomised clinical trials in patients with smear-positive tuberculosis in China. In one trial, there was no difference in sputum culture conversion rates in patients treated with rifapentine once weekly or rifampicin twice weekly in combination with isoniazid and ethambutol during the continuation phase of treatment. Hyperuricaemia, which was reported only during the intensive phase, elevated ALT and AST levels and neutropenia were the most common treatment-related adverse events reported in patients receiving rifapentine- or rifampicin-containing regimens for tuberculosis in 1 Western study.

Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Humans; Rifampin; Tuberculosis

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Clinical Trials as Topic; Colony Count, Microbial; Drug Evaluation; Humans; Mycobacterium tuberculosis; Paromomycin; Recurrence; Rifabutin; Rifampin; Sputum; Time Factors; Tuberculosis, Pulmonary

Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH).. PWH and CD4+ counts ≥100 cells/μL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months after randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% noninferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV status. PWH were enrolled in a staged fashion to support cautious evaluation of drug-drug interactions between rifapentine and efavirenz.. A total of 2516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4+ count was 344 cells/μL (interquartile range: 223-455). The rifapentine-moxifloxacin regimen was noninferior to control (absolute difference in unfavorable outcomes -7.4%; 95% confidence interval [CI] -20.8% to 6.0%); the rifapentine regimen was not noninferior to control (+7.5% [95% CI, -7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%).. In people with HIV-associated DS-PTB with CD4+ counts ≥100 cells/μL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was noninferior to the 6-month control regimen and was safe.. NCT02410772.

Topics: Antitubercular Agents; Drug Therapy, Combination; HIV; HIV Infections; Humans; Isoniazid; Moxifloxacin; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

Standard treatment for drug-susceptible tuberculosis (DS-TB) includes a multidrug regimen requiring at least 6 months of treatment, and this lengthy treatment easily leads to poor adherence. There is an urgent need to simplify and shorten treatment regimens to reduce interruption and adverse event rates, improve compliance, and reduce costs.. ORIENT is a multicenter, randomized controlled, open-label, phase II/III, non-inferiority trial involving DS-TB patients to evaluate the safety and efficacy of short-term regimens compared with the standardized six-month treatment regimen. In stage 1, corresponding to a phase II trial, a total of 400 patients are randomly divided into four arms, stratified by site and the presence of lung cavitation. Investigational arms include 3 short-term regimens with rifapentine 10 mg/kg, 15 mg/kg, and 20 mg/kg, while the control arm uses the standardized six-month treatment regimen. A combination of rifapentine, isoniazid, pyrazinamide, and moxifloxacin is administered for 17 or 26 weeks in rifapentine arms, while a 26-week regimen containing rifampicin, isoniazid, pyrazinamide, and ethambutol is applied in the control arm. After the safety and preliminary effectiveness analysis of patients in stage 1, the control arm and the investigational arm meeting the conditions will enter into stage 2, which is equivalent to a phase III trial and will be expanded to recruit DS-TB patients. If all investigational arms do not meet the safety conditions, stage 2 will be canceled. In stage 1, the primary safety endpoint is permanent regimen discontinuation at 8 weeks after the first dose. The primary efficacy endpoint is the proportion of favorable outcomes at 78 weeks after the first dose for both two stages.. This trial will contribute to the optimal dose of rifapentine in the Chinese population and suggest the feasibility of the short-course treatment regimen containing high-dose rifapentine and moxifloxacin for DS-TB.. The trial has been registered on ClinicalTrials.gov on 28 May 2022 with the identifier NCT05401071.

Topics: Clinical Trials, Phase II as Topic; Humans; Isoniazid; Moxifloxacin; Multicenter Studies as Topic; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis

Previous studies have suggested that a single dose of rifampin has protective effects against leprosy in close contacts of patients with the disease. Rifapentine was shown to have greater bactericidal activity against. We conducted a cluster-randomized, controlled trial to investigate whether single-dose rifapentine is effective in preventing leprosy in household contacts of patients with leprosy. The clusters (counties or districts in Southwest China) were assigned to one of three trial groups: single-dose rifapentine, single-dose rifampin, or control (no intervention). The primary outcome was the 4-year cumulative incidence of leprosy among household contacts.. A total of 207 clusters comprising 7450 household contacts underwent randomization; 68 clusters (2331 household contacts) were assigned to the rifapentine group, 71 (2760) to the rifampin group, and 68 (2359) to the control group. A total of 24 new cases of leprosy occurred over the 4-year follow-up, for a cumulative incidence of 0.09% (95% confidence interval [CI], 0.02 to 0.34) with rifapentine (2 cases), 0.33% (95% CI, 0.17 to 0.63) with rifampin (9 cases), and 0.55% (95% CI, 0.32 to 0.95) with no intervention (13 cases). In an intention-to-treat analysis, the cumulative incidence in the rifapentine group was 84% lower than that in the control group (cumulative incidence ratio, 0.16; multiplicity-adjusted 95% CI, 0.03 to 0.87; P = 0.02); the cumulative incidence did not differ significantly between the rifampin group and the control group (cumulative incidence ratio, 0.59; multiplicity-adjusted 95% CI, 0.22 to 1.57; P = 0.23). In a per-protocol analysis, the cumulative incidence was 0.05% with rifapentine, 0.19% with rifampin, and 0.63% with no intervention. No severe adverse events were observed.. The incidence of leprosy among household contacts over 4 years was lower with single-dose rifapentine than with no intervention. (Funded by the Ministry of Health of China and the Chinese Academy of Medical Sciences; Chinese Clinical Trial Registry number, ChiCTR-IPR-15007075.).

Topics: Family Characteristics; Humans; Incidence; Leprostatic Agents; Leprosy; Mycobacterium leprae; Rifampin

A 4-month regimen containing rifapentine and moxifloxacin has noninferior efficacy compared to the standard 6-month regimen for drug-sensitive tuberculosis. We evaluated the effect of regimens containing daily, high-dose rifapentine on efavirenz pharmacokinetics and viral suppression in patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB).. In the context of a Phase 3 randomized controlled trial, HIV-positive individuals already virally suppressed on efavirenz--containing antiretroviral therapy (ART) (EFV1), or newly initiating efavirenz (EFV2) received TB treatment containing rifapentine (1200 mg), isoniazid, pyrazinamide, and either ethambutol or moxifloxacin. Mid-interval efavirenz concentrations were measured (a) during ART and TB cotreatment (Weeks 4, 8, 12, and 17, different by EFV group) and (b) when ART was taken alone (pre- or post-TB treatment, Weeks 0 and 22). Apparent oral clearance (CL/F) was estimated and compared. Target mid-interval efavirenz concentrations were > 1 mg/L. Co-treatment was considered acceptable if > 80% of participants had mid-interval efavirenz concentrations meeting this target.. EFV1 and EFV2 included 70 and 41 evaluable participants, respectively. The geometric mean ratio comparing efavirenz CL/F with vs without TB drugs was 0.79 (90% confidence interval [CI] .72-.85) in EFV1 and 0.84 [90% CI .69-.97] in EFV2. The percent of participants with mid-interval efavirenz concentrations > 1mg/L in EFV1 at Weeks 0, 4, 8, and 17 was 96%, 96%, 88%, and 89%, respectively. In EFV2, at approximately 4 and 8 weeks post efavirenz initiation, the value was 98%.. TB treatment containing high-dose daily rifapentine modestly decreased (rather than increased) efavirenz clearance and therapeutic targets were met supporting the use of efavirenz with these regimens, without dose adjustment.. NCT02410772.

Topics: Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Cyclopropanes; HIV Infections; HIV-1; Humans; Moxifloxacin; Rifampin; Tuberculosis

Diabetes mellitus (DM) increases the risk of tuberculosis (TB) and will hamper global TB control due to the dramatic rise in type 2 DM in TB-endemic settings. In this trial, we will examine the efficacy and safety of TB preventive therapy against the development of TB disease in people with DM who have latent TB infection (LTBI), with a 12-week course of rifapentine and isoniazid (3HP).. The 'Prevention of tuberculosis in diabetes mellitus' (PROTID) consortium will randomise 3000 HIV-negative eligible adults with DM and LTBI, as evidenced by a positive tuberculin skin test or interferon gamma release assay, to 12 weeks of 3HP or placebo. Participants will be recruited through screening adult patients attending DM clinics at referral hospitals in Tanzania and Uganda. Patients with previous TB disease or treatment with a rifamycin medication or isoniazid (INH) in the previous 2 years will be excluded. The primary outcome is the occurrence of definite or probable TB disease; secondary outcome measures include adverse events, all-cause mortality and treatment completion. The primary efficacy analysis will be intention-to-treat; per-protocol analyses will also be carried out. We will estimate the ratio of TB incidence rates in intervention and control groups, adjusting for the study site using Poisson regression. Results will be reported as efficacy estimates (1-rate ratio). Cumulative incidence rates allowing for death as a competing risk will also be reported. Approximately 1000 LTBI-negative, HIV-negative participants will be enrolled consecutively into a parallel cohort study to compare the incidence of TB in people with DM who are LTBI negative vs positive. A number of sub-studies will be conducted among others to examine the prevalence of LTBI and active TB, estimate the population impact and cost-effectiveness of LTBI treatment in people living with DM in these African countries and address gaps in the prevention and therapeutic management of combined TB-DM.. PROTID is anticipated to generate key evidence to guide decisions over the use of TB preventive treatment among people with DM as an important target group for better global TB control.. ClinicalTrials.gov NCT04600167 . Registered on 23 October 2020.

Topics: Adult; Antitubercular Agents; Cohort Studies; Diabetes Mellitus, Type 2; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Randomized Controlled Trials as Topic; Rifampin; Tanzania

The successful scale-up of a latent tuberculosis (TB) infection testing and treatment programme is essential to achieve TB elimination. However, poor adherence compromises its therapeutic effectiveness. Novel rifapentine-based regimens and treatment support based on behavioural science theory may improve treatment adherence and completion.. A pragmatic multicentre, open-label, randomised controlled trial assessing the effect of novel short-course rifapentine-based regimens for TB prevention and additional theory-based treatment support on treatment adherence against standard-of-care. Participants aged between 16 and 65 who are eligible to start TB preventive therapy will be recruited in England. 920 participants will be randomised to one of six arms with allocation ratio of 5:5:6:6:6:6: daily isoniazid +rifampicin for 3 months (3HR), routine treatment support (control); 3HR, additional treatment support; weekly isoniazid +rifapentine for 3 months (3HP), routine treatment support; weekly 3HP, additional treatment support ; daily isoniazid +rifapentine for 1 month (1HP), routine treatment support; daily 1HP, additional treatment support. Additional treatment support comprises reminders using an electronic pillbox, a short animation, and leaflets based on the perceptions and practicalities approach. The primary outcome is adequate treatment adherence, defined as taking ≥90% of allocated doses within the pre-specified treatment period, measured by electronic pillboxes. Secondary outcomes include safety and TB incidence within 12 months. We will conduct process evaluation of the trial interventions and assess intervention acceptability and fidelity and mechanisms for effect and estimate the cost-effectiveness of novel regimens. The protocol was developed with patient and public involvement, which will continue throughout the trial.. Ethics approval has been obtained from The National Health Service Health Research Authority (20/LO/1097). All participants will be required to provide written informed consent. We will share the results in peer-reviewed journals.. EudraCT 2020-004444-29.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Humans; Isoniazid; Latent Tuberculosis; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Rifampin; State Medicine; United Kingdom; Young Adult

Pregnancy increases the risk of tuberculosis and its complications. A 3-month regimen of weekly isoniazid and rifapentine (3HP) is safe and effective for tuberculosis prevention in adults and children, including those with HIV, but 3HP has not been evaluated in pregnancy.. IMPAACT 2001 was a phase I/II trial evaluating the pharmacokinetics and safety of 3HP among pregnant women with indications for tuberculosis preventative therapy in Haiti, Kenya, Malawi, Thailand, and Zimbabwe (NCT02651259). Isoniazid and rifapentine were provided at standard doses (900 mg/week). Pharmacokinetic sampling was performed with the first (second/third trimester) and twelfth (third trimester/postpartum) doses. Nonlinear mixed-effects models were used to estimate drug population pharmacokinetics.. Of 50 participants, 20 had HIV and were taking efavirenz-based antiretroviral therapy. Among women without HIV, clearance of rifapentine was 28% lower during pregnancy than postpartum (1.20 vs 1.53 L/hour, P < .001), with area under the concentration-time curve (AUCSS) of 786 and 673 mg × hour/L, respectively. In pregnant women with HIV, clearance was 30% higher than women without HIV (P < .001), resulting in lower AUCss (522 mg × hour/L); clearance did not change significantly between pregnancy and postpartum. Pregnancy did not impact isoniazid pharmacokinetics. There were no drug-related serious adverse events, treatment discontinuations, or tuberculosis cases in women or infants.. 3HP does not require dose adjustment in pregnancy. Rifapentine clearance is higher among women with HIV, but all women achieved exposures of rifapentine and isoniazid associated with successful tuberculosis prevention. The data support proceeding with larger safety-focused studies of 3HP in pregnancy.. ClinicalTrials.gov, NCT02651259.

Topics: Adult; Antitubercular Agents; Child; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Pregnancy; Pregnant Women; Rifampin; Tuberculosis

Scaling up shorter regimens for tuberculosis (TB) prevention such as once weekly isoniazid-rifapentine (3HP) taken for 3 months is a key priority for achieving targets set forth in the World Health Organization's (WHO) END TB Strategy. However, there are few data on 3HP patient acceptance and completion in the context of routine HIV care in sub-Saharan Africa.. The 3HP Options Trial is a pragmatic, parallel type 3 effectiveness-implementation randomized trial comparing 3 optimized strategies for delivering 3HP-facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between DOT and SAT using a shared decision-making aid-to people receiving care at a large urban HIV clinic in Kampala, Uganda. Participants and healthcare providers were not blinded to arm assignment due to the nature of the 3HP delivery strategies. We conducted an interim analysis of participants who were enrolled and exited the 3HP treatment period between July 13, 2020 and April 30, 2021. The primary outcome, which was aggregated across trial arms for this interim analysis, was the proportion who accepted and completed 3HP (≥11 of 12 doses within 16 weeks of randomization). We used Bayesian inference analysis to estimate the posterior probability that this proportion would exceed 80% under at least 1 of the 3HP delivery strategies, a coprimary hypothesis of the trial. Through April 2021, 684 participants have been enrolled, and 479 (70%) have exited the treatment period. Of these 479 participants, 309 (65%) were women, mean age was 41.9 years (standard deviation (SD): 9.2), and mean time on antiretroviral therapy (ART) was 7.8 years (SD: 4.3). In total, 445 of them (92.9%, 95% confidence interval (CI): [90.2 to 94.9]) accepted and completed 3HP treatment. There were no differences in treatment acceptance and completion by sex, age, or time on ART. Treatment was discontinued due to a documented adverse event (AE) in 8 (1.7%) patients. The probability that treatment acceptance and completion exceeds 80% under at least 1 of the three 3HP delivery strategies was greater than 99%. The main limitations are that the trial was conducted at a single site, and the interim analysis focused on aggregate outcome data to maintain blinding of investigators to arm-specific outcomes.. 3HP was widely accepted by people living with HIV (PLHIV) in Uganda, and very high levels of treatment completion were achieved in a programmatic setting. These findings show that 3HP can enable effective scale-up of tuberculosis preventive therapy (TPT) in high-burden countries, particularly when delivery strategies are tailored to target known barriers to treatment completion.. ClinicalTrials.gov NCT03934931.

Topics: Adult; Antitubercular Agents; Directly Observed Therapy; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis; Uganda

The aim was to evaluate the efficacy, safety and completion rate of 3-month, once-weekly rifapentine and isoniazid for tuberculosis (TB) prevention among Chinese silicosis patients.. Male silicosis patients without human immunodeficiency virus infection, aged 18 years to 65 years, with or without latent TB infection, were randomized 1:1 to receive rifapentine/isoniazid under direct observation (3RPT/INH group) or were untreated (observation group). Active TB incidence was compared between the two groups with 37 months of follow-up. Safety profile and complete rates were evaluated.. A total of 1227 adults with silicosis were screened; 513 eligible participants were enrolled and assigned to 3RPT/INH (n = 254) vs. observation (n = 259). Twenty-eight participants were diagnosed with active TB, and 9 and 19 in the 3RPT/INH group and observation groups, respectively. In the intention-to-treat analysis, the cumulative active TB rate was 3.5% (9/254) in the 3RPT/INH group and 7.3% (19/259) in the observation group (log rank p 0.055). On per protocol analysis, the cumulative active TB rates were 0.7% (1/139) and 7.3% (19/259), respectively (log rank p 0.01). Owing to an unexpected high frequency of adverse events (70.4%) and Grade 3 or 4 AEs (7.9%), the completion rate of the 3RPT/INH regimen was 54.7% (139/254). Twenty-six (10.8%) participants had flu-like systemic drug reactions; five (2.1%) experienced hepatotoxicity.. Weekly rifapentine/isoniazid prophylaxis prevented active TB among Chinese people with silicosis when taken, irrespective of LTBI screening; efficacy was reduced by lack of compliance. The regimen must be used with caution because of the high rates of adverse effects.. ClinicalTrials.gov number: NCT02430259.

Topics: Antitubercular Agents; Area Under Curve; China; Drug Administration Schedule; Half-Life; Humans; Isoniazid; Male; Medication Adherence; Middle Aged; Rifampin; Silicosis; Tuberculosis, Pulmonary

The effect of rifapentine plus isoniazid on efavirenz pharmacokinetics was characterized in AIDS Clinical Trials Group protocol A5279 (NCT01404312). The present analyses characterize pharmacogenetic interactions between these drugs, and with nevirapine.. A subset of HIV-positive individuals receiving efavirenz- or nevirapine-containing antiretroviral therapy in A5279 underwent pharmacokinetic evaluations at baseline, and again weeks 2 and 4 after initiating daily rifapentine plus isoniazid. Associations with polymorphisms relevant to efavirenz, nevirapine, isoniazid, and rifapentine pharmacokinetics were assessed.. Of 128 participants, 101 were evaluable for associations with rifapentine and its active 25-desacetyl metabolite, 87 with efavirenz, and 38 with nevirapine. In multivariable analyses, NAT2 slow acetylators had greater week 4 plasma concentrations of rifapentine (P = 2.6 × 10) and 25-desacetyl rifapentine (P = 7.0 × 10) among all participants, and in efavirenz and nevirapine subgroups. NAT2 slow acetylators also had greater plasma efavirenz and nevirapine concentration increases from baseline to week 4, and greater decreases from baseline in clearance. CYP2B6 poor metabolizers had greater efavirenz concentrations at all weeks and greater nevirapine concentrations at baseline. None of 47 additional polymorphisms in 11 genes were significantly associated with pharmacokinetics.. Among HIV-positive individuals receiving efavirenz or nevirapine, and who then initiated rifapentine plus isoniazid in A5279, NAT2 slow acetylators had greater rifapentine and 25-desacetyl rifapentine concentrations, and greater increases from baseline in plasma efavirenz and nevirapine concentrations. These associations are likely mediated by greater isoniazid exposure in NAT2 slow acetylators.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Arylamine N-Acetyltransferase; Benzoxazines; Cyclopropanes; Drug Synergism; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Nevirapine; Pharmacogenetics; Rifampin; Young Adult

The use of rifamycin antibiotics for TB prevention carries a risk of detrimental drug-drug interactions with concomitantly used ART.. To evaluate the interaction of the antiretroviral drug nevirapine in combination with 4 weeks of daily rifapentine and isoniazid for TB prevention in people living with HIV.. Participants were individuals enrolled in the BRIEF-TB study receiving nevirapine and randomized to the rifapentine/isoniazid arm of the study. Participants provided sparse pharmacokinetic (PK) sampling at baseline and weeks 2 and 4 for trough nevirapine determination. Nevirapine apparent oral clearance (CL/F) was estimated and the geometric mean ratio (GMR) of CL/F prior to and during rifapentine/isoniazid was calculated.. Seventy-eight participants had evaluable PK data: 61 (78%) female, 51 (65%) black non-Hispanic and median (range) age of 40 (13-66) years. Median (IQR) nevirapine trough concentrations were: week 0, 7322 (5266-9302) ng/mL; week 2, 5537 (3552-8462) ng/mL; and week 4, 5388 (3516-8243) ng/mL. Sixty out of 78 participants (77%) had nevirapine concentrations ≥3000 ng/mL at both week 2 and 4. Median (IQR) nevirapine CL/F values were: week 0 pre-rifapentine/isoniazid, 2.03 (1.58-2.58) L/h; and during rifapentine/isoniazid, 2.62 (1.81-3.42) L/h. The GMR (90% CI) for nevirapine CL/F was 1.30 (1.26-1.33).. The CL/F of nevirapine significantly increased with concomitant rifapentine/isoniazid. The decrease in nevirapine trough concentrations during rifapentine/isoniazid therapy suggests induction of nevirapine metabolism, consistent with known rifapentine effects. The magnitude of this drug-drug interaction suggests daily rifapentine/isoniazid for TB prevention should not be co-administered with nevirapine-containing ART.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Antitubercular Agents; Female; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Nevirapine; Rifampin; Young Adult

Ending the global tuberculosis (TB) epidemic requires a focus on treating individuals with latent TB infection (LTBI) to prevent future cases. Promising trials of shorter regimens have shown them to be effective as preventative TB treatment, however there is a paucity of data on self-administered treatment completion rates. This pilot trial assessed treatment completion, adherence, safety and the feasibility of treating LTBI in the UK using a weekly rifapentine and isoniazid regimen versus daily rifampicin and isoniazid, both self-administered for 12 weeks.. An open label, randomised, multi-site pilot trial was conducted in London, UK, between March 2015 and January 2017. Adults between 16 and 65 years with LTBI at two TB clinics who were eligible for and agreed to preventative therapy were consented and randomised 1:1 to receive either a weekly combination of rifapentine/isoniazid ('intervention') or a daily combination of rifampicin/isoniazid ('standard'), with both regimens taken for twelve weeks; treatment was self-administered in both arms. The primary outcome, completion of treatment, was self-reported, defined as taking more than 90% of prescribed doses and corroborated by pill counts and urine testing. Adverse events were recorded.. Fifty-two patients were successfully enrolled. In the intervention arm 21 of 27 patients completed treatment (77.8, 95% confidence interval [CI] 57.7-91.4), compared with 19 of 25 (76.0%, CI 54.9-90.6) in the standard of care arm. There was a similar adverse effect profile between the two arms.. In this pilot trial, treatment completion was comparable between the weekly rifapentine/isoniazid and the daily rifampicin/isoniazid regimens. Additionally, the adverse event profile was similar between the two arms. We conclude that it is safe and feasible to undertake a fully powered trial to determine whether self-administered weekly treatment is superior/non-inferior compared to current treatment.. The trial was funded by the NIHR, UK and registered with ISRCTN ( 26/02/2013-No.04379941 ).

Topics: Adolescent; Adult; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; London; Male; Middle Aged; Pilot Projects; Rifampin; Self Administration; Treatment Outcome; Young Adult

Targeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design.. Adult volunteers aged 18-59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie, <3 years before screening), or comorbidities at screening. RISK11-positive participants were block randomised (1:2; block size 15) to once-weekly, directly-observed, open-label isoniazid and rifapentine for 12 weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11 positive and 3HP negative). A subset of eligible RISK11-negative volunteers were randomly assigned to no treatment (ie, RISK11 negative and 3HP negative). Diagnostic discrimination of prevalent tuberculosis was tested in all participants at baseline. Thereafter, prognostic discrimination of incident tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative groups, and treatment efficacy in the 3HP-treated versus untreated RISK11-positive groups, during active surveillance through 15 months. The primary endpoint was microbiologically confirmed pulmonary tuberculosis. The primary outcome measures were risk ratio [RR] for tuberculosis of RISK11-positive to RISK11-negative participants, and treatment efficacy. This trial is registered with ClinicalTrials.gov, NCT02735590.. 20 207 volunteers were screened, and 2923 participants were enrolled, including RISK11-positive participants randomly assigned to 3HP (n=375) or no 3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in RISK11-negative participants (RR 3·69, 95% CI 2·25-6·05) over 15 months. Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in RISK11-positive compared with RISK11-negative participants, respectively (diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in RISK11-positive (3HP-negative) participants compared with RISK11-negative participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious adverse events related to 3HP included one hospitalisation for seizures (unintentional isoniazid overdose) and one death of unknown cause (possibly temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35 to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3HP-treated RISK11-positive participants compared with untreated RISK11-positive participants (efficacy 7·0%, 95% CI -145 to 65).. The RISK11 signature discriminated between individuals with prevalent tuberculosis, or progression to incident tuberculosis, and individuals who remained healthy, but provision of 3HP to signature-positive individuals after exclusion of baseline disease did not reduce progression to tuberculosis over 15 months.. Bill and Melinda Gates Foundation, South African Medical Research Council.

Topics: Adult; Antitubercular Agents; Biomarkers; Drug Administration Schedule; Female; HIV Seronegativity; Humans; Incidence; Isoniazid; Male; Mycobacterium tuberculosis; Reverse Transcriptase Polymerase Chain Reaction; Rifampin; RNA, Bacterial; South Africa; Treatment Outcome; Tuberculosis; Young Adult

Tuberculosis preventive therapy for persons with HIV infection is effective, but its durability is uncertain.. To compare treatment completion rates of weekly isoniazid-rifapentine for 3 months versus daily isoniazid for 6 months as well as the effectiveness of the 3-month rifapentine-isoniazid regimen given annually for 2 years versus once.. Randomized trial. (ClinicalTrials.gov: NCT02980016).. South Africa, Ethiopia, and Mozambique.. Persons with HIV infection who were receiving antiretroviral therapy, were aged 2 years or older, and did not have active tuberculosis.. Participants were randomly assigned to receive weekly rifapentine-isoniazid for 3 months, given either annually for 2 years or once, or daily isoniazid for 6 months. Participants were screened for tuberculosis symptoms at months 0 to 3 and 12 of each study year and at months 12 and 24 using chest radiography and sputum culture.. Treatment completion was assessed using pill counts. Tuberculosis incidence was measured over 24 months.. Between November 2016 and November 2017, 4027 participants were enrolled; 4014 were included in the analyses (median age, 41 years; 69.5% women; all using antiretroviral therapy). Treatment completion in the first year for the combined rifapentine-isoniazid groups (. If rifapentine-isoniazid is effective in curing subclinical tuberculosis, then the intensive tuberculosis screening at month 12 may have reduced its effectiveness.. Treatment completion was higher with rifapentine-isoniazid for 3 months compared with isoniazid for 6 months. In settings with high tuberculosis transmission, a second round of preventive therapy did not provide additional benefit to persons receiving antiretroviral therapy.. The U.S. Agency for International Development through the CHALLENGE TB grant to the KNCV Tuberculosis Foundation.

Topics: Adolescent; Adult; Anti-HIV Agents; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Ethiopia; Female; HIV Infections; Humans; Isoniazid; Male; Mozambique; Rifampin; South Africa; Tuberculosis, Pulmonary; Young Adult

Whether T-cell interferon-γ responses to Mycobacterium tuberculosis-specific antigens can be influenced by tuberculosis preventive treatment in a high-endemic country is uncertain.. In this prospective, open-label, controlled study, 513 individuals with silicosis were randomly selected for TB preventive treatment with rifapentine and isoniazid or for observation. QuantiFERON-TB Gold in-tube (QFT-GIT) assay was used to measure IFN-γ response to M. tuberculosis antigens at baseline (T0) and at 6 (T1) and 33 (T2) months after completion of therapy.. A total of 220 subjects were included in the final analysis: 105 and 115 in the prevention and observation arms, respectively. The proportions of QFT-GIT reversion from baseline to T1 were similar in the prevention and observation arms (18.4% vs 12.8%, P=0.566). However, reversion from baseline to T2 was more frequent in the prevention arm than in the observation arm, but the difference was not significant (24.2% vs 6.3%, P=0.881). No significant difference was observed in the quantitative responses of QFT-GIT between the two arms during follow-up at T1 (P=0.648) and T2 (P=0.918).. Preventive tuberculosis treatment has no effect on interferon-γ responses measured by serial QFT-GIT assays in a high tuberculosis-endemic country.. http://www.clinicaltrials.gov NCT02430259.

Topics: Antigens, Bacterial; Antitubercular Agents; China; Diagnostic Tests, Routine; Endemic Diseases; Female; Follow-Up Studies; Humans; Interferon-gamma; Interferon-gamma Release Tests; Isoniazid; Male; Middle Aged; Prospective Studies; Rifampin; Tuberculin Test; Tuberculosis

Phase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen.. S31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority.. This phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels.. NCT02410772. Registered 8 April 2015,https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1.

Topics: Adolescent; Adult; Antitubercular Agents; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Equivalence Trials as Topic; Ethambutol; Female; HIV Infections; Humans; Male; Middle Aged; Moxifloxacin; Rifampin; Tuberculosis, Pulmonary; Young Adult

Using QuantiFERON-TB Gold In-Tube (QFT-GIT) for monitoring tuberculosis (TB) and latent TB infection treatment effect is controversial. The present study aimed to evaluate the dynamic changes of interferon gamma (IFN-γ) levels along with latent TB infection treatment via a randomized controlled study.. A total of 910 participants treated with 8 weeks of once-weekly rifapentine plus isoniazid (group A), 890 treated with 6 weeks of twice-weekly rifapentine plus isoniazid (group B) and 818 untreated controls (group C) were followed for 2 years to track active TB development. QFT-GIT tests were repeated three times for all groups: before treatment (T0), at completion of treatment (T1) and 3 months after completion of treatment (T2).. Similar rates of persistent QFT-GIT reversion were observed in groups A (19.0%, 173/910), B (18.5%, 165/890) and C (20.7%, 169/818) (p 0.512). The dynamic changes of IFN-γ levels were not statistically significant among the three groups. In treated participants, individuals with higher baseline IFN-γ levels showed increased TB occurrence (1.0%, 9/896) compared to those with lower baseline levels (0.2%, 2/904) (p 0.037). A similar but statistically insignificant trend was also observed in untreated controls (1.8% (7/400) vs. 0.5% (2/418), p 0.100). When TB cases were matched with non-TB cases on baseline IFN-γ levels, no significant differences were found with respect to the dynamic changes in IFN-γ levels with time, regardless of whether they received treatment.. QFT-GIT reversion or decreased IFN-γ levels should not be used for monitoring host response to latent TB infection treatment.

Topics: Antitubercular Agents; Biomarkers; China; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Interferon-gamma; Interferon-gamma Release Tests; Isoniazid; Latent Tuberculosis; Male; Rifampin; Treatment Outcome

Short-course preventive therapy with 12 doses of once-weekly rifapentine (900 mg) plus isoniazid (900 mg) could greatly improve tuberculosis control, especially in areas with high co-endemicity with HIV. However, a small previous trial of such therapy with dolutegravir in healthy, HIV-negative adults was halted early after two of the four patients developed serious adverse events. Because of the potential use of this therapy, and variable safety outcomes of tuberculosis drugs seen in patients with and without HIV, we aimed to characterise safety, pharmacokinetics, and virological suppression in adults who are HIV positive.. DOLPHIN was a phase 1/2, single-arm trial done at The Aurum Institute (Tembisa Clinical Research Site, Tembisa, South Africa), with pharmacokinetic visits done at VxPharma (Pretoria, South Africa). Adults (≥18 years) with HIV infection and undetectable viral load (<40 copies per mL) after at least 8 weeks of efavirenz-based or dolutegravir-based regimens were recruited in three consecutive groups, subject to approval by the independent safety monitoring committee. Participants received 50 mg of daily dolutegravir in place of efavirenz for 8 weeks, then began once-weekly rifapentine (900 mg)-isoniazid (900 mg) for 12 weeks. Groups 1A (n=12) and 1B (n=18) had intensive dolutegravir pharmacokinetic sampling at week 8 (before rifapentine-isoniazid), at week 11 (after the third dose of rifapentine)-isoniazid and at week 16 after the eighth dose. Group 2 (n=30) were treated with the same schedule and had sparse dolutegravir pharmacokinetic sampling at weeks 8, 11, and 16. Participants were followed 4 weeks after completion of prophylactic tuberculosis treatment. HIV viral loads were measured at baseline and at weeks 11 and 24. Primary endpoints were adverse events (grade 3 or higher) and dolutegravir population pharmacokinetics, assessed in participants who began rifapentine-isoniazid. This trial was registered at ClinicalTrials.gov, NCT03435146.. Between Jan 24, 2018, and Nov 25, 2018, 61 participants were enrolled into three groups; one participant withdrew (from group 1A). 43 (70%) of 60 participants were women and all participants were black African. Median age was 40 years (IQR 35-48), CD4 cell count was 683 cells per μL (447-935), and body-mass index was 28·9 kg/m. Our results suggest 12 doses of once-weekly rifapentine-isoniazid can be given for tuberculosis prophylaxis to patients with HIV taking dolutegravir-based antiretroviral therapy, without dose adjustments. Further exploration of the pharmacokinetics, safety, and efficacy in children and pharmacodynamics in individuals naive to antiretroviral therapy is needed.. UNITAID.

Topics: Adult; Drug Administration Schedule; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Isoniazid; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Rifampin; South Africa; Treatment Outcome; Tuberculosis; Viral Load

Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1. Its use in combination with rifapentine (RPT), an antituberculosis (TB) antibiotic, may reduce the exposure of DOR compromising viral suppression in those living with HIV-1 co-infected with TB. We conducted a prospective, phase I, open label, two-period, fixed sequence, drug interaction study to evaluate the effect of once-weekly RPT and isoniazid (INH) on the pharmacokinetics (PKs) of DOR in healthy volunteers. DOR 100 mg was administered alone twice-daily for 4 days in period 1. In period 2, once-weekly RPT + INH were co-administered with multiple doses of DOR 100 mg twice-daily for study days 7, 14, and 21. Plasma was obtained for DOR PKs when given alone and co-administered with RPT + INH. Eleven healthy volunteers enrolled and completed the study. The geometric mean ratios and 90% confidence intervals for DOR area under the concentration-time curve from zero to 12 hours (AUC

Topics: Adolescent; Adult; Antitubercular Agents; Area Under Curve; Drug Administration Schedule; Drug Interactions; Female; Healthy Volunteers; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Prospective Studies; Pyridones; Reverse Transcriptase Inhibitors; Rifampin; Triazoles; Tuberculosis; Young Adult

Rifapentine is a rifamycin used to treat tuberculosis. As is the case for rifampin, plasma exposures of rifapentine are associated with the treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, the pregnane X receptor (PXR), constitutive androstane (CAR), and arylacetamide deacetylase (AADAC) on rifapentine exposure. Two studies evaluating novel regimens among southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In the RIFAQUIN study, rifapentine was administered in the continuation phase of antituberculosis treatment in 1,200-mg-once-weekly or 900-mg-twice-weekly doses. In the Daily RPE study, 450 or 600 mg was given daily during the intensive phase of treatment. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1,144 drug concentration measurements from 326 patients were included in the analysis. Pharmacogenetic information was available for 162 patients. A one-compartment model with first-order elimination and transit compartment absorption described the data well. In a typical patient (body weight, 56 kg; fat-free mass, 45 kg), the values of clearance and volume of distribution were 1.33 liters/h and 25 liters, respectively. Patients carrying the AA variant (65.4%) of

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Antitubercular Agents; Carboxylic Ester Hydrolases; Constitutive Androstane Receptor; Female; HIV Infections; Humans; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Pharmacogenomic Testing; Polymorphism, Single Nucleotide; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear; Rifampin; Tuberculosis, Pulmonary; Young Adult

To investigate treatment outcomes and associated characteristics of persons experiencing homelessness who received 12-weekly doses of directly observed isoniazid and rifapentine (3HP/DOT) treatment for latent TB infection (LTBI).. Among homeless persons treated with 3HP/DOT during July 2011 -June 2015 in 11 U.S. TB programs, we conducted descriptive analyses of observational data, and identified associations between sociodemographic factors and treatment outcomes. Qualitative interviews were conducted to understand programmatic experiences.. Of 393 persons experiencing homelessness (median age: 50 years; range: 13-74 years), 301 (76.6%) completed treatment, 55 (14.0%) were lost to follow-up, 18 (4.6%) stopped because of an adverse event (AE), and 19 (4.8%) stopped after relocations or refusing treatment. Eighty-one (20.6%) had at least one AE. Persons aged ≥65 were more likely to discontinue treatment than persons aged 31-44 years. Programs reported difficulty in following up with persons experiencing homelessness because of relocations, mistrust, and alcohol or drug use.. This study demonstrates the feasibility of administering the 3HP/DOT LTBI regimen to persons experiencing homelessness, a high-risk population.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Ill-Housed Persons; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; United States

Tuberculosis is the leading killer of patients with human immunodeficiency virus (HIV) infection. Preventive therapy is effective, but current regimens are limited by poor implementation and low completion rates.. We conducted a randomized, open-label, phase 3 noninferiority trial comparing the efficacy and safety of a 1-month regimen of daily rifapentine plus isoniazid (1-month group) with 9 months of isoniazid alone (9-month group) in HIV-infected patients who were living in areas of high tuberculosis prevalence or who had evidence of latent tuberculosis infection. The primary end point was the first diagnosis of tuberculosis or death from tuberculosis or an unknown cause. Noninferiority would be shown if the upper limit of the 95% confidence interval for the between-group difference in the number of events per 100 person-years was less than 1.25.. A total of 3000 patients were enrolled and followed for a median of 3.3 years. Of these patients, 54% were women; the median CD4+ count was 470 cells per cubic millimeter, and half the patients were receiving antiretroviral therapy. The primary end point was reported in 32 of 1488 patients (2%) in the 1-month group and in 33 of 1498 (2%) in the 9-month group, for an incidence rate of 0.65 per 100 person-years and 0.67 per 100 person-years, respectively (rate difference in the 1-month group, -0.02 per 100 person-years; upper limit of the 95% confidence interval, 0.30). Serious adverse events occurred in 6% of the patients in the 1-month group and in 7% of those in the 9-month group (P = 0.07). The percentage of treatment completion was significantly higher in the 1-month group than in the 9-month group (97% vs. 90%, P<0.001).. A 1-month regimen of rifapentine plus isoniazid was noninferior to 9 months of isoniazid alone for preventing tuberculosis in HIV-infected patients. The percentage of patients who completed treatment was significantly higher in the 1-month group. (Funded by the National Institute of Allergy and Infectious Diseases; BRIEF TB/A5279 ClinicalTrials.gov number, NCT01404312.).

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Medication Adherence; Rifampin; Tuberculosis

Data are limited regarding the safety of 12-dose once-weekly isoniazid (H, 900 mg) plus rifapentine (P, 900 mg) (3HP) for latent infection treatment during pregnancy.. To assess safety and pregnancy outcomes among pregnant women who were inadvertently exposed to study medications in two latent tuberculosis infection trials (PREVENT TB or iAdhere) evaluating 3HP and 9 months of daily isoniazid (H, 300 mg) (9H).. Data from reproductive-age (15-51 yr) women who received one or more study dose of 3HP or 9H in either trial were analyzed. Drug exposure during pregnancy occurred if the estimated date of conception was on or before the last dose date.. Of 126 pregnancies (125 participants) that occurred during treatment or follow-up, 87 were exposed to study drugs. Among these, fetal loss was reported for 4/31 (13%) and 8/56 (14%), 3HP and 9H, respectively (difference, 13% - 14% = -1%; 95% confidence interval = -17% to +18%) and congenital anomalies in 0/20 and 2/41 (5%) live births, 3HP and 9H, respectively (difference, 0% - 5% = -5%; 95% confidence interval = -18% to +16%). All fetal losses occurred in pregnancies of less than 20 weeks. Of the total 126 pregnancies, fetal loss was reported in 8/54 (15%) and 9/72 (13%), 3HP and 9H, respectively; and congenital anomalies in 1/37 (3%) and 2/56 (4%) live births, 3HP and 9H, respectively. The overall proportion of fetal loss (17/126 [13%]) and anomalies (3/93 [3%]) were similar to those estimated for the United States, 17% and 3%, respectively.. Among reported pregnancies in these two latent tuberculosis infection trials, there was no unexpected fetal loss or congenital anomalies. These data offer some preliminary reassurance to clinicians and patients in circumstances when these drugs and regimens are the best option in pregnancy or in women of child-bearing potential. This work used the identifying trial registration numbers NCT00023452 and NCT01582711, corresponding to the primary clinical trials PREVENT TB and iAdhere (Tuberculosis Trials Consortium Study 26 and 33).

Topics: Adolescent; Adult; Antitubercular Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infant, Newborn; Isoniazid; Latent Tuberculosis; Middle Aged; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Rifampin; Young Adult

Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication.. This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5-19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points.. The study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third isoniazid-rifapentine dose. Markedly elevated levels of interferon-γ, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27-110%; P = .13) on day 14. Rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas isoniazid AUCs were approximately 67%-92% higher in the subjects who developed toxicities.. The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications.. NCT02771249.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Cytokines; Drug Administration Schedule; Drug Interactions; Female; Healthy Volunteers; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Rifampin; Young Adult

Treatment of latent tuberculosis (TB) infection (LTBI) effectively prevents its progression to active TB. However, long treatment duration and drug-related hepatotoxicity limit the effectiveness of the 9-month daily isoniazid (9H). Data on the 3-month weekly rifapentine plus isoniazid (3 HP) in Asian populations are currently unavailable. We prospectively randomised the LTBI contacts aged ≥12 years with positive tuberculin skin test into 9H and 3 HP groups in four hospitals between January 2014 and May 2016 in Taiwan. The primary and secondary outcomes were treatment completion rate and adverse drug reactions (ADRs), respectively. Overall, 263 participants with LTBI were randomised into the 3 HP (n = 132) and 9H groups (n = 131); 14 (10.6%) and 29 (22.1%) participants in the 3 HP and 9H groups, respectively, discontinued therapy (p = 0.011). Discontinuation rates owing to ADRs were 9.1% (3 HP) and 5.3% (9H) (p = 0.241). Clinically relevant hepatotoxicity was more common in the 9H than in the 3 HP group (5.3% vs. 1.5%; p = 0.103), whereas systemic drug reaction was more common in the 3 HP than in the 9H group (3.8% vs. 0%; p = 0.060). Women had a significantly higher rate of Grade II fever than men (13.7% vs. 1.2%; p = 0.003). Compared with the 9H regimen, the 3 HP regimen had a higher completion rate with lower hepatotoxicity and well-tolerated ADR.. number NCT02208427.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Child; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Taiwan; Time Factors; Treatment Outcome; Young Adult

Latent tuberculosis infection (LTBI) management is now a critical component of the World Health Organization's End TB Strategy.In this randomised controlled trial (Chinese Clinical Trial Registry identifier ChiCTR-IOR-15007202), two short-course regimens with rifapentine plus isoniazid (a 3-month once-weekly regimen and a 2-month twice-weekly regimen) were initially designed to be evaluated for rural residents aged 50-69 years with LTBI in China.Due to the increasingly rapid growth and unexpected high frequency of adverse effects, the treatments were terminated early (after 8 weeks for the once-weekly regimen and after 6 weeks for the twice-weekly regimen). In the modified intention-to-treat analysis on the completed doses, the cumulative rate of active disease during 2 years of follow-up was 1.21% (14 out of 1155) in the untreated controls, 0.78% (10 out of 1284) in the group that received the 8-week once-weekly regimen and 0.46% (six out of 1299) in the group that received the 6-week twice-weekly regimen. The risk of active disease was decreased, with an adjusted hazard ratio of 0.63 (95% CI 0.27-1.43) and 0.41 (95% CI 0.15-1.09) for the treatments, respectively. No significant difference was found in the occurrence of hepatotoxicity (1.02% (13 out of 1279)

Topics: Aged; Antibiotics, Antitubercular; China; Communicable Disease Control; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Mycobacterium tuberculosis; Proportional Hazards Models; Rifampin; Risk Factors; Rural Population; Treatment Outcome

Expanding latent tuberculosis treatment is important to decrease active disease globally. Once-weekly isoniazid and rifapentine for 12 doses is effective but limited by requiring direct observation.. To compare treatment completion and safety of once-weekly isoniazid and rifapentine by self-administration versus direct observation.. An open-label, phase 4 randomized clinical trial designed as a noninferiority study with a 15% margin. Seventy-five percent or more of study patients were enrolled from the United States for a prespecified subgroup analysis. (ClinicalTrials.gov: NCT01582711).. Outpatient tuberculosis clinics in the United States, Spain, Hong Kong, and South Africa.. 1002 adults (aged ≥18 years) recommended for treatment of latent tuberculosis infection.. Participants received once-weekly isoniazid and rifapentine by direct observation, self-administration with monthly monitoring, or self-administration with weekly text message reminders and monthly monitoring.. The primary outcome was treatment completion, defined as 11 or more doses within 16 weeks and measured using clinical documentation and pill counts for direct observation, and self-reports, pill counts, and medication event-monitoring devices for self-administration. The main secondary outcome was adverse events.. Median age was 36 years, 48% of participants were women, and 77% were enrolled at the U.S. sites. Treatment completion was 87.2% (95% CI, 83.1% to 90.5%) in the direct-observation group, 74.0% (CI, 68.9% to 78.6%) in the self-administration group, and 76.4% (CI, 71.3% to 80.8%) in the self-administration-with-reminders group. In the United States, treatment completion was 85.4% (CI, 80.4% to 89.4%), 77.9% (CI, 72.7% to 82.6%), and 76.7% (CI, 70.9% to 81.7%), respectively. Self-administered therapy without reminders was noninferior to direct observation in the United States; no other comparisons met noninferiority criteria. A few drug-related adverse events occurred and were similar across groups.. Persons with latent tuberculosis infection enrolled in South Africa would not routinely be treated programmatically.. These results support using self-administered, once-weekly isoniazid and rifapentine to treat latent tuberculosis infection in the United States, and such treatment could be considered in similar settings when direct observation is not feasible.. Centers for Disease Control and Prevention.

Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Medication Adherence; Middle Aged; Reminder Systems; Rifampin; Self Administration; Text Messaging

Currently, treatment of latent tuberculosis infection (LTBI) in Australia consists most commonly of a 9-month course of isoniazid (9H). A 3-month course of weekly isoniazid and rifapentine (3HP) has been shown to be as effective as 9 months of daily isoniazid, and associated with less hepatotoxicity; however, rifapentine is not currently available in Australia. Introduction of this regimen would have apparent advantages for people with LTBI in Victoria by safely shortening duration of LTBI therapy. However, the cost benefit of this new therapeutic approach is uncertain.. Cost-analysis of standard and short-course therapy for LTBI in an Australian context.. Single-centre randomised controlled trial conducted between December 2013-March 2016. Participants underwent 1:1 randomisation to either a 9-month course of daily isoniazid or a 12-week course of weekly isoniazid and rifapentine. The primary outcome measure was total healthcare system costs (in Australian dollars; AUD) per completed course of LTBI therapy. Secondary cost analyses were performed to consider varying assumptions regarding commercial cost of rifapentine.. Overall, 34 of 40 (85%) participants in the 9H group and 36/40 (90%) in the 3HR group completed therapy. One patient in the 3HP group was hospitalised for a febrile illness; no hospitalisations were recorded in the 9H group. The cost per completed course of 9H was 601 AUD, while that of 3HP was significantly lower at 511 AUD (P < 0.01).. This study provides cost analysis evidence to support the use of 3HP for the treatment of LTBI in Australia.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Australia; Cost-Benefit Analysis; Disease Eradication; Drug Administration Schedule; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; New Zealand; Prospective Studies; Rifampin; Self Administration; Young Adult

Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses.

Topics: Adult; Antibiotics, Antitubercular; Dose-Response Relationship, Drug; Female; Humans; Male; Rifampin; Tuberculosis, Pulmonary

Shorter treatment regimens for tuberculosis (TB) are deemed vital for advancing TB control. Murine studies have suggested potential new regimens; however, Phase II human studies of these drug combinations have not shown clear improvement in 2-month culture conversion over current therapy. Nevertheless, drugs such as rifapentine (RPT) may have additional sterilizing effects after 2 months that are difficult to measure in current Phase II studies.. To model potential bactericidal effects of RPT in a Phase III trial of a 4-month anti-tuberculosis regimen.. We developed a Markov model of anti-tuberculosis treatment to compare two regimens for treating TB: a 6-month standard (rifampin-based) treatment and a 4-month regimen using high-dose RPT. The primary outcome was the number of relapses.. In the base-case scenario, standard therapy resulted in fewer relapses; improvement in 2-month culture conversion rates in the RPT arm did not change this result. However, while RPT has better sterilizing ability during months 3 and 4 (as observed in the mouse model), the 4-month regimen results in fewer relapses.. Higher 2-month culture conversion rates are neither sufficient nor necessary for making a theoretical 4-month anti-tuberculosis treatment regimen advantageous.

Topics: Antitubercular Agents; Decision Support Techniques; Ethambutol; Humans; Isoniazid; Markov Chains; Pyrazinamide; Recurrence; Rifampin; Treatment Outcome; Tuberculosis

The combination of rifapentine and moxifloxacin administered daily with other anti-tuberculosis drugs is highly active in mouse models of tuberculosis chemotherapy. The objective of this phase 2 clinical trial was to determine the bactericidal activity, safety, and tolerability of a regimen comprised of rifapentine, moxifloxacin, isoniazid, and pyrazinamide administered daily during the first 8 weeks of pulmonary tuberculosis treatment.. Adults with sputum smear-positive pulmonary tuberculosis were randomized to receive either rifapentine (approximately 7.5 mg/kg) plus moxifloxacin (investigational arm), or rifampin (approximately 10 mg/kg) plus ethambutol (control) daily for 8 weeks, along with isoniazid and pyrazinamide. The primary endpoint was sputum culture status at completion of 8 weeks of treatment.. 121 participants (56% of accrual target) were enrolled. At completion of 8 weeks of treatment, negative cultures using Löwenstein-Jensen (LJ) medium occurred in 47/60 (78%) participants in the investigational arm vs. 43/51 (84%, p = 0.47) in the control arm; negative cultures using liquid medium occurred in 37/47 (79%) in the investigational arm vs. 27/41 (66%, p = 0.23) in the control arm. Time to stable culture conversion was shorter for the investigational arm vs. the control arm using liquid culture medium (p = 0.03), but there was no difference using LJ medium. Median rifapentine area under the concentration-time curve (AUC0-24) was 313 mcg*h/mL, similar to recent studies of rifapentine dosed at 450-600 mg daily. Median moxifloxacin AUC0-24 was 28.0 mcg*h/mL, much lower than in trials where rifapentine was given only intermittently with moxifloxacin. The proportion of participants discontinuing assigned treatment for reasons other than microbiological ineligibility was higher in the investigational arm vs. the control arm (11/62 [18%] vs. 3/59 [5%], p = 0.04) although the proportions of grade 3 or higher adverse events were similar (5/62 [8%] in the investigational arm vs. 6/59 [10%, p = 0.76] in the control arm).. For intensive phase daily tuberculosis treatment in combination with isoniazid and pyrazinamide, a regimen containing moxifloxacin plus low dose rifapentine was at least as bactericidal as the control regimen containing ethambutol plus standard dose rifampin.. www.ClinicalTrials.gov NCT00728507.

Topics: Adult; Antitubercular Agents; Case-Control Studies; Drug Therapy, Combination; Female; Fluoroquinolones; Humans; Isoniazid; Male; Middle Aged; Moxifloxacin; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Compare the effectiveness, tolerability, and safety of 3 months of weekly rifapentine and isoniazid under direct observation (3HP) versus 9 months of daily isoniazid (9H) in HIV-infected persons.. Prospective, randomized, and open-label noninferiority trial.. The United States , Brazil, Spain, Peru, Canada, and Hong Kong.. HIV-infected persons who were tuberculin skin test positive or close contacts of tuberculosis cases.. 3HP versus 9H.. The effectiveness endpoint was tuberculosis; the noninferiority margin was 0.75%. The tolerability endpoint was treatment completion; the safety endpoint was drug discontinuation because of adverse drug reaction.. Median baseline CD4 cell counts were 495 (IQR 389-675) and 538 (IQR 418-729) cells/μl in the 3HP and 9H arms, respectively (P = 0.09). In the modified intention-to-treat analysis, there were two tuberculosis cases among 206 persons [517 person-years (p-y) of follow-up] in the 3HP arm (0.39 per 100 p-y) and six tuberculosis cases among 193 persons (481 p-y of follow-up) in the 9H arm (1.25 per 100 p-y). Cumulative tuberculosis rates were 1.01 versus 3.50% in the 3HP and 9H arms, respectively (rate difference: -2.49%; upper bound of the 95% confidence interval of the difference: 0.60%). Treatment completion was higher with 3HP (89%) than 9H (64%) (P < 0.001), and drug discontinuation because of an adverse drug reaction was similar (3 vs. 4%; P = 0.79) in 3HP and 9H, respectively.. Among HIV-infected persons with median CD4 cell count of approximately 500 cells/μl, 3HP was as effective and safe for treatment of latent Mycobacterium tuberculosis infection as 9H, and better tolerated.

Topics: Adolescent; Adult; Americas; Antitubercular Agents; Asia; Child; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Isoniazid; Male; Prospective Studies; Rifampin; Treatment Outcome; Tuberculosis; Young Adult

Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown.. We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment.. Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase.. A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively).. Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).

Topics: Adolescent; Adult; Africa; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Asia; Drug Administration Schedule; Drug Therapy, Combination; Europe; Female; Humans; Male; Middle Aged; North America; Rifampin; Single-Blind Method; South America; Treatment Outcome; Tuberculosis, Pulmonary

This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0-t), and AUC extrapolated to infinity (AUC0-inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the Cmax, AUC0-t, and AUC0-inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The Cmax, AUC0-t, and AUC0-inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier NCT02216331.).

Topics: Adult; Diarylquinolines; Female; Healthy Volunteers; Humans; Male; Middle Aged; Rifampin; Young Adult

Bedaquiline is the first drug of a new class approved for the treatment of TB in decades. Bedaquiline is metabolized by cytochrome P450 (CYP) 3A4 to a less-active M2 metabolite. Its terminal half-life is extremely long (5-6 months), complicating evaluations of drug-drug interactions. Rifampicin and rifapentine, two anti-TB drugs now being optimized to shorten TB treatment duration, are potent inducers of CYP3A4. This analysis aimed to predict the effect of repeated doses of rifampicin or rifapentine on the steady-state pharmacokinetics of bedaquiline and its M2 metabolite from single-dose data using a model-based approach.. Pharmacokinetic data for bedaquiline and M2 were obtained from a Phase I study involving 32 individuals each receiving two doses of bedaquiline, alone or together with multiple-dose rifampicin or rifapentine. Sampling was performed over 14 days following each bedaquiline dose. Pharmacokinetic analyses were performed using non-linear mixed-effects modelling. Models were used to simulate potential dose adjustments.. Rifamycin co-administration increased bedaquiline clearance substantially: 4.78-fold [relative standard error (RSE) 9.10%] with rifampicin and 3.96-fold (RSE 5.00%) with rifapentine. Induction of M2 clearance was equally strong. Average steady-state concentrations of bedaquiline and M2 are predicted to decrease by 79% and 75% when given with rifampicin or rifapentine, respectively. Simulations indicated that increasing the bedaquiline dosage to mitigate the interaction would yield elevated M2 concentrations during the first treatment weeks.. Rifamycin antibiotics reduce bedaquiline concentrations substantially. In line with current treatment guidelines for drug-susceptible TB, concomitant use is not recommended, even with dose adjustment.

Topics: Adult; Antitubercular Agents; Diarylquinolines; Drug Interactions; Female; Humans; Male; Middle Aged; Rifampin; Young Adult

Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited.. To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children.. A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection.. Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months.. We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%.. Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazid-only group (P = .003). The 95% CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74% and an upper bound of the 95% CI of the difference of +0.32%, which met the noninferiority criterion.. Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe.. clinicaltrials.gov Identifier: NCT00023452.

Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Rifampin; Treatment Outcome

Rifapentine is a potent antituberculosis drug currently in phase III trials. Bioavailability decreases with increasing dose, yet high daily exposures are likely needed to improve efficacy and shorten the tuberculosis treatment duration. Further, the limits of tolerability are poorly defined. The phase I multicenter trial in healthy adults described here investigated two strategies to increase rifapentine exposures: dividing the dose or giving the drug with a high-fat meal. In arm 1, rifapentine was administered at 10 mg/kg of body weight twice daily and 20 mg/kg once daily, each for 14 days, separated by a 28-day washout; the dosing sequence was randomized. In arm 2, 15 mg/kg rifapentine once daily was given with a high-fat versus a low-fat breakfast. Sampling for pharmacokinetic analysis was performed on days 1 and 14. Population pharmacokinetic analyses were performed. This trial was stopped early for poor tolerability and because of safety concerns. Of 44 subjects, 20 discontinued prematurely; 11 of these discontinued for protocol-defined toxicity (a grade 3 or higher adverse event or grade 2 or higher rifamycin hypersensitivity). Taking rifapentine with a high-fat meal increased the median steady-state area under the concentration-time curve from time zero to 24 h (AUC0-24ss) by 31% (relative standard error, 6%) compared to that obtained when the drug was taken with a low-fat breakfast. Dividing the dose increased exposures substantially (e.g., 38% with 1,500 mg/day). AUC0-24ss was uniformly higher in our study than in recent tuberculosis treatment trials, in which toxicity was rare. In conclusion, two strategies to increase rifapentine exposures, dividing the dose or giving it with a high-fat breakfast, successfully increased exposures, but toxicity was common in healthy adults. The limits of tolerability in patients with tuberculosis remain to be defined. (AIDS Clinical Trials Group study A5311 has been registered at ClinicalTrials.gov under registration no. NCT01574638.).

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Administration Schedule; Female; Healthy Volunteers; Humans; Male; Middle Aged; Rifampin; Young Adult

Weekly rifapentine plus isoniazid for 3 months (3HP) is as effective as daily isoniazid for 9 months (9H) for latent tuberculosis infection in high-risk persons, but there have been reports of possible flu-like syndrome.. We identified clinically significant systemic drug reactions (SDR) and evaluated risk factors in patients who did not complete treatment in the PREVENT Tuberculosis study.. Among 7552 persons who received ≥ 1 dose of study drug, 153 had a SDR: 138/3893 (3.5%) with 3HP vs 15/3659 (0.4%) with 9H (P < .001). In the 3HP arm, 87 (63%) had flu-like syndrome and 23 (17%) had cutaneous reactions; 13/3893 (0.3%) had severe reactions (6 were hypotensive) and 6 reported syncope. Symptoms occurred after a median of 3 doses, and 4 hours after the dose; median time to resolution was 24 hours. There were no deaths. In multivariate logistic regression analysis, factors independently associated with SDR included receipt of 3HP (adjusted odds ratio [aOR] 9.4; 95% confidence interval [CI], 5.5, 16.2), white non-Hispanic race/ethnicity (aOR 3.3; 95% CI, 2.3, 4.7), female sex (aOR 2.0; 95% CI, 1.4, 2.9), age ≥ 35 years (aOR 2.0; 95% CI, 1.4, 2.9), and lower body mass index (body mass index [BMI]; P = .009). In a separate multivariate analysis among persons who received 3HP, severe SDR were associated with white non-Hispanic race/ethnicity (aOR 5.4; 95% CI, 1.8, 16.3), and receipt of concomitant non-study medications (aOR 5.9; 95% CI, 1.3, 27.1).. SDR were more common with 3HP, and mostly flu-like. Persons of white race, female sex, older age, and lower BMI were at increased risk. Severe reactions were rare and associated with 3HP, concomitant medication, and white race. The underlying mechanism is unclear.. NCT00023452.

Topics: Adolescent; Adult; Antitubercular Agents; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Prospective Studies; Respiratory Tract Diseases; Rifampin

Rifapentine (RPT) has potent activity against Mycobacterium tuberculosis; however, the optimal dose for anti-tuberculosis treatment is unknown.. To determine the antimicrobial activity, safety and tolerability of RPT 450 mg or 600 mg administered daily during the first 8 weeks of treatment for pulmonary tuberculosis (TB).. In a two-stage, randomised open-label study, adults with sputum smear-positive TB were randomised to receive RPT 450 mg, RPT 600 mg or rifampicin (RMP) 600 mg daily for 8 weeks with isoniazid, pyrazinamide and ethambutol. The primary endpoint was sputum culture status on Löwenstein-Jensen (LJ) medium at completion of 8 weeks of treatment.. A total of 153 participants were enrolled. Both RPT regimens met pre-specified criteria to advance to stage 2. At completion of 8 weeks of treatment, LJ culture conversion occurred in 85% (35/41), 96% (43/45) and 94% (34/36) of participants in the RPT 450 mg, RPT 600 mg and RMP groups, respectively. The proportions of participants discontinuing treatment were similar (respectively 1/54 [2.0%], 1/51 [2.0%] and 4/48 [8.3%] in the RPT 450 mg, RPT 600 mg and RMP groups), as were ⩾grade 3 adverse events (0/54 [0%], 1/51 [2.0%] and 4/48 [8.3%]).. There was a trend towards greater efficacy with RPT 600 mg than with RPT 450 mg. Daily RPT was safe and well-tolerated.

Topics: Adult; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; South Africa; Sputum; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

Concomitant use of rifamycins to treat or prevent tuberculosis can result in subtherapeutic concentrations of antiretroviral drugs. We studied the interaction of efavirenz with daily rifapentine and isoniazid in human immunodeficiency virus (HIV)-infected individuals receiving a 4-week regimen to prevent tuberculosis.. Participants receiving daily rifapentine and isoniazid with efavirenz had pharmacokinetic evaluations at baseline and weeks 2 and 4 of concomitant therapy. Efavirenz apparent oral clearance was estimated and the geometric mean ratio (GMR) of values before and during rifapentine and isoniazid was calculated. HIV type 1 (HIV-1) RNA was measured at baseline and week 8.. Eighty-seven participants were evaluable: 54% were female, and the median age was 35 years (interquartile range [IQR], 29-44 years). Numbers of participants with efavirenz concentrations ≥1 mg/L were 85 (98%) at week 0; 81 (93%) at week 2; 78 (90%) at week 4; and 75 (86%) at weeks 2 and 4. Median efavirenz apparent oral clearance was 9.3 L/hour (IQR, 6.42-13.22 L/hour) at baseline and 9.8 L/hour (IQR, 7.04-15.59 L/hour) during rifapentine/isoniazid treatment (GMR, 1.04 [90% confidence interval, .97-1.13]). Seventy-nine of 85 (93%) participants had undetectable HIV-1 RNA (<40 copies/mL) at entry; 71 of 75 (95%) participants had undetectable HIV-1 RNA at week 8. Two participants with undetectable HIV-1 RNA at study entry were detectable (43 and 47 copies/mL) at week 8.. The proportion of participants with midinterval efavirenz concentrations ≥1 mg/L did not cross below the prespecified threshold of >80%, and virologic suppression was maintained. Four weeks of daily rifapentine plus isoniazid can be coadministered with efavirenz without clinically meaningful reductions in efavirenz mid-dosing concentrations or virologic suppression.. NCT 01404312.

Topics: Administration, Oral; Adult; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Isoniazid; Male; Reverse Transcriptase Inhibitors; Rifampin; RNA, Viral; Tuberculosis

Nine months of daily isoniazid (9H) and 3 months of once-weekly rifapentine plus isoniazid (3HP) are recommended treatments for latent tuberculous infection (LTBI). The risk profile for 3HP and the contribution of hepatitis C virus (HCV) infection to hepatotoxicity are unclear.. To evaluate the hepatotoxicity risk associated with 3HP compared to 9H, and factors associated with hepatotoxicity.. Hepatotoxicity was defined as aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN) with symptoms (nausea, vomiting, jaundice, or fatigue), or AST >5 x ULN. We analyzed risk factors among adults who took at least 1 dose of their assigned treatment. A nested case-control study assessed the role of HCV.. Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic; 1.8% (61/3317) were on 9H and 0.4% (15/3545) were on 3HP (P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, HCV infection was associated with hepatotoxicity when controlling for other factors.. The risk of hepatotoxicity during LTBI treatment with 3HP was lower than the risk with 9H. HCV and elevated baseline AST were risk factors for hepatotoxicity. For persons with these risk factors, 3HP may be preferred.

Topics: Adult; Antitubercular Agents; Aspartate Aminotransferases; Brazil; Canada; Case-Control Studies; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Therapy, Combination; Female; Hepatitis C; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Multivariate Analysis; Rifampin; Risk Factors; Spain; United States

Latent tuberculosis infection and tuberculosis disease are prevalent worldwide. However, antimycobacterial rifamycins have drug interactions with many antiretroviral drugs. We evaluated the effect of rifapentine on the pharmacokinetic properties of raltegravir.. In this open-label, fixed-sequence, three-period study, 21 healthy volunteers were given: raltegravir alone (400 mg every 12 h for 4 days) on days 1-4 of Period 1; rifapentine (900 mg once weekly for 3 weeks) on days 1, 8 and 15 of Period 2 and raltegravir (400 mg every 12 h for 4 days) on days 12-15 of Period 2; and rifapentine (600 mg once daily for 10 scheduled doses) on days 1, 4-8 and 11-14 of Period 3 and raltegravir (400 mg every 12 h for 4 days) on days 11-14 of Period 3. Plasma raltegravir concentrations were measured. ClinicalTrials.gov database: NCT00809718.. In 16 subjects who completed the study, coadministration of raltegravir with rifapentine (900 mg once weekly; Period 2) compared with raltegravir alone resulted in the geometric mean of the raltegravir AUC from 0 to 12 h (AUC0-12) being increased by 71%; the peak concentration increased by 89% and the trough concentration decreased by 12%. Coadministration of raltegravir with rifapentine in Period 3 did not change the geometric mean of the raltegravir AUC0-12 or the peak concentration, but it decreased the trough concentration by 41%. Raltegravir coadministered with rifapentine was generally well tolerated.. The increased raltegravir exposure observed with once-weekly rifapentine was safe and tolerable. Once-weekly rifapentine can be used with raltegravir to treat latent tuberculosis infection in patients who are infected with HIV.

Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Drug Interactions; Female; Healthy Volunteers; Humans; Male; Plasma; Pyrrolidinones; Raltegravir Potassium; Rifampin

Rifapentine is under active investigation as a potent drug that may help shorten the tuberculosis (TB) treatment duration. A previous rifapentine dose escalation study with daily dosing indicated a possible decrease in bioavailability as the dose increased and an increase in clearance over time for rifapentine and its active metabolite, desacetyl rifapentine. This study aimed to assess the effects of increasing doses on rifapentine absorption and bioavailability and to evaluate the clearance changes over 14 days. A population analysis was performed with nonlinear mixed-effects modeling. Absorption, time-varying clearance, bioavailability, and empirical and semimechanistic autoinduction models were investigated. A one-compartment model linked to a transit compartment absorption model best described the data. The bioavailability of rifapentine decreased linearly by 2.5% for each 100-mg increase in dose. The autoinduction model suggested a dose-independent linear increase in clearance of the parent drug and metabolite over time from 1.2 and 3.1 liters · h(-1), respectively, after a single dose to 2.2 and 5.0 liters · h(-1), respectively, after 14 once-daily doses, with no plateau being reached by day 14. In clinical trial simulations using the final model, rifapentine demonstrated less-than-dose-proportional pharmacokinetics, but there was no plateau in exposures over the dose range tested (450 to 1,800 mg), and divided dosing increased exposures significantly. Thus, the proposed compartmental model incorporating daily dosing of rifapentine over a wide range of doses and time-related changes in bioavailability and clearance provides a useful tool for estimation of drug exposure that can be used to optimize rifapentine dosing for TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01162486.).

Topics: Adult; Antibiotics, Antitubercular; Biological Availability; Cohort Studies; Dose-Response Relationship, Drug; Female; Healthy Volunteers; Humans; Male; Middle Aged; Nonlinear Dynamics; Rifampin; Time Factors; Tuberculosis; Young Adult

The quantification of antituberculosis drug concentrations in multinational trials currently requires the collection of modest blood volumes, centrifugation, aliquoting of plasma, freezing, and keeping samples frozen during shipping. We prospectively enrolled healthy individuals into the Tuberculosis Trials Consortium Study 29B, a phase I dose escalation study of rifapentine, a rifamycin under evaluation in tuberculosis treatment trials. We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying rifapentine in whole blood on dried blood spots (DBS) to facilitate pharmacokinetic/pharmacodynamic analyses in clinical trials. Paired plasma and whole-blood samples were collected by venipuncture, and whole blood was spotted on Whatman protein saver 903 cards. The methods were optimized for plasma and then validated for DBS. The analytical measuring range for quantification of rifapentine and its metabolite was 50 to 80,000 ng/ml in whole-blood DBS. The analyte was stable on the cards for 11 weeks with a desiccant at room temperature and protected from light. The method concordance for paired plasma and whole-blood DBS samples was determined after correcting for participant hematocrit or population-based estimates of bias from Bland-Altman plots. The application of either correction factor resulted in acceptable correlation between plasma and whole-blood DBS (Passing-Bablok regression corrected for hematocrit; y = 0.98x + 356). Concentrations of rifapentine may be determined from whole-blood DBS collected via venipuncture after normalization in order to account for the dilutional effects of red blood cells. Additional studies are focused on the application of this methodology to capillary blood collected by finger stick. The simplicity of processing, storage, shipping, and low blood volume makes whole-blood DBS attractive for rifapentine pharmacokinetic evaluations, especially in international and pediatric trials.

Topics: Antitubercular Agents; Chromatography, Liquid; Dried Blood Spot Testing; Drug Monitoring; High-Throughput Screening Assays; Humans; Prospective Studies; Reproducibility of Results; Rifampin; Tandem Mass Spectrometry; Tuberculosis, Pulmonary

Tuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed.. We randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin; a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals.. We enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4).. The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.).

Topics: Adolescent; Adult; Antitubercular Agents; Coinfection; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Fluoroquinolones; HIV Seropositivity; Humans; Isoniazid; Kaplan-Meier Estimate; Male; Middle Aged; Moxifloxacin; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary; Young Adult

Rifapentine (RP T) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RI F).The maximal tolerated daily dose of RP T and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high asa prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RP T concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AU C0–24) and maximum concentration (Cmax)were similar in the 15- and 20-mg/kg cohorts. Although RP T pharmacokinetics (PK) appeared to be time-dependent,accumulation occurred with daily dosing. The mean AU C0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP 3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01).Changes in the oral clearance of MDZ did not vary by RP T dose. In conclusion, RP T was tolerated at doses as high as20 mg/kg/day, its PK were less than dose-proportional, and its CYP 3A induction was robust.

Topics: Adult; Antitubercular Agents; Area Under Curve; Cytochrome P-450 CYP3A; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Midazolam; Middle Aged; Rifampin

We described the population pharmacokinetics of moxifloxacin and the effect of high-dose intermittent rifapentine in patients with pulmonary tuberculosis who were randomized to a continuation-phase regimen of 400 mg moxifloxacin and 900 mg rifapentine twice weekly or 400 mg moxifloxacin and 1,200 mg rifapentine once weekly. A two-compartment model with transit absorption best described moxifloxacin pharmacokinetics. Although rifapentine increased the clearance of moxifloxacin by 8% during antituberculosis treatment compared to that after treatment completion without rifapentine, it did not result in a clinically significant change in moxifloxacin exposure.

Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Aza Compounds; Drug Administration Schedule; Drug Therapy, Combination; Fluoroquinolones; Humans; Moxifloxacin; Mycobacterium tuberculosis; Quinolines; Rifampin; Tuberculosis, Pulmonary

Rifapentine administered 5 days per week has potent activity in mouse models of antituberculosis chemotherapy, but efficacy and safety data are limited in humans. We compared the antimicrobial activity and safety of rifapentine vs rifampin during the first 8 weeks of pulmonary tuberculosis treatment.. In total, 531 adults with sputum smear-positive pulmonary tuberculosis were randomized to rifapentine 10 mg/kg/dose or rifampin 10 mg/kg/dose, administered 5 days per week for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. Coprimary outcomes were negative sputum culture on liquid and on solid media at completion of intensive phase.. Negative cultures on solid media occurred in 145 of 174 participants (83.3%) in the rifampin group and 171 of 198 participants (86.4%) in the rifapentine group (difference, 3.0%; 95% confidence interval [CI]: -4.3, 10.5); negative cultures in liquid media occurred in 110 of 169 (65.1%) in the rifampin group and 133 of 196 (67.9%) in the rifapentine group (difference, 2.8%; 95% CI: -6.9, 12.4). Among 529 participants who received study therapy, 40 of 254 participants (15.7%) in the rifampin group and 40 of 275 participants (14.5%) in the rifapentine group prematurely discontinued treatment (P=.79).. The rifapentine regimen was safe but not significantly more active than a standard rifampin regimen, by the surrogate endpoint of culture status at completion of intensive phase. Assessment of higher exposures to rifapentine for tuberculosis treatment is warranted.. NCT00694629.

Topics: Adult; Antibiotics, Antitubercular; Drug Substitution; Female; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Treatment of latent tuberculosis in patients infected with the human immunodeficiency virus (HIV) is efficacious, but few patients around the world receive such treatment. We evaluated three new regimens for latent tuberculosis that may be more potent and durable than standard isoniazid treatment.. We randomly assigned South African adults with HIV infection and a positive tuberculin skin test who were not taking antiretroviral therapy to receive rifapentine (900 mg) plus isoniazid (900 mg) weekly for 12 weeks, rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks, isoniazid (300 mg) daily for up to 6 years (continuous isoniazid), or isoniazid (300 mg) daily for 6 months (control group). The primary end point was tuberculosis-free survival.. The 1148 patients had a median age of 30 years and a median CD4 cell count of 484 per cubic millimeter. Incidence rates of active tuberculosis or death were 3.1 per 100 person-years in the rifapentine-isoniazid group, 2.9 per 100 person-years in the rifampin-isoniazid group, and 2.7 per 100 person-years in the continuous-isoniazid group, as compared with 3.6 per 100 person-years in the control group (P>0.05 for all comparisons). Serious adverse reactions were more common in the continuous-isoniazid group (18.4 per 100 person-years) than in the other treatment groups (8.7 to 15.4 per 100 person-years). Two of 58 isolates of Mycobacterium tuberculosis (3.4%) were found to have multidrug resistance.. On the basis of the expected rates of tuberculosis in this population of HIV-infected adults, all secondary prophylactic regimens were effective. Neither a 3-month course of intermittent rifapentine or rifampin with isoniazid nor continuous isoniazid was superior to 6 months of isoniazid. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00057122.).

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-Retroviral Agents; Antitubercular Agents; Cause of Death; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Isoniazid; Kaplan-Meier Estimate; Male; Mycobacterium tuberculosis; Patient Compliance; Proportional Hazards Models; Rifampin; Risk; Tuberculosis; Tuberculosis, Multidrug-Resistant

Treatment of latent Mycobacterium tuberculosis infection is an essential component of tuberculosis control and elimination. The current standard regimen of isoniazid for 9 months is efficacious but is limited by toxicity and low rates of treatment completion.. We conducted an open-label, randomized noninferiority trial comparing 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus isoniazid (900 mg) (combination-therapy group) with 9 months of self-administered daily isoniazid (300 mg) (isoniazid-only group) in subjects at high risk for tuberculosis. Subjects were enrolled from the United States, Canada, Brazil, and Spain and followed for 33 months. The primary end point was confirmed tuberculosis, and the noninferiority margin was 0.75%.. In the modified intention-to-treat analysis, tuberculosis developed in 7 of 3986 subjects in the combination-therapy group (cumulative rate, 0.19%) and in 15 of 3745 subjects in the isoniazid-only group (cumulative rate, 0.43%), for a difference of 0.24 percentage points. Rates of treatment completion were 82.1% in the combination-therapy group and 69.0% in the isoniazid-only group (P<0.001). Rates of permanent drug discontinuation owing to an adverse event were 4.9% in the combination-therapy group and 3.7% in the isoniazid-only group (P=0.009). Rates of investigator-assessed drug-related hepatotoxicity were 0.4% and 2.7%, respectively (P<0.001).. The use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment-completion rate. Long-term safety monitoring will be important. (Funded by the Centers for Disease Control and Prevention; PREVENT TB ClinicalTrials.gov number, NCT00023452.).

Topics: Adult; Antitubercular Agents; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Humans; Intention to Treat Analysis; Isoniazid; Male; Middle Aged; Prospective Studies; Rifampin; Risk Factors; Self Administration; Tuberculosis; Virus Latency

Rifapentine and its primary metabolite, 25-desacetyl rifapentine, are active against mycobacterium tuberculosis. The objectives of this study were to describe the population pharmacokinetics of rifapentine and 25-desacetyl rifapentine in fasting and fed states. Thirty-five male healthy volunteers were enrolled in an open-label, randomized, sequential, five-way crossover study. Participants received a single 900-mg dose of rifapentine after meals with high fat (meal A), bulk and low fat (meal B), bulk and high fat (meal C), high fluid and low fat (meal D), or 200 ml of water (meal E). Venous blood samples were collected over 72 h after each rifapentine dose, and plasma was analyzed for rifapentine and 25-desacetyl rifapentine using high-performance liquid chromatography. Pharmacokinetic data were analyzed by nonlinear mixed-effect modeling using NONMEM. Compared with the fasting state, meal A had the greatest effect on rifapentine oral bioavailability, increasing it by 86%. Meals B, C, and D resulted in 33%, 46%, and 49% increases in rifapentine oral bioavailability, respectively. Similar trends were observed for 25-desacetyl rifapentine. As meal behavior has a substantial impact on rifapentine exposure, it should be considered in the evaluation of optimal dosing approaches.

Topics: Administration, Oral; Adult; Antibiotics, Antitubercular; Biological Availability; Chromatography, High Pressure Liquid; Cross-Over Studies; Dietary Fats; Fasting; Humans; Male; Rifampin; Treatment Outcome; Young Adult

Clinico-roentgenologic and bacteriologic efficacy and safety of rifapex (rifapentin) were investigated in the complex therapy of 90 patients with newly recorded drug-susceptible tuberculosis. Pifapex was shown to be effective in the treatment of the patients during the acute phase of the disease, during the treatment completeness and during the short preoperative period.

Topics: Adult; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Radiography; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Moxifloxacin- and rifapentine-based regimens are under investigation for the treatment of tuberculosis. However, rifapentine may induce enzymes that metabolize moxifloxacin, resulting in decreased moxifloxacin concentrations. In this phase I, two-period, sequential-design study, 13 subjects received 400 mg moxifloxacin daily for 4 days followed by daily moxifloxacin coadministered with 900 mg rifapentine thrice weekly. Pharmacokinetic analyses were performed after the 4th and 19th doses of moxifloxacin and after the 1st and 7th doses of rifapentine. For moxifloxacin, the mean area under the concentration-time curve from 0 to 24 h (AUC(0-24)) decreased by 17.2% (P = 0.0006) when the drug was coadministered with rifapentine, and the mean half-life (t(1/2)) decreased from 11.1 to 8.9 h (P = 0.0033). For rifapentine, the mean AUC(0-48) after seven thrice-weekly doses decreased by 20.3% (P = 0.0035) compared to the AUC(0-48) after the first dose, and the mean t(1/2) decreased from 18.5 to 14.8 h (P = 0.0004). The AUC(0-48) for the 25-desacetyl-rifapentine metabolite diminished 21%. Two days after completing the study drugs, one subject developed a fever and hepatitis, and another developed a flu-like illness with a rash. In conclusion, rifapentine modestly reduced moxifloxacin concentrations. Changes consistent with rifapentine autoinduction of metabolism were seen. Adverse reactions in two subjects may have represented rifamycin hypersensitivity syndrome, although some features were atypical.

Topics: Adult; Antitubercular Agents; Aza Compounds; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Drug Tolerance; Female; Fluoroquinolones; Humans; Male; Middle Aged; Moxifloxacin; Quinolines; Rifampin; Safety; Tuberculosis, Pulmonary; Young Adult

Treatment of latent tuberculosis (TB) infection with weekly rifapentine and isoniazid is a potentially effective alternative to current therapies.. To compare the efficacy of weekly rifapentine/isoniazid to daily rifampin/pyrazinamide in preventing TB in household contacts of patients with pulmonary TB in Brazil.. Contacts of patients with TB were randomized to rifapentine 900 mg/isoniazid 900 mg once weekly for 12 wk or rifampin 450-600 mg/pyrazinamide 750-1,500 mg daily for 8 wk and followed for at least 2 yr.. TB rates, adverse events, and adherence to therapy.. A total of 399 household contacts were enrolled, 206 in the rifapentine/isoniazid arm and 193 in the rifampin/pyrazinamide arm. The median age was 34 yr, median weight was 63 kg, 60% of participants were female, and only one patient was HIV infected. Rifapentine/isoniazid was well tolerated, but the trial was halted by the investigators before completion because of unanticipated hepatotoxicity in the rifampin/pyrazinamide arm. Twenty of 193 participants (10%) receiving rifampin/pyrazinamide experienced grade 3 or 4 hepatotoxicity, compared with 2 of 206 participants (1%) on rifapentine/isoniazid (p<0.001). There were no hospitalizations or deaths due to hepatotoxicity, and all participants' liver enzyme levels returned to normal during follow-up. During follow-up, four cases of active TB developed, three in the rifapentine/isoniazid group and one in the rifampin/pyrazinamide group (1.46 vs. 0.52%; difference, 0.94%; 95% confidence interval, -1.6 to 3.7%).. Rifapentine/isoniazid was better tolerated than rifampin/pyrazinamide and was associated with good protection against TB. Rifapentine/isoniazid weekly for 12 wk is likely a promising therapy for latent TB infection.

Topics: Adult; Antitubercular Agents; Disease Progression; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Incidence; Isoniazid; Male; Pyrazinamide; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

To evaluate the curative effect and safety of a long course regimen containing Chinese-made rifabutin as compared to the regimen containing rifapentine in the treatment of multi-drug resistant pulmonary tuberculosis.. During 18 month treatment, 130 patients with multi-drug resistant pulmonary tuberculosis were divided into a treatment group (rifabutin, pasiniazide, levofloxacin, ethambutol, ethionamide, amikacin for 3 months, rifabutin, pasiniazide, levofloxacin, ethambutol, ethionamide for 6 months, rifabutin, pasiniazide, levofloxacin, ethambutol for 9 months), and a control group (rifapentine, pasiniazide, levofloxacin, ethambutol, ethionamide, amikacin for 3 months, rifabutin, pasiniazide, levofloxacin, ethambutol, ethionamide for 6 months, rifabutin, pasiniazide, levofloxacin, ethambutol for 9 months) with proportion 1:1 random, and parallel compared method.. After intensive phase, the sputum negative conversion rates (smear negative, culture negative) of the treatment group and the control group were 41.54% (27/65) and 35.94% (23/65), chi(2) = 2.42, P > 0.05, respectively. The remarkable effective rates in chest X-ray of the two groups were all 10.77% (7/65), chi(2) = 0.01, P > 0.05, and the effective rates were 67.69% (44/65) and 56.92% (37/65), chi(2) = 1.44, P > 0.05, respectively. At the end of the treatment, the sputum negative conversion rate (smear negative, culture negative) of the treatment group was 75.0% (48/65), and of the control group was 65.08% (41/65), chi(2) = 1.88, P > 0.05. The remarkable effective rates in chest X-ray of the two groups were 46.15% (30/65) and 44.62% (29/65), chi(2) = 0.02, P > 0.05, and the effective rates were 76.92% (50/65) and 73.85% (48/65), chi(2) = 0.19, P > 0.05, respectively. The cavity closure rates were 23.64% (13/55) and 33.33% (17/51), chi(2) = 0.00, P > 0.05, respectively.. Regimens containing rifabutin or rifapentine. are very effective in sputum negative conversion rate, lesion absorption and cavity closing for the treatment of multi-drug resistant pulmonary tuberculosis, with good safety and tolerance.

Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Rifabutin; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Comparison of the early bactericidal activity (EBA) of rifapentine and its pharmacokinetics with those of rifampin to determine the cause of poor clinical response and regrowth between doses, leading to rifamycin monoresistance at relapse.. Determination of the dose size of rifapentine that gives sufficient drug exposure to prevent regrowth.. EBA study over initial 5 days of treatment of 123 patients, half at Durban and half at Cape Town, who received single rifapentine doses of 300, 600, 900, or 1,200 mg rifapentine or five daily doses of 150, 300, or 600 mg rifampin, with a pharmacokinetic study on 58 patients measuring standard parameters for each dose size of rifamycin and their desacetyl metabolites.. The EBAs for both rifamycins were similar, with a linear relationship to log dose at lower doses and a curvilinear response at higher doses giving a plateau at 1,136 mg rifapentine. The area under the concentration-time curve (AUC) divided by the minimal inhibitory concentration (MIC) agreed well for both rifamycins on the assumption that the only free 2% of free rifapentine and the 14% of free rifampin after plasma binding were active in the lesions.. Only the free proportions of the rifamycins were active in lesions. From consideration of the pulse size and the duration of the postantibiotic lag, a 1,200-mg dose of rifapentine seemed necessary to improve response and to prevent regrowth between doses, and hence rifamycin monoresistance.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Area Under Curve; Dose-Response Relationship, Drug; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Rifampin; Rifamycins; Secondary Prevention; South Africa; Sputum; Time Factors; Tuberculosis, Pulmonary

The pharmacokinetics of rifapentine at 600, 900, and 1,200 mg were studied during once-weekly continuation phase therapy in 35 patients with tuberculosis. Mean area under the plasma concentration-time curve (AUC(0-infinity)) increased significantly with dose (rifapentine AUC(0- infinity): 296, 410, and 477 microg.hour/ml at 600, 900, and 1,200 mg, respectively; p = 0.02 by linear regression). In multivariate stepwise regression analyses, AUC(0-infinity) values for rifapentine and the active 25-desacetyl metabolite were associated with drug dose and plasma albumin concentration, and were lower among men and among white individuals. Fifty-four percent of patients had total (free and protein-bound) plasma concentrations of rifapentine and of desacetyl rifapentine detected for more than 36 hours after clearance of concurrently administered isoniazid. Serious adverse effects of therapy in these study patients were infrequent (1 of 35 cases; 3%) and not linked with higher rifapentine AUC(0-infinity) or peak concentration. The present pharmacokinetic study supports further trials to determine the optimal rifapentine dose for treatment of tuberculosis.

Topics: Adult; Antibiotics, Antitubercular; Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Female; Humans; Isoniazid; Male; Middle Aged; Multivariate Analysis; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

To characterise the pharmacokinetics of two consecutive doses of rifapentine (RPT) in patients diagnosed with pulmonary tuberculosis at a South African hospital.. Forty-five patients received RPT doses of 600, 750 and 900 mg, based on body weight, after receiving a soup-based meal. Doses were administered to each subject on study days 1 and 5. All patients had already received not less than 4 weeks and not more than 6 weeks of standard antimycobacterial therapy (including isoniazid, rifampicin, pyrazinamide and ethambutol). Serial blood samples were collected between 0 and 72 h post-dose. RPT and 25-desacetyl-RPT concentrations were determined using validated high performance liquid chromatography methods. The plasma concentration-time data were analysed using a noncompartmental approach and compared to healthy volunteer data from a previous study.. Median peak plasma concentrations for RPT in the patient cohort were 15.19 and 15.48 microg/ml on study days 1 and 5, respectively. Time to reach these concentrations was 5.00 and 5.08 h and plasma elimination half-lives were 11.63 and 12.03 h, respectively. Areas under the plasma concentration-time curve (0-72 h) were 355.81 and 371.89 microg x h/ml on the two occasions, respectively.. A 15 mg/kg dose of RPT was well absorbed and well tolerated. The variability observed between individuals and between occasions was small, and similar to that seen in data from previous studies in healthy volunteers.

Topics: Administration, Oral; Adolescent; Adult; Antibiotics, Antitubercular; Drug Administration Schedule; Female; Half-Life; Humans; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Recurrence of active tuberculosis after treatment can be due to relapse of infection with the same strain or reinfection with a new strain of Mycobacterium tuberculosis. The proportion of recurrent tuberculosis cases caused by reinfection has varied widely in previous studies. We evaluated cases of recurrent tuberculosis in two prospective clinical trials: a randomized study of two regimens for the last 4 months of treatment (n = 1,075) and a study of a twice-weekly rifabutin-containing regimen for human immunodeficiency virus-infected tuberculosis (n = 169). Isolates at diagnosis and from positive cultures after treatment completion underwent genotyping using IS6110 (with secondary genotyping for isolates with less than six copies of IS6110). Of 85 patients having a positive culture after completing treatment, 6 (7.1%) were classified as false-positive cultures by a review committee blinded to treatment assignment. Of the remaining 75 cases with recurrent tuberculosis and genotyping data available, 72 (96%; 95% confidence interval, 88.8-99.2%) paired isolates had the same genotype; only 3 (4%; 95% confidence interval, 0.8-11.2%) had a different genotype and were categorized as reinfection. We conclude that recurrent tuberculosis in the United States and Canada, countries with low rates of tuberculosis, is rarely due to reinfection with a new strain of M. tuberculosis.

Topics: Adult; Antitubercular Agents; Canada; Female; Genotype; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Prospective Studies; Recurrence; Rifampin; Tuberculosis, Pulmonary; United States

Rifapentine has a long half-life in serum, which suggests a possible treatment once a week for tuberculosis. We aimed to compare rifapentine and isoniazid once a week with rifampicin and isoniazid twice a week.. We did a randomised, multicentre, open-label trial in the USA and Canada of HIV-negative people with drug-susceptible pulmonary tuberculosis who had completed 2 months of a 6-month treatment regimen. We randomly allocated patients directly observed treatment with either 600 mg rifapentine plus 900 mg isoniazid once a week or 600 mg rifampicin plus 900 mg isoniazid twice a week. Primary outcome was failure/relapse. Analysis was by intention to treat.. 1004 patients were enrolled (502 per treatment group). 928 successfully completed treatment, and 803 completed the 2-year 4-month study. Crude rates of failure/relapse were 46/502 (9.2%) in those on rifapentine once a week, and 28/502 (5.6%) in those given rifampicin twice a week (relative risk 1.64, 95% CI 1.04-2.58, p=0.04). By proportional hazards regression, five characteristics were independently associated with increased risk of failure/relapse: sputum culture positive at 2 months (hazard ratio 2.8, 95% CI 1.7-4.6); cavitation on chest radiography (3.0, 1.6-5.9); being underweight (3.0, 1.8-4.9); bilateral pulmonary involvement (1.8, 1.0-3.1); and being a non-Hispanic white person (1.8, 1.1-3.0). Adjustment for imbalances in 2-month culture and cavitation diminished the association of treatment group with outcome (1.34; 0.83-2.18; p=0.23). Of participants without cavitation, rates of failure/relapse were 6/210 (2.9%) in the once a week group and 6/241 (2.5%) in the twice a week group (relative risk 1.15; 95% CI 0.38-3.50; p=0.81). Rates of adverse events and death were similar in the two treatment groups.. Rifapentine once a week is safe and effective for treatment of pulmonary tuberculosis in HIV-negative people without cavitation on chest radiography. Clinical, radiographic, and microbiological data help to identify patients with tuberculosis who are at increased risk of failure or relapse when treated with either regimen.

Topics: Antibiotics, Antitubercular; Drug Administration Schedule; Drug Therapy, Combination; Ethnicity; Female; Humans; Isoniazid; Male; Middle Aged; Radiography, Thoracic; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

Clinical trial in 672 patients with newly diagnosed pulmonary tuberculosis in Hong Kong. After an initial 2 months of a four-drug intensive phase consisting of thrice-weekly streptomycin, isoniazid, rifampicin and pyrazinamide (SHRZ), a random allocation was made to a continuation phase of once-weekly 600 mg rifapentine + 15 mg/kg isoniazid (HRp1), HRp1 given in 2 of every 3 weeks (HRp1.2/3), or to thrice-weekly isoniazid + rifampicin (HR3), the standard treatment in Hong Kong.. Final report evaluating adverse events (46 relapses and one failure) after 5 years and the prognostic influence of various factors.. Kaplan-Meier analysis of adverse events and Cox proportional hazards analysis of prognostic factors.. The two rifapentine regimens, HRp1 and HRp1.2/3 had similar final rates of adverse events of 10.8% and 11.7%, respectively, compared to 4.2% for the HR3 regimen (P = 0.02 and 0.009, respectively). In the initial univariate proportional hazards analysis, adverse events were significantly related to the regimen, age, sex, pretreatment radiographic extent of disease and cavitation, and also to sputum culture at 2 months. In the final multivariate analysis, after step-wise removal of non-significant factors, adverse events were related only to the regimen, patients' sex and pretreatment radiographic extent of disease. Elderly male patients were more at risk of an adverse event, as were those with more severe disease. Adverse events occurred at life table rates of 9.0% in patients with drug-sensitive strains and in 8.9% of those with initially isoniazid-resistant organisms at 5 years.. The two rifapentine regimens were unsatisfactory because of their high incidence of adverse events. Isoniazid appeared not to contribute to preventing relapse. Further studies with increased rifapentine dosage are necessary.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Antitubercular Agents; Child; Drug Therapy, Combination; Female; Hong Kong; Humans; Isoniazid; Life Tables; Male; Middle Aged; Prognosis; Proportional Hazards Models; Pyrazinamide; Rifampin; Streptomycin; Treatment Outcome; Tuberculosis, Pulmonary

Once-weekly rifapentine 600 mg plus isoniazid (INH) during the continuation phase treatment of tuberculosis is associated with a relapse rate higher than that of twice-weekly rifampin plus INH. The safety and tolerability of higher rifapentine doses need to be determined. We conducted a prospective, randomized, double-blind trial of rifapentine at three doses (600, 900, and 1,200 mg) plus INH 15 mg/kg once weekly in the continuation phase treatment of culture-positive tuberculosis in 150 human immunodeficiency virus-seronegative adults. Outcome measures were discontinuation of therapy for any reason and adverse events on therapy. Treatment was discontinued in 3 of 52 (6%), 2 of 51 (4%), and 3 of 47 (6%) in the rifapentine 600-, 900-, and 1,200-mg treatment arms, respectively. Only one discontinuation, in the rifapentine 1,200-mg arm, was due to an adverse event possibly associated with study therapy. There was a trend toward more adverse events, possibly associated with study therapy, in the highest-dose arms (p = 0.051). Rifapentine 900-mg, once-weekly dosing appears to be safe and well tolerated and is being evaluated in Phase III efficacy trials of treatment of latent tuberculosis. Further evaluation of the safety and tolerability of rifapentine 1,200 mg is warranted.

Topics: Adult; Aged; Antitubercular Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Prospective Studies; Reference Values; Rifampin; Treatment Outcome; Tuberculosis

The intrapulmonary pharmacokinetics of rifapentine were studied in 30 volunteers who received a single, oral dose of rifapentine (600 mg). Subgroups of five subjects each underwent bronchoscopy and bronchoalveolar lavage (BAL) at timed intervals following drug administration. Drug concentrations, including the concentration of the primary metabolite 25-desacetyl rifapentine, were determined in plasma, BAL fluid, and alveolar cells (AC) by high-pressure liquid chromatography. The concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. The concentration-time data were fit to two-compartment (plasma) or one-compartment (AC and ELF) models. The peak concentrations in plasma, ELF, and AC, 26.2, 3. 7, and 5.3 microg/ml, respectively, occurred at 5, 5, and 7 h after drug administration, respectively. The half-lives and areas under the curve for plasma, ELF, and AC were 18.3 h and 520 microg. h/ml, 20.8 h and 111 microg. h/ml, and 13.0 h and 133 microg. h/ml, respectively. Although the intrapulmonary rifapentine concentrations were less than the plasma rifapentine concentrations at all time periods, they remained above the proposed breakpoint for M. tuberculosis (0.5 microg/ml) for the 48-h observation period. These data provide a pharmacokinetic rationale for extended-interval dosing. The optimum dosing regimen for rifapentine will have to be determined by controlled clinical trials.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Biotransformation; Bronchoalveolar Lavage Fluid; Bronchoscopy; Epithelium; Female; Humans; Lung; Male; Middle Aged; Models, Biological; Prospective Studies; Pulmonary Alveoli; Rifampin; Specimen Handling

Clinical trial amongst 762 patients with newly diagnosed pulmonary tuberculosis in Hong Kong. After an initial 2 months of a four-drug intensive phase consisting of streptomycin, isoniazid, rifampicin and pyrazinamide (SHRZ), a random allocation in continuation to once-weekly rifapentine + isoniazid (HRp1), HRp1 given in 2 of every 3 weeks (HRp1.2/3), or to three times weekly isoniazid + rifampicin (HR3).. Interim report evaluating progress of study and the role of isoniazid in the continuation phase.. Kaplan-Meier analysis and response of patients related to susceptibility of pretreatment organisms to isoniazid and to rate of isoniazid acetylation determined by NAT2 genotyping.. In the 30-month follow-up, rates for adverse treatment events (failure and relapse) were 4.2% in the HR3, 10.2% in the HRp1 and 11.2% in the HRp1.2/3 series (P = 0.02 for HR3 vs HRp1 and P = 0.01 for HR3 vs HRp1.2/3). Occurrence of adverse events was not related to initial susceptibility to isoniazid nor to the rate of acetylation of isoniazid.. The two rifapentine regimens had similar final rates of adverse events which were unsatisfactory. Isoniazid had little or no activity in the continuation phase, indicating that no improvement of the continuation regimen is likely to be obtained by alteration of the isoniazid dosage.

Topics: Acetylation; Antitubercular Agents; Arylamine N-Acetyltransferase; Drug Therapy, Combination; Genotype; Hong Kong; Humans; Isoniazid; Polymorphism, Restriction Fragment Length; Rifampin; Tuberculosis, Pulmonary

Rifapentine is undergoing development for the treatment of pulmonary tuberculosis. This study was conducted to characterize the single-dose pharmacokinetics of rifapentine and its 25-desacetyl metabolite and to assess the effect of food on the rate and extent of absorption in participants infected with human immunodeficiency virus (HIV). Twelve men and four women, mean age, 38.6 +/- 6.9 years, received a single 600-mg oral dose of rifapentine in an open-label, randomized two-way, complete crossover study. Each volunteer received rifapentine following a high-fat breakfast or during a fasting period. Serial blood samples were collected for 72 h and both rifapentine and its metabolite were assayed by a validated high-performance liquid chromatography method. Pharmacokinetics of rifapentine and 25-desacetylrifapentine were determined by noncompartmental methods. Mean (+/- the standard deviation) maximum concentrations of rifapentine in serum and areas under the curve from time zero to infinity following a high-fat breakfast were 14.09 +/- 2.81 and 373.63 +/- 78.19 micrograms/ml, respectively, and following a fasting period they were 9.42 +/- 2.67 and 256.10 +/- 86.39 micrograms. h/ml, respectively. Pharmacokinetic data from a previously published healthy volunteer study were used for comparison. Administration of rifapentine with a high-fat breakfast resulted in a 51% increase in rifapentine bioavailability, an effect also observed in healthy volunteers. Although food increased the exposure of these patients to rifapentine, the infrequent dosing schedule for the treatment of tuberculosis (e.g., once- or twice-weekly dosing) would be unlikely to lead to accumulation. Additionally, autoinduction has been previously studied and has not been demonstrated with this compound, unlike with rifabutin and rifampin. Rifapentine was well tolerated by HIV-infected study participants. The results of our study suggest that no dosage adjustments may be required for rifapentine in HIV-infected patients (Centers for Disease Control and Prevention classification A1, A2, B1, or B2) undergoing treatment for tuberculosis.

Topics: Administration, Oral; Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Cross-Over Studies; Female; Food; HIV Seropositivity; HIV-1; Humans; Male; Middle Aged; Mycobacterium Infections; Rifampin; Tuberculosis

To determine the effects of rifapentine on hepatic mixed function oxidase activity and to assess the effect of enzyme induction on the steady-state pharmacokinetics of rifapentine.. Twenty-three healthy males were randomized to receive two of the following treatments in a two-period, four-treatment, incomplete block, crossover design: single daily oral rifapentine doses of 150 mg (group A), 300 mg (group B), or 600 mg (group C) on study days 1 and 4-10, or single oral rifapentine 600 mg doses given every 3 days for a total of four doses (group D). Serial blood samples were collected after the first and last rifapentine dose and assayed for rifapentine and its active metabolite, 25-desacetyl-rifapentine. Urine was collected for determination of cortisol and 6-hydroxycortisol concentrations.. The ratio of 6beta-hydroxycortisol:cortisol increased during rifapentine administration (+229%, +317%, and +357% on day 10 for groups A, B, and C, respectively). Ratios returned to baseline 2 weeks after the last dose. The per cent increase in the ratio of 6beta-hydroxycortisol:cortisol following daily doses (+357%) was much higher compared with every 72-hour dosing (+236%). Single-dose and steady-state comparisons of AUCss(0-24) and AUC(0-->infinity) for both rifapentine and 25-desacetyl-rifapentine were similar (P = NS) at corresponding doses of rifapentine. Mean t(1/2) at steady-state was 84-98% of corresponding single-dose values.. Rifapentine is a potent inducer of CYP3A activity. However, single-dose pharmacokinetics of rifapentine predict steady-state exposure, indicating no autoinduction of rifapentine metabolism with repeated administration. Enzyme activity returns to predose levels within 2 weeks of the last daily dose of rifapentine.

Topics: Adult; Antitubercular Agents; Aryl Hydrocarbon Hydroxylases; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Enzyme Induction; Humans; Hydrocortisone; Male; Oxidoreductases, N-Demethylating; Rifampin

To characterize the pharmacokinetics of rifapentine following single, multiple, and intermittent doses.. Twenty-three healthy male volunteers were randomized in a two-period, incomplete block, crossover design to receive two of four possible treatments: single daily oral rifapentine doses of 150, 300, or 600 mg given on day 1 and again on days 4-10, or a single oral 600 mg dose given on days 1, 4, 7, and 10.. Maximum rifapentine plasma concentrations were observed in 4-5 hours. Mean rifapentine t(1/2) ranged from 13.2-14.1 hours and was similar across the 150-600 mg dose range. The changes in rifapentine Cmax (R = 0.86) and AUC(0-->infinity) (R + 0.90) were dose linear. The active 25-desacetyl metabolite appeared slowly in plasma, with mean Tmax of 14.4-17.8 hours. Mean t(1/2) for 25-desacetyl-rifapentine ranged from 13.3-24.3 hours. Disproportionate, dose-dependent increases in rifapentine and 25-desacetyl-rifapentine AUC were observed as single doses of rifapentine increased from 150 to 600 mg. At steady state, however, the magnitude of dose dependency was much less.. Maximum plasma rifapentine concentrations were well above minimum inhibitory concentrations for Mycobacterium tuberculosis and M. avium following single 600 mg doses. In addition, the extended t(1/2) of rifapentine and its active metabolite support clinical investigation of once or twice-weekly rifapentine dosage regimens of rifapentine for the management of tuberculosis.

Topics: Adult; Antitubercular Agents; Cross-Over Studies; Humans; Male; Rifampin

Rifapentine is a cyclopentyl-substituted rifamycin whose serum half-life is five times that of rifampin. The US Public Health Service Study 22 compared a once-weekly regimen of isoniazid and rifapentine with twice weekly isoniazid and rifampin in the continuation phase (the last 4 months) of treatment for pulmonary tuberculosis in HIV-seropositive and HIV-seronegative patients. This report concerns only the HIV-seropositive part of the trial, which has ended. The HIV-seronegative part will stop follow-up in 2001.. Adults with culture-positive, drug-susceptible pulmonary tuberculosis who completed 2 months of four-drug (isoniazid, rifampin, pyrazinamide, ethambutol) treatment (induction phase) were randomly assigned 900 mg isoniazid and 600 mg rifapentine once weekly, or 900 mg isoniazid and 600 mg rifampin twice weekly. All therapy was directly observed. Statistical analysis used univariate, Kaplan-Meier, and logistic and proportional hazards regression methods.. 71 HIV-seropositive patients were enrolled: 61 completed therapy and were assessed for relapse. Five of 30 patients in the once-weekly isoniazid/rifapentine group relapsed, compared with three of 31 patients in the twice-weekly isoniazid/rifampin group (log rank chi2=0.69, p=0.41). However, four of five relapses in the once-weekly isoniazid/rifapentine group had monoresistance to rifamycin, compared with none of three in the rifampin group (p=0.05). Patients who relapsed with rifamycin monoresistance were younger (median age 29 vs 41 years), had lower baseline CD4 cell counts (median 16 vs 144 microL), and were more likely to have extrapulmonary involvement (75% vs 18%, p=0.03) and concomitant therapy with antifungal agents (75% vs 9%, p=0.006). No rifamycin monoresistant relapse has occurred among 1004 HIV-seronegative patients enrolled to date.. Relapse with rifamycin monoresistant tuberculosis occurred among HIV-seropositive tuberculosis patients treated with a once-weekly isoniazid/rifapentine continuation-phase regimen. Until more effective regimens have been identified and assessed in clinical trials, HIV-seropositive people with tuberculosis should not be treated with a once-weekly isoniazid/rifapentine regimen.

Topics: Adult; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Recurrence; Rifampin; Time Factors; Tuberculosis, Pulmonary

Determination of rifapentine pharmacokinetics in healthy adolescent children.. Prospective Phase II clinical trial.. Clinical research center within a university children's hospital.. Twelve subjects ranging in age from 12 to 15 years, male and female.. A single oral dose of rifapentine was administered to healthy adolescent volunteers, 450 mg if <45 kg or 600 mg if > or =45 kg. Blood was collected at serial intervals (0, 2, 3, 4, 5, 6, 8, 12, 18, 24, 48 and 72 h postdose). Subjects were observed for adverse effects during the period of study.. High pressure liquid chromatography was used to measure the plasma concentration of rifapentine and 25-desacetyl rifapentine in each blood sample. For each subject a plot of mean plasma concentration vs. time data for rifapentine and its metabolite (i.e. 25-desacetyl rifapentine) were created. Subsequently model-independent methods were used to determine the pharmacokinetic profiles for each subject.. All subjects tolerated rifapentine without adverse effects. The 2-h postdose plasma concentrations of rifapentine (6.59 to 9.05 microg/ml) and 25-desacetyl rifapentine (0.57 to 2.64 microg/ml) far exceeded the MIC of Mycobacterium tuberculosis to rifapentine (approximately 0.12 microg/ml). The combination of a high Cmax (rifapentine, 9.95 to 18.63 microg/ml; 25-desacetyl rifapentine, 3.73 to 7.46 microg/ml) and lengthy terminal elimination phase t1/2 (rifapentine, 10 to 23 h; 25-desacetyl rifapentine, 14 to 35 h) resulted in potentially effective plasma concentrations of both compounds that persisted for at least 48 h in most subjects.. A well-tolerated oral rifapentine dose produced rapid and sustained plasma drug concentrations in adolescents that should effectively treat infections caused by M. tuberculosis. Rifapentine pharmacokinetics appears to be similar in adolescent and adult populations.

Topics: Adolescent; Antibiotics, Antitubercular; Area Under Curve; Chromatography, High Pressure Liquid; Female; Humans; Male; Prospective Studies; Rifampin

A randomized comparison has been made of three times weekly rifampin plus isoniazid (HR3) with rifapentine plus isoniazid given once weekly (HRp1) or on 2 of 3 wk (HRp1.2/3) in the continuation phase of 6-mo regimens (each starting with an initial 2 mo of 4-drug therapy) for the treatment of pulmonary tuberculosis in 672 Chinese patients in Hong Kong. Because of poor bioavailability of the rifapentine used (produced in China), its dose size was increased from 600 mg initially to about 750 mg in the last third of patients to obtain serum concentrations similar to those with rifapentine of Western origin; all doses were given after a meal promoting absorption. After initial exclusions, an intent to treat analysis, done on the remaining 592 patients, showed 45 adverse treatment events in 7 of 190 HR3 patients, in 17 of 199 HRp1 patients, and in 21 of 203 HRp1.2/3 patients; of these, 42 were bacteriological or radiographic relapses after the end of treatment (HR3 versus HRp1, p = 0.04; HR3 versus HRp1.2/3, p = 0.01). Patients with organisms initially sensitive or resistant to isoniazid or streptomycin had similar relapse rates. The high relapse rate in the HRp1 regimen suggests that the rifapentine dose should be increased. Similarity of relapse rates, 8.9% and 10.4%, after the HRp1 and HRp1.2/3 regimens, respectively, indicates that irregularity in taking rifapentine/isoniazid could be tolerated. The few adverse side effects in the continuation phase in the rifapentine regimens were less frequent than in the HR3 regimen.

Topics: Adolescent; Adult; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Treatment Outcome; Tuberculosis, Pulmonary

In this open-label investigation, the pharmacokinetics of rifapentine and its active metabolite, 25-desacetyl-rifapentine, were characterized in patients with varying degrees of hepatic dysfunction. Eight patients with mild-to-moderate chronic, stable hepatic dysfunction and seven patients with moderate-to-severe hepatic dysfunction received single oral 600-mg doses of rifapentine. Maximum plasma concentration of rifapentine was lower, time to maximum plasma concentration (tmax) was greater, and elimination half-life (t 1/2) was longer in the patients with moderate-to-severe hepatic dysfunction than in those with mild-to-moderate dysfunction. However, mean area under the concentration-time curve extrapolated to infinity (AUC0-infinity) for the two groups was similar. AUC0-infinity values in patients with hepatic dysfunction were 19% to 25% higher than values previously reported for healthy volunteers. The 25-desacetyl metabolite appeared in plasma slowly after the single oral dose of rifapentine. Similar to findings for the parent drug, comparable plasma exposures of 25-desacetyl-rifapentine based on AUC0-infinity were found in the two groups of patients with mild-to-moderate and moderate-to-severe hepatic dysfunction. Rifapentine was well tolerated in this patient population, irrespective of the etiology or severity of hepatic dysfunction. These safety and pharmacokinetic results suggest that no dosage adjustments for rifapentine are needed in patients with hepatic impairment.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Area Under Curve; Female; Humans; Liver Diseases; Male; Middle Aged; Rifampin

This study was undertaken to characterize the pharmacokinetic profiles of rifapentine and its active metabolite, 25-desacetlyl rifapentine, in elderly men.. Fourteen healthy, nonsmoking male volunteers between the ages of 65 and 82 years received a single oral 600 mg dose of rifapentine. Plasma samples were collected at frequent intervals for up to 72 hours postdose. The control group consisted of 20 healthy, young (18-45 years) males volunteers from a previous, single-dose (600 mg) rifapentine pharmacokinetic study.. Plasma rifapentine concentrations above the minimum inhibitory concentration for M. tuberculosis were observed at 2 hours after dosing. Disposition of rifapentine was monophasic with a mean terminal half-life of 19.6 hours. The peak plasma concentration of 25 desacetyl-rifapentine was found 21.7 hours, on average, after the rifapentine dose; the mean 25-desacetyl-rifapentine t1/2 was 22.9 hours. Compared to the younger subjects, apparent oral clearance of rifapentine (24%) was lower in the elderly male (p < 0.05), and Cmax (28%) was higher. The only adverse event reported in both the older and younger subjects in these single-dose studies was discoloration of the urine.. Because the aged-related changes in the pharmacokinetic profile of rifapentine observed in this study were modest and unlikely to be associated with toxicity, no dosage adjustments for this antibiotic are recommended in elderly patients.

Topics: Aged; Aged, 80 and over; Antitubercular Agents; Half-Life; Humans; Male; Reference Values; Rifampin

To assess the therapeutic efficacy of rifapentine (L), to reduce the duration of treatment and the frequency of drug administration, and to observe the influence on efficacy and adverse reactions of using pyrazinamide (Z) through whole-course.. Two 5-month regimens respectively including rifampin (R) and L and two whole course intermittent regimens were designed as following: I: 2SHRZ/3R2H2Z2; II: 2SHRZ/3L1H2Z2; III: 2S3H3R3Z3/4L1H2Z2; IV: 2S3H3R3Z3/4L1H2E2. A total of 366 newly-diagnosed bacillary pulmonary tuberculosis patients were admitted and randomly allocated.. 339 cases completed the prescribed short course chemotherapy. The sputum conversion rates at the end of the treatment of groups I, II, III and IV were 97.0%, 94.1%, 100.0% and 97.2% respectively. X-ray resolution rates were 96.0%, 97.6%, 100.0% and 94.4% respectively. Cavity-close rates of the 5-month regimens and the 6-month regimens were 77% and 76%. Comparing the results among groups, there were no statistically significant differences (P > 0.05), and no obvious side-effect was found. 305 patients have been followed up for 3 years since completion of the chemotherapy. The bacteriological relapse and bacteriological relapse with deterioration on chest X-ray in groups I, II, III and IV were seen in 2,3,6 and 3 cases respectively.. Domestic-made rifapentine is a long-acting, highly effective antituberculosis drug. It is unnecessary to use Z in continuation phase, and it is possible to shorten the duration to 5 months with the appropriate combination of essential drugs, which is worthwhile for further study.

Topics: Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Humans; Mycobacterium tuberculosis; Pyrazinamide; Recurrence; Rifampin; Sputum; Tuberculosis, Pulmonary

A clinical trial of rifapentine in Hong Kong.. Assessment of the bioavailability of the Chinese rifapentine used in the trial.. The content of rifapentine in serum samples taken from 287 patients during the administration of four batches of the drug was measured by microbiological assay.. An initial comparison of areas under curve obtained in a random allocation to 40 patients of rifapentine either of Western or Chinese origin indicated that the bioavailability of the Chinese drug was 74% of the Western drug. The bioavailability of the second batch was found to be about 66% of the Western drug. The dose of the last two batches of rifapentine was therefore increased from the planned 600 mg to 750 mg, or briefly to 900 mg; serum concentrations were then similar to those obtained with the Western drug. Bioavailability did not change during the use of each drug batch.. A comparison of the results obtained in the trial with the initial two batches and the final batches will estimate the effects of rifapentine dose size on its efficacy and toxicity.

Topics: Adult; Antitubercular Agents; Area Under Curve; Biological Availability; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Design; Drug Stability; Female; Hong Kong; Humans; Male; Middle Aged; Regression Analysis; Rifampin; Treatment Outcome; Tuberculosis

Studies have shown clarithromycin (Biaxin) and rifabutin to be effective against Mycobacterium avium complex (MAC), and to improve survivability. Abbott Laboratories is seeking approval from the Food and Drug Administration (FDA) for clarithromycin use in preventing MAC. Marion Merrell Dow, the manufacturer of rifabutin, is planning a prophylaxis trial with a close cousin of the drug, rifapentine. Rifapentine has a long half-life, and has the potential to lengthen intermittent treatment for tuberculosis. It is believed that this long half-life may mean it can maintain a higher blood level and thereby maintain better effectiveness than rifabutin against fast-growing MAC organisms.

Topics: AIDS-Related Opportunistic Infections; Animals; Antitubercular Agents; CD4 Lymphocyte Count; Clarithromycin; Half-Life; Humans; Mycobacterium avium-intracellulare Infection; Placebos; Randomized Controlled Trials as Topic; Rifabutin; Rifampin

A clinical study about the efficacy of rifapentine in the treatment and 3 years' follow up on initial pulmonary tuberculous patient. Altogether 267 patients of initial pulmonary tuberculosis with positive smears were randomly divided into 3 groups; Group I with DL473 twice-weekly (2HE+L2/7H2L2), Group IIARFp twice-weekly (2HE+R2/7H2R2) and Group IIBRFP daily (2HRE/7HR) for controls. Results are: the conversion rate to smear negative are 96.0%, 96.4% and 97.1% respectively (P > 0.05); the sputum conversion rate by cultures are 98.0%, 95.7% and 96.4% respectively (P > 0.05). From X-Ray pictures, the treatment effect of Group I are similar to that of Group IIB. But in Group I with less side action were observed. The relapse rate of the three groups are 2.6%, 3.8% and 3.1% respectively (P > 0.05). From this investigation, we can draw a conclusion that the twice-weekly of rifapentine has at least an effect similar to rifampicin given daily. Further investigation of DL473 once weekly will soon be followed.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Antitubercular Agents; Drug Therapy, Combination; Ethionamide; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use of long-acting injectable (LAI) drug formulations may simplify and shorten regimens for this indication. Rifapentine and rifabutin have antituberculosis activity and physiochemical properties suitable for LAI formulation, but there are limited data available for determining the target exposure profiles required for efficacy in TPT regimens. The objective of this study was to determine exposure-activity profiles of rifapentine and rifabutin to inform development of LAI formulations for TPT. We used a validated paucibacillary mouse model of TPT in combination with dynamic oral dosing of both drugs to simulate and understand exposure-activity relationships to inform posology for future LAI formulations. This work identified several LAI-like exposure profiles of rifapentine and rifabutin that, if achieved by LAI formulations, could be efficacious as TPT regimens and thus can serve as experimentally determined targets for novel LAI formulations of these drugs. We present novel methodology to understand the exposure-response relationship and inform the value proposition for investment in development of LAI formulations that have utility beyond latent tuberculosis infection.

Topics: Animals; Antitubercular Agents; Latent Tuberculosis; Mice; Rifabutin; Rifampin

Topics: Humans; Leprosy; Rifampin

Topics: Humans; Leprosy; Rifampin

We present a case of a 53-year-old person living with human immunodeficiency virus and a new diagnosis of latent tuberculosis. The patient had baseline suppressed HIV viral load on fixed dose combination dolutegravir/abacavir/lamivudine when once-weekly rifapentine 900 mg/isoniazid 900 mg/pyridoxine 25 mg was initiated for 12 weeks. An additional 50 mg dolutegravir dose, administered in the evenings, was added to the daily antiretroviral regimen for treatment duration secondary to rifapentine uridine diphosphate glucuronsyl transferase induction. Dolutegravir trough concentrations decreased during concurrent therapy with noted slight HIV viral load rebound. Upon completion of rifapentine use, and a return to dolutegravir 50 mg daily dose, the trough concentrations increased with a return to an undetectable viral load. We provide suggested dolutegravir dosing considerations with concomitant rifapentine use, not currently addressed in recommended guidelines.

Topics: Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Middle Aged; Rifampin

Topics: Antitubercular Agents; Drug Interactions; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Rifampin

Systemic drug reaction (SDR) is a major safety concern with weekly rifapentine plus isoniazid for 12 doses (3HP) for latent tuberculosis infection (LTBI). Identifying SDR predictors and at-risk participants before treatment can improve cost-effectiveness of the LTBI program.. We prospectively recruited 187 cases receiving 3HP (44 SDRs and 143 non-SDRs). A pilot cohort (8 SDRs and 12 non-SDRs) was selected for generating whole-blood transcriptomic data. By incorporating the hierarchical system biology model and therapy-biomarker pathway approach, candidate genes were selected and evaluated using reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Then, interpretable machine learning models presenting as SHapley Additive exPlanations (SHAP) values were applied for SDR risk prediction. Finally, an independent cohort was used to evaluate the performance of these predictive models.. Based on the whole-blood transcriptomic profile of the pilot cohort and the RT-qPCR results of 2 SDR and 3 non-SDR samples in the training cohort, 6 genes were selected. According to SHAP values for model construction and validation, a 3-gene model for SDR risk prediction achieved a sensitivity and specificity of 0.972 and 0.947, respectively, under a universal cutoff value for the joint of the training (28 SDRs and 104 non-SDRs) and testing (8 SDRs and 27 non-SDRs) cohorts. It also worked well across different subgroups.. The prediction model for 3HP-related SDRs serves as a guide for establishing a safe and personalized regimen to foster the implementation of an LTBI program. Additionally, it provides a potential translational value for future studies on drug-related hypersensitivity.

Topics: Antitubercular Agents; Decision Support Techniques; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Humans; Isoniazid; Latent Tuberculosis; Rifampin

On May 5, 2021, CDC's Tuberculosis Trials Consortium and the National Institutes of Health (NIH)-sponsored AIDS Clinical Trials Group (ACTG) published results from a randomized controlled trial indicating that a 4-month regimen containing rifapentine (RPT), moxifloxacin (MOX), isoniazid (INH), and pyrazinamide (PZA) was as effective as the standard 6-month regimen for tuberculosis (TB) treatment (1). On the basis of these findings, CDC recommends the 4-month regimen as a treatment option for U.S. patients aged ≥12 years with drug-susceptible pulmonary TB and provides implementation considerations for this treatment regimen.

Topics: Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Moxifloxacin; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Pulmonary; United States

Yellow fever virus (YFV) infection is a major public concern that threatens a large population in South America and Africa. No specific anti-YFV drugs are available till now. Here, we report that rifapentine is a potent YFV inhibitor in various cell lines by high-throughput drugs screening, acting at both cell entry and replication steps. Kinetic test and binding assay suggest that rifapentine interferes the viral attachment to the target cells. The application of YFV replicon and surface plasmon resonance assay indicates that rifapentine suppresses viral replication by binding to the RNA-dependent RNA polymerase (RdRp) domain of viral nonstructural protein NS5. Further molecular docking suggests that it might interact with the active centre of RdRp. Rifapentine significantly improves the survival rate, alleviates clinical signs, and reduces virus load and injury in targeted organs both in YFV-infected type I interferon receptor knockout A129

Topics: Animals; Mice; Molecular Docking Simulation; Rifampin; Viral Nonstructural Proteins; Virus Replication; Yellow Fever; Yellow fever virus

Topics: Humans; Rifampin; Tuberculosis

Topics: Humans; Rifampin; Tuberculosis

A robust analytical method based on liquid chromatography coupled to tandem mass spectrometry was developed and validated to quantify rifapentine and 25-O-desacetyl rifapentine in human breast milk to aid in determining the breastfed infant risk to the excreted drug in human milk. Samples were extracted by a combination of protein precipitation and solid phase extraction using rifampicin-d3 as an internal standard. An Agilent® Poroshell 120 EC-C18 (4.6 mm × 50 mm, 2.7 µm) column was used for chromatographic separation employing an isocratic mobile phase consisting of acetonitrile: methanol: 0.1% formic acid (55/5/40, v/v/v) at a flow rate of 450 µL/min, and with a total run time of four minutes. Mass detection was on an AB Sciex API 4000 mass spectrometer using electrospray ionization in the positive mode and based on multiple reaction monitoring data acquisition. Rifapentine was accurately quantified across a concentration range of 2.00-2000 ng/mL and 25-O-desacetyl rifapentine from 4.00 to 2000 ng/mL. During validation, the inter- and intra-day accuracy and precision at the tested QC concentrations (N = 18) for rifapentine were between 97.4% and 100.6%, and 3.1% and 8.3%, respectively. The inter- and intra-day accuracy and precision for 25-O-desacetyl rifapentine were between 96.4% and 106.3%, and 6.7% and 11.8%, respectively. No significant matrix effects were observed, and the method was shown to be specific for rifapentine and 25-O-desacetyl rifapentine. Human milk samples (N = 22) generated during a phase I/II clinical trial were successfully analysed for rifapentine and 25-O-desacetyl rifapentine using this validated method. Concentrations for rifapentine and 25-O-desacetyl rifapentine in human milk samples (N = 22) ranged from 11.2-1180 ng/mL and 7.11-573 ng/mL, respectively.

Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Female; Humans; Milk, Human; Reproducibility of Results; Rifampin; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Drug Therapy, Combination; Europe; Humans; Rifampin; Tuberculosis

Topics: Europe; Humans; Isoniazid; Rifampin; Tuberculosis

Topics: Humans; Isoniazid; Rifampin; Syndrome

A once-weekly oral dose of isoniazid and rifapentine for 3 months (3HP) is recommended by the CDC for treatment of latent tuberculosis infection (LTBI). The aim of this study is to assess 3HP-mediated clearance of M. tuberculosis bacteria in macaques with asymptomatic LTBI. Twelve Indian-origin rhesus macaques were infected with a low dose (~10 CFU) of M. tuberculosis CDC1551 via aerosol. Six animals were treated with 3HP and 6 were left untreated. The animals were imaged via PET/CT at frequent intervals. Upon treatment completion, all animals except 1 were coinfected with SIV to assess reactivation of LTBI to active tuberculosis (ATB). Four of 6 treated macaques showed no evidence of persistent bacilli or extrapulmonary spread until the study end point. PET/CT demonstrated the presence of significantly more granulomas in untreated animals relative to the treated group. The untreated animals harbored persistent bacilli and demonstrated tuberculosis (TB) reactivation following SIV coinfection, while none of the treated animals reactivated to ATB. 3HP treatment effectively reduced persistent infection with M. tuberculosis and prevented reactivation of TB in latently infected macaques.

Topics: Animals; Antitubercular Agents; Isoniazid; Latent Tuberculosis; Lung; Macaca mulatta; Mycobacterium tuberculosis; Positron Emission Tomography Computed Tomography; Rifampin; Tuberculosis

Topics: Alkynes; Anti-Retroviral Agents; Antitubercular Agents; Benzoxazines; Cyclopropanes; HIV Infections; Humans; Isoniazid; Nevirapine; Rifampin

Topics: Antitubercular Agents; Drug Prescriptions; Humans; Isoniazid; Rifampin; Tuberculosis; United States; United States Food and Drug Administration

Topics: Animals; Antitubercular Agents; Drug Therapy, Combination; Isoniazid; Latent Tuberculosis; Mice; Rifampin

Short-course preventive therapy with 1-month course of daily administration of isoniazid (300-mg) plus rifapentine (600-mg) (1HP) and 3-month course of weekly administration of isoniazid (900-mg) plus rifapentine (900-mg) (3HP) has higher completion rates than 9-month course of daily isoniazid (9H) for individuals with latent tuberculosis infection (LTBI). We aimed to evaluate the effect, safety and tolerability of 1HP in people living with HIV (PLWH) and LTBI who received coformulated bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF).. PLWH testing positive by interferon-gamma release assay and having received BIC/FTC/TAF for >2 weeks with plasma HIV RNA load (PVL) <200 copies/ml were enrolled. BIC trough plasma concentrations and cytokine profiles were determined before the first dose (day 1/baseline), 24 h after the 14th (day 15) and 28th (day 29) doses of 1HP. PVL were determined on days 15 and 29 of 1HP and every 3 months subsequently after discontinuation of 1HP.. BIC/FTC/TAF in combination with 1HP was well tolerated with a high completion rate. BIC trough plasma concentrations were significantly decreased with concurrent use of 1HP among PLWH with LTBI. While transient viral blips were observed during 1HP without causing subsequent treatment failure, such combination should be applied with caution.

Topics: Adenine; Alanine; Amides; Anti-HIV Agents; Emtricitabine; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Piperazines; Pyridones; Rifampin; Tenofovir

Tuberculosis (TB) remains an important problem among children in the United States and throughout the world. There is no diagnostic reference standard for latent tuberculosis infection (also referred to as tuberculosis infection [TBI]). The tuberculin skin test (TST) has many limitations, including difficulty in administration and interpretation, the need for a return visit by the patient, and false-positive results caused by cross-reaction with Mycobacterium bovis-bacille Calmette-Guerin vaccines and many nontuberculous mycobacteria. Interferon-gamma release assays (IGRAs) are blood tests that use antigens specific for M tuberculosis; as a result, IGRAs yield fewer false-positive results than the TST. Both IGRAs and the TST have reduced sensitivity in immunocompromised children, including children with severe TB disease. Both methods have high positive predictive value when applied to children with risk factors for TBI, especially recent contact with a person who has TB disease. The advantages of using IGRAs and diminished experience with the placement and interpretation of the TST favor expanded use of IGRAs in children in the United States. There are now several effective and safe regimens for the treatment of TBI in children. For improved adherence to therapy, the 3 rifamycin-based regimens are preferred because of their short duration. Daily isoniazid can be used if there is intolerance or drug interactions with rifamycins. A TB specialist should be involved when there are questions regarding testing interpretation, selection of an appropriate treatment regimen, or management of adverse effects.

Topics: Adolescent; Age Factors; Antitubercular Agents; BCG Vaccine; Child; Child, Preschool; Cross Reactions; False Positive Reactions; Humans; Immunocompromised Host; Infant; Interferon-gamma Release Tests; Isoniazid; Latent Tuberculosis; Mycobacterium bovis; Mycobacterium tuberculosis; Nontuberculous Mycobacteria; Rifampin; Sensitivity and Specificity; Tuberculin Test

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Child; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Rifampin

Treatment of latent tuberculosis (LTBI) is important for tuberculosis (TB) prevention, and short course rifamycin-based therapies are preferred. Once-weekly isoniazid-rifapentine by self-administered therapy (3HP-SAT) has never been compared with 4 months of daily rifampin (4R).. Retrospective cohort study of adults ≥18 years of age initiating LTBI treatment with either 3HP-SAT or 4R in a United States (US)-based TB clinic between 11 April 2016 and 31 December 2018. We evaluated treatment completion through pharmacy fills and reviewed charts for reasons of noncompletion, including adverse events (AEs). The χ 2 test and a log-binomial multivariable model were used to compare treatment completion and AEs.. Five hundred sixty individuals (42%) initiated 3HP-SAT and 773 (58%) initiated 4R. Median age was 38, 55% were female, and 89% were born outside of the US. Among those aged 18-49 years, treatment completion with 3HP-SAT was 79% compared to 68% with 4R (adjusted risk ratio [aRR], 1.17 [95% CI, 1.17-1.27]; P < .0001). Among individuals aged ≥50 years, treatment completion with 3HP-SAT was 87% compared to 64% with 4R (aRR, 1.35 [95% CI, 1.19-1.52]; P < .0001). Compared to 4R, there was no difference in risk of AEs in the 18-49 age group (aRR, 0.93 [95% CI, .58-1.48]; P = .75). Reduced risk of AEs was noted among patients aged ≥50 years who received 3HP-SAT (aRR, 0.37 [95% CI, .16-.85]; P = .02).. 3HP-SAT was associated with higher LTBI treatment completion and lower rates of AEs compared to 4R in individuals aged 50 and older. Expanding 3HP-SAT as an option for patients with LTBI may enhance TB prevention strategies in the US.

Topics: Adult; Aged; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Middle Aged; Retrospective Studies; Rifampin; United States

Topics: Anti-Bacterial Agents; Humans; Prosthesis-Related Infections; Rifabutin; Rifampin; Staphylococcus epidermidis

Weekly rifapentine and isoniazid (3HP) is gaining popularity for latent tuberculosis infection treatment because of its short course and high completion rate. Prior to widespread use, comprehensive 3HP treatment assessment covering an all-age population is essential.. Participants receiving ≥1 3HP dose from September 2014 to December 2019 were stratified into elderly (≥65 years), middle-aged (>35 & <65 years), and younger (≤35 years) age groups. This study investigated the impact of age on treatment outcome, particularly systemic drug reactions (SDRs) and 3HP discontinuation.. Overall, 134 of 579 (23.1%) participants were elderly. The completion rate was 83.1% overall and was highest and lowest in the younger group (94.5%) and elderly (73.9%) group, respectively. However, the 3HP discontinuation rate was not significantly different among the 3 groups in multivariate logistic regression analysis. In total, 362 (62.5%) participants experienced 1 or more adverse drug reactions (ADRs), of which 38 (10.5%) and 98 (27.1%) required temporary and permanent treatment interruption, respectively. The SDR risk was 11.2% in overall and 17.1% in the middle-aged group, 3.04-fold higher than that in the elderly group (P = .025). This finding was consistently observed in different clinical settings. Hypertensive events accompanied with flu-like symptoms occurred in 11.2% of elderly participants, and accounted for 50% of grade ≥3 ADRs.. With proper medical support and programmatic follow-up, the 3HP completion rate is >70% even in elderly participants. In middle-aged and elderly individuals, 3HP should be employed with caution because of risk of SDRs and hypertensive events, respectively. Summary: Under programmatic medical support, widespread use of weekly rifapentine and isoniazid (3HP) for latent tuberculosis treatment is possible for its high completion rate. 3HP should be employed with caution for risk of systemic drug reactions and hypertensive events in middle-aged and elderly individuals, respectively.

Topics: Aged; Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Middle Aged; Rifampin

Successful delivery and completion of tuberculosis preventive treatment are necessary for tuberculosis elimination. Shorter preventive treatment regimens currently have higher medication costs, but patients spend less time in care and are more likely to complete treatment. It is unknown how economic costs of successful delivery differ between longer and shorter regimens in high-tuberculosis-burden settings.. We developed survey instruments to collect costs from program and patient sources, considering costs incurred from when household contacts first entered the health system. We compared the cost per completed course of preventive treatment with either 6 months of daily isoniazid (6H) or 3 months of weekly isoniazid and rifapentine (3HP), delivered by the Indus Health Network tuberculosis program in Karachi, Pakistan, between October 2016 and February 2018.. During this period, 459 individuals initiated 6H and 643 initiated 3HP; 39% and 61% completed treatment, respectively. Considering costs to both the program and care recipients, the cost per completed course was 394 US dollars (USD) for 6H and 333 USD for 3HP. Using a new 2020 price for rifapentine reduced the cost per completed course of 3HP to 290 USD. Under varying assumptions about drug prices and costs incurred by care recipients, the cost per completed course was lower for 3HP in all scenarios, and the largest cost drivers were the salaries of clinical staff.. In a high-burden setting, the cost of successful delivery of 3HP was lower than that of 6H, driven by higher completion.

Topics: Antitubercular Agents; Cost-Benefit Analysis; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Tuberculosis

Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered.. To investigate a genomic association with interindividual variation of rifapentine exposure, SNPs of six human genes involving rifamycin metabolism (AADAC, CES2), drug transport (SLCO1B1, SLCO1B3) and gene regulation (HNF4A, PXR) were evaluated.. We characterized these genes in 173 adult participants in treatment trials of the Tuberculosis Trials Consortium. Participants were stratified by self-identified race (black or non-black), and rifapentine AUC from 0 to 24 h (AUC0-24) was adjusted by analysis of covariance for SNPs, rifapentine dose, sex, food and HIV coinfection. This study was registered at ClinicalTrials.gov under identifier NCT01043575.. The effect on rifapentine least squares mean AUC0-24 in black participants overall decreased by -10.2% for AADAC rs1803155 G versus A allele (Wald test: P = 0.03; false discovery rate, 0.10). Black participants with one G allele in AADAC rs1803155 were three times as likely to have below target bactericidal rifapentine exposure than black participants with the A allele (OR, 2.97; 95% CI: 1.16, 7.58). With two G alleles, the OR was greater. In non-black participants, AADAC rs1803155 SNP was not associated with rifapentine exposure. In both black and non-black participants, other evaluated genes were not associated with rifapentine exposure (P > 0.05; false discovery rate > 0.10).. Rifapentine exposure in black participants varied with AADAC rs1803155 genotype and the G allele was more likely to be associated with below bactericidal target rifapentine exposure. Further pharmacogenomic study is needed to characterize the association of the AADAC rs1803155 with inadequate rifapentine exposure in different patient groups.

Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Carboxylic Ester Hydrolases; Humans; Liver-Specific Organic Anion Transporter 1; Pharmaceutical Preparations; Polymorphism, Single Nucleotide; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

A 12-dose weekly regimen of rifapentine plus isoniazid (3HP) is recommended for the prevention of active tuberculosis (TB); however, it is unclear whether 3HP should be provided by directly observed therapy (DOT) or self-administered therapy (SAT). In addition, the introduction of patient informed choice between delivery modalities may have a positive impact on factors leading to treatment completion. The authors randomized 252 participants with HIV to a hypothetical scenario of providing preventive therapy by either DOT or an informed choice between DOT and SAT. Out of 104 participants who were randomized to a choice between DOT and SAT, 103 chose therapy by SAT. Participants rated their level of confidence and intention to complete therapy. Compared to those assigned to the DOT scenario, patients assigned to the choice scenario expressed greater confidence and intention to complete preventive therapy. Convenience and travel required to complete 3HP therapy were important factors in deciding between delivery modalities. Those assigned to DOT identified more barriers to completing therapy than those given a choice. Empowering patients to make informed decisions about how they receive TB preventive therapy may improve completion rates.

Topics: Adult; Decision Making; Directly Observed Therapy; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Patient Preference; Random Allocation; Rifampin; Self Administration; Self Efficacy; Uganda

Shorter regimens for tuberculosis prevention can improve completion rates and protection against developing active tuberculosis disease after tuberculosis exposure. We aimed to assess the safety and feasibility of 1 month of daily isoniazid and rifapentine (1HP) in children and adolescents in a low-resource setting in south Asia with low prevalence of HIV.. This prospective cohort study was done in eight tuberculosis facilities in Karachi, Pakistan. Eligible participants were aged 2-19 years and were household contacts of patients with drug-susceptible tuberculosis infection. After clinical, radiological, and laboratory evaluation to rule out tuberculosis disease, participants were prescribed 1HP as a preventive regimen. Isoniazid was administered as 100 mg or 300 mg oral tablets and rifapentine was administered as 150 mg oral tablets. Dosing was according to participant bodyweight. The primary endpoints were the cumulative probability of a household contact completing all stages of the preventive care cascade, assessed in all eligible participants, and the proportion of household contacts completing 1HP, assessed among all those who initiated the regimen. Safety was assessed in all household contacts who initiated the 1HP regimen.. Between Dec 21, 2019, and March 20, 2020, 1395 household contacts of 253 patients with tuberculosis were identified, including 678 household contacts who were eligible to participate. 628 (93%) completed evaluation, of whom ten (2%) had active tuberculosis disease. Of the 618 individuals eligible for tuberculosis prevention, 408 (66%) initiated 1HP, 385 (94%) of whom completed the regimen. The median duration of 1HP was 31 days (IQR 30-32) in those who completed the regimen. The cumulative probability of completing all steps of the tuberculosis prevention cascade was 58%. A girl aged 11 years developed tuberculosis disease within 6 months of completing 1HP. A boy aged 14 years developed a burning sensation during 1HP therapy and discontinued the regimen. No other adverse events were observed.. 1HP can be safely and feasibly implemented as tuberculosis prevention in children and adolescents in programmatic settings.. The Global Fund to Fight AIDS, Tuberculosis and Malaria.

Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Cohort Studies; Duration of Therapy; Female; Humans; Isoniazid; Male; Pakistan; Prospective Studies; Rifampin; Treatment Adherence and Compliance; Tuberculosis; Young Adult

Topics: Humans; Moxifloxacin; Rifampin; Tuberculosis

To assess the cost effectiveness of once weekly rifapentine and isoniazid for 12 weeks (3HP) to the current standard care for latent tuberculosis (TB) infection (LTBI) in Iqaluit, Nunavut.. A cost-effectiveness analysis using a Markov model reflecting local practices for LTBI treatment.. A remote Canadian arctic community with a high incidence of TB.. Hypothetical patients with LTBI.. The cost effectiveness of 3HP was compared with the existing standard of care in the study region which consists of 9 months of twice weekly isoniazid (9H) given by directly observed therapy.. Effectiveness was measured in quality-adjusted life years (QALYs) with model parameters were derived from historical programmatic data, a local implementation study of 3HP and published literature. Costs from the perspective of the Nunavut healthcare system were measured in 2019 US dollars and were obtained primarily from local, empirically collected data. Secondary health outcomes included estimated TB cases and TB deaths averted using 3HP versus 9H. One way and probabilistic sensitivity analyses were performed.. The 3HP regimen was dominant over 9H: costs were lower (US$628 vs US$924/person) and health outcomes slightly improved (20.14 vs 20.13 QALYs/person). In comparison to 9H, 3HP treatment resulted in fewer TB cases (27.89 vs 30.16/1000 persons) and TB deaths (2.29 vs 2.48/1000 persons). 3HP completion, initiation and risk of fatal adverse events were the primary drivers of cost effectiveness.. In a remote Canadian arctic setting, using 3HP instead of 9H for LTBI treatment may result in cost savings and similar or improved health outcomes.

Topics: Antitubercular Agents; Canada; Cost-Benefit Analysis; Humans; Isoniazid; Latent Tuberculosis; Rifampin

Three months of weekly rifapentine plus isoniazid (3HP) is a short course regimen for latent tuberculosis infection treatment with satisfied safety and efficacy. However, research on its use in children is limited. In this study, we evaluated the completion rate and safety of the 3HP regimen among children in China. Participants aged 1-14 years receiving 3HP for TB prevention at Shanghai Public Health Clinical Center were followed from December 2019 to November 2020 to evaluate the safety and completion rate of the treatment. Thirty-one children were eligible for inclusion, but five were excluded from the analysis (three were treated with a lower than recommended dose, and two were lost to follow-up). Of the 26 children included in the analysis, the treatment completion rate was 100%. Adverse drug reactions (ADRs) were reported in 38.5% (10/26) of the patients. The most common ADRs were gastrointestinal symptoms (19.2%,5/26), and all ADRs were rated as Grade 1. The 3HP regimen has a high completion rate, and it seems well tolerated in our study population. However, further randomized controlled clinical trial with larger sample size are warranted.

Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; China; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infant; Isoniazid; Latent Tuberculosis; Male; Medication Adherence; Rifampin

After staphylococci, streptococci and enterococci are the most frequent causes of periprosthetic joint infection (PJI). MICs and minimum biofilm bactericidal concentrations of rifampin, rifabutin, and rifapentine were determined for 67 enterococcal and 59 streptococcal PJI isolates. Eighty-eight isolates had rifampin MICs of ≤1 μg/ml, among which rifabutin and rifapentine MICs were ≤ 8 and ≤4 μg/ml, respectively. There was low rifamycin

Topics: Anti-Bacterial Agents; Bacterial Infections; Biofilms; Enterococcus; Humans; Microbial Sensitivity Tests; Prosthesis-Related Infections; Rifabutin; Rifampin; Staphylococcal Infections; Staphylococcus

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Drug Therapy, Combination; Isoniazid; Latent Tuberculosis; Macaca; Models, Animal; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis

Efficient recruitment of eligible participants, optimizing time and sample size, is a crucial component in conducting a successful clinical trial. Inefficient participant recruitment can impede study progress, consume staff time and resources, and limit quality and generalizability or the power to assess outcomes. Recruitment for disease prevention trials poses additional challenges because patients are asymptomatic. We evaluated candidates for a disease prevention trial to determine reasons for nonparticipation and to identify factors that can be addressed to improve recruitment efficiency.. During 2001-2009, the Tuberculosis Trials Consortium conducted Study 26 (PREVENT TB), a randomized clinical trial at 26 sites in four countries, among persons with latent tuberculosis infection at high risk for tuberculosis disease progression, comparing 3 months of directly observed once-weekly rifapentine plus isoniazid with 9 months of self-administered daily isoniazid. During March 2005-February 2008, non-identifying demographic information, risk factors for experiencing active tuberculosis disease, and reasons for not enrolling were collected from screened patients to facilitate interpretation of trial data, to meet Consolidated Standards of Reporting Trials standards, and to evaluate reasons for nonparticipation.. Of the 7452 candidates screened in Brazil, Canada, Spain, and the United States, 3584 (48%) were not enrolled, because of ineligibility (41%), site decision (10%), or patient choice (49%). Among those who did not enroll by own choice, and for whom responses were recorded on whether they would accept treatment outside of the study (n = 1430), 68% reported that they planned to accept non-study latent tuberculosis infection treatment. Among 1305 patients with one or more reported reasons for nonparticipation, study staff recorded a total of 1886 individual reasons (reason count: median = 1/patient; range = 1-9) for why patients chose not to enroll, including grouped concerns about research (24% of 1886), work or school conflicts (20%), medication or health beliefs (16%), latent tuberculosis infection beliefs (11%), and patient lifestyle and family concerns (10%).. Educational efforts addressing clinical research concerns and beliefs about medication and health, as well as study protocols that accommodate patient-related concerns (e.g. work, school, and lifestyle) might increase willingness to enter clinical trials. Findings from this evaluation can support development of communication and education materials for clinical trial sites at the beginning of a trial to allow study staff to address potential participant concerns during study screening.

Topics: Adolescent; Adult; Antitubercular Agents; Child; Child, Preschool; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Patient Selection; Randomized Controlled Trials as Topic; Refusal to Participate; Rifampin; Risk Factors; Young Adult

Topics: Animals; Isoniazid; Latent Tuberculosis; Macaca; Mycobacterium tuberculosis; Rifampin

Treatment data for latent tuberculosis infection (LTBI) among potential living kidney donors are scarce.. This retrospective study was performed to evaluate the prevalence of positive QuantiFERON-TB Gold In-Tube (QFT-GIT) among potential living kidney donors that were screened from 2009 to 2017. We investigated if there was any difference in the time to donation between QFT-GIT-positive and QFT-GIT-negative donors. We assessed the regimens used to treat LTBI and whether the recipients of QFT-GIT-positive donors developed active tuberculosis (TB).. Forty out of 427 (9%) potential living kidney donors had a positive QFT-GIT. QFT-GIT-positive donors were as likely as negative donors to undergo donation (30 [75%] vs 315 [81%], P = .33). The time from QFT-GIT testing to donation was longer among QFT-GIT-positive donors (median 221 days [range: 4-1139] vs 86 days [range: 3-1887], P = .001). Twelve-week rifapentine (RPT)/Isoniazid (INH) was the most common treatment used and was not associated with significant adverse reactions. There was a trend toward longer time to donation among QFT-GIT-positive donors who were treated for LTBI compared with QFT-GIT-positive donors who were not (252 days [range: 88-1139] vs 95 days [range: 4-802], P = .05). Twenty-nine recipients of QFT-GIT-positive living kidney donors were evaluated. Eleven of these recipients received kidneys from donors that were not treated for LTBI. Two of these recipients were treated with INH post-transplantation.. The time from QFT-GIT testing to donation was longer among QFT-GIT-positive donors. The short-course regimens appear to be excellent options for LTBI treatment among living kidney donors and avoid delaying organ donation further.

Topics: Adult; Antibiotics, Antitubercular; Drug Administration Schedule; Humans; Interferon-gamma Release Tests; Kidney; Kidney Transplantation; Latent Tuberculosis; Living Donors; Male; Middle Aged; Mycobacterium tuberculosis; Prevalence; Retrospective Studies; Rifampin

The objective of this study was to evaluate a novel collaborative care model using community pharmacies as additional access points for latent tuberculosis infection (LTBI) treatment for patients using combination weekly therapy with isoniazid and rifapentine (3HP) plus directly observed therapy for 12 weeks.. This prospective pilot study included adult patients diagnosed with LTBI. Patients were eligible for study participation if they spoke English or Spanish and were followed by the New Mexico Department of Health (NM DOH). Patients were excluded if they were pregnant, receiving concomitant HIV antiretroviral therapy, or had contraindications to 3HP due to allergy or drug interactions. Community pharmacy sites included chain, independent, and hospital outpatient pharmacies in Albuquerque and Santa Fe, New Mexico.. A total of 40 patients initiated treatment with 3HP and were included. Most were female (55%) and had a mean age of 46 years (standard deviation, 12.6 y). A total of 75.0% of patients completed LTBI treatment with 3HP in a community pharmacy site. Individuals of Hispanic ethnicity were more likely to complete treatment (76.7% vs 40.0%, P = .04). Most patients (60%; n = 24) reported experiencing an adverse drug event (ADE) with 3HP therapy. Patients who completed treatment were less likely to experience an ADE than patients who discontinued treatment (50.0% vs 90.0%, P = .03). Pharmacists performed 398 LTBI treatment visits (40 initial visits, 358 follow-up visits), saving the NM DOH approximately 143 hours in patient contact time.. High completion rates and safe administration of LTBI treatment can be achieved in the community pharmacy setting.

Topics: Adult; Antibiotics, Antitubercular; Drug Therapy, Combination; Feasibility Studies; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; New Mexico; Pharmacies; Pilot Projects; Prospective Studies; Public Health; Rifampin

China is one of the countries with a high burden of tuberculosis (TB) and latent tuberculosis infection (LTBI). It was recently estimated that China had the highest LTBI burden in the world, with approximately 350 million persons living with the infection. The prevalence of LTBI in China is overestimated by tuberculin skin test (TST) as compared to interferon-gamma release assay (IGRA). A population-based study found that IGRA positivity rates ranged between 13.5% and 19.8%. The annual TB infection rate in the rural population was 1.5% based on persistent positive IGRA results in converters. The development of active TB from LTBI in the general rural population was 0.87 per 100 person-years in the first 2 years among individuals who newly converted to IGRA-positive. TB control in students has been paid more attention by the government, which also improved LTBI management among students in close contact with active TB patients. A 3-month regimen of twice-weekly rifapentine plus isoniazid (3H

Topics: Antitubercular Agents; China; Humans; Incidence; Interferon-gamma Release Tests; Isoniazid; Latent Tuberculosis; Prevalence; Rifampin; Rural Population; Tuberculin Test; Tumor Necrosis Factor-alpha

To estimate the cost of a screening program for identifying latent tuberculosis (TB) infections in migrants to Oman.. A Markov model was used to estimate the cost of screening using an interferon-gamma release assay (IGRA) applied to all migrants from high TB endemic countries, followed by preventive TB treatment.. The model compared seven different scenarios, with a comparison of the direct cost and the quality-adjusted life-years (QALYs) saved.. IGRA testing followed by 3 months of preventive treatment with rifapentine/isoniazid (3HP) was the most cost-effective intervention.

Topics: Cost-Benefit Analysis; Female; Humans; Interferon-gamma Release Tests; Isoniazid; Latent Tuberculosis; Markov Chains; Mass Screening; Oman; Quality-Adjusted Life Years; Rifampin; Transients and Migrants; Tuberculosis

We analyzed data from 2012 to 2016 for patients who were hospitalized or who died after ≥1 dose of isoniazid-rifapentine for treatment of latent Mycobacterium tuberculosis infection. No patients died; 15 were hospitalized. Nine patients experienced hypotension, and 5 had elevated serum aminotransferases, reinforcing the need for vigilant monitoring during treatment.

Topics: Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Rifampin; United States

This study aimed to develop and evaluate a sustained drug delivery system for the treatment of osteoarticular tuberculosis (TB) to address the issues surrounding low drug concentration in lesions and bone defects or nonunion after debridement.. The effects of rifapentine on the proliferation and cell cycle of bone marrow mesenchymal stem cells (BMSCs) were evaluated by Cell Counting Kit-8 (CCK-8) and flow cytometry. Rifapentine polylactic acid (PLA) sustained-release microspheres (RPSMs) were prepared through the double emulsion solvent evaporation method and investigated the antibacterial activity in vitro. In this study, two sustained drug delivery systems were prepared by integrating RPSMs and BMSCs into hydroxyapatite/β-tricalcium phosphate (HA/β-TCP) or allogeneic bone. We evaluated these drug delivery systems for dynamics of drug release and osteogenic ability by in vitro release test, alkaline phosphatase (ALP) and alizarin red staining, and real-time PCR.. The results showed that rifapentine concentrations up to 45.0 μg/mL had no effect on cell proliferation and cell cycle. The encapsulation and drug loading efficiency of the fabricated RPSMs were 78.11%±1.16% and 35.57%±0.85%, respectively. The RPSMs had uniform particle size distribution and a long-term anti-bacterium effect. The HA/β-TCP-implanted drug delivery system was found to be more effective in reducing the burst release and having a longer duration of sustained release and retention compared to allogeneic bone. The ALP and alizarin red staining and real-time PCR results showed that it had excellent osteoconductive and osteoinductive properties.. In conclusion, the sustained drug delivery system with HA/β-TCP as scaffold material represents a potential new strategy for TB infections and bone defects.

Topics: Animals; Antitubercular Agents; Cell Differentiation; Cell Proliferation; Delayed-Action Preparations; Drug Delivery Systems; Flow Cytometry; Mesenchymal Stem Cells; Osteogenesis; Rabbits; Rifampin; Tuberculosis, Osteoarticular

Topics: Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Isoniazid; Oxazines; Piperazines; Pyridones; Rifampin; Tuberculosis

The detection and treatment of latent tuberculosis infection (LTBI) is a key step in eliminating tuberculosis (TB), but information on safety and on treatment interruption in elderly LTBI patients remains limited.. This multicenter prospective observational study included individuals with LTBI who underwent preventive therapy. Incidents of systemic adverse reactions (SARs) and treatment interruption rates in an elderly group (≥60 years old) and a young group (<60 years old) were analyzed.. A total of 406 LTBI patients, comprising 167 elderly and 239 young patients, were included in the analyses. The incidence of SARs was similar in the elderly group (18%) and the young group (15.1%). Being middle-aged (35-59 years), body mass index <23 kg/m. The occurrence of SARs was similar in the elderly (≥60 years old) and young (<60 years old) LTBI patients receiving preventive therapy. Extremely old (≥80 years old) LTBI patients had a higher treatment interruption rate, especially when they had SARs.

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Incidence; Isoniazid; Kidney Failure, Chronic; Latent Tuberculosis; Male; Middle Aged; Prospective Studies; Rifampin; Taiwan

Topics: Humans; Isoniazid; Latent Tuberculosis; Rifampin

A series of novel benzothiazinone derivatives containing a N-((methylene)amino)piperazine moiety, inspired by rifampicin/rifapentine, were designed and synthesized. Seven compounds 1a and 1e-j show excellent in vitro activity against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates (MIC: <0.029-0.110 μM), and accepted selective index (>1100->4000). Compound 1h displays good safety and pharmacokinetic profiles, suggesting its promising potential to be lead compound for future antitubercular drug discovery.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Cell Proliferation; Chlorocebus aethiops; Dose-Response Relationship, Drug; Drug Design; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Rifampin; Structure-Activity Relationship; Thiazines; Vero Cells

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with a daily combination of rifampin and either injectable streptomycin or oral clarithromycin. An intermittent oral regimen would facilitate treatment supervision. We first evaluated the bactericidal activity of newer antimicrobials against M. ulcerans using a BU animal model. The imidazopyridine amine telacebec (Q203) exhibited high bactericidal activity whereas tedizolid (an oxazolidinone closely related to linezolid), selamectin and ivermectin (two avermectine compounds) and the benzothiazinone PBTZ169 were not active. Consequently, telacebec was evaluated for its bactericidal and sterilizing activities in combined intermittent regimens. Telacebec given twice a week in combination with a long-half-life compound, either rifapentine or bedaquiline, sterilized mouse footpads in 8 weeks, i.e. after a total of only 16 doses, and prevented relapse during a period of 20 weeks after the end of treatment. These results are very promising for future intermittent oral regimens which would greatly simplify BU treatment in the field.

Topics: Animals; Antitubercular Agents; Buruli Ulcer; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Imidazoles; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Oxazolidinones; Piperidines; Pyridines; Rifampin; Tetrazoles

Owing to patient intolerance or drug interactions, alternative agents to rifampin are needed for management of staphylococcal periprosthetic joint infection. In the current study, we evaluated rifabutin, rifapentine and rifampin, with and without vancomycin, in a rat model of foreign body osteomyelitis.. Proximal tibiae were inoculated with methicillin-resistant Staphylococcus aureus (MRSA) and a Kirschner wire (K-wire) implanted in each. After 4 weeks of infection, rifampin, rifabutin, or rifapentine were administered, alone or with vancomycin. Tibiae and K-wires were cultured, and medians were reported as log10 colony-forming units (CFUs) per gram of bone or log10 CFUs per K-wire, respectively.. Rifampin, rifabutin or rifapentine administered with vancomycin yielded less MRSA from bones (0.10, 3.02, and 0.10 log10 CFUs/g, respectively) than did no treatment (4.36 log10 CFUs/g) or vancomycin alone (4.64 log10 CFUs/g) (both P ≤ .02). The K-wires of animals receiving no treatment or vancomycin monotherapy recovered medians of 1.76 and 2.91 log10 CFUs/g per K-wire, respectively. In contrast, rifampin, rifabutin and rifapentine administered with vancomycin yielded medians of 0.1 log10 CFUs per K-wire, respectively. Rifampin resistance was detected in a single animal in the rifampin monotherapy group.. Rifabutin or rifapentine with vancomycin were as active as rifampin with vancomycin against MRSA in rat foreign body osteomyelitis, suggesting that rifabutin and/or rifapentine may be alternatives to rifampin in the clinical management of staphylococcal periprosthetic joint infections.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Therapy, Combination; Foreign Bodies; Male; Methicillin-Resistant Staphylococcus aureus; Osteomyelitis; Rats; Rats, Wistar; Rifabutin; Rifampin; Staphylococcal Infections; Vancomycin

Topics: Animals; Foreign Bodies; Methicillin-Resistant Staphylococcus aureus; Osteomyelitis; Rats; Rifabutin; Rifampin

Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Rifampin; United States

Subclinical infection with Mycobacterium leprae is one potential source of leprosy transmission, and post-exposure prophylaxis (PEP) regimens have been proposed to control this source. Because PEP trials require considerable investment, we applied a sensitive variation of the kinetic mouse footpad (MFP) screening assay to aid in the choice of drugs and regimens for clinical trials.. Athymic nude mice were inoculated in the footpad (FP) with 6 x 103 viable M. leprae and treated by gastric gavage with a single dose of Rifampin (SDR), Rifampin + Ofloxacin + Minocycline (SD-ROM), or Rifapentine + Minocycline + Moxifloxacin (SD-PMM) or with the proposed PEP++ regimen of three once-monthly doses of Rifampin + Moxifloxacin (RM), Rifampin + Clarithromycin (RC), Rifapentine + Moxifloxacin (PM), or Rifapentine + Clarithromycin (PC). At various times post-treatment, DNA was purified from the FP, and M. leprae were enumerated by RLEP quantitative PCR. A regression analysis was calculated to determine the expected RLEP value if 99.9% of the bacilli were killed after the administration of each regimen. SDR and SD-ROM induced little growth delay in this highly susceptible murine model of subclinical infection. In contrast, SD-PMM delayed measurable M. leprae growth above the inoculum by 8 months. The four multi-dose regimens delayed bacterial growth for >9months post-treatment cessation.. The delay in discernable M. leprae growth post-treatment was an excellent indicator of drug efficacy for both early (3-4 months) and late (8-9 months) drug efficacy. Our data indicates that multi-dose PEP may be required to control infection in highly susceptible individuals with subclinical leprosy to prevent disease and decrease transmission.

Topics: Animals; Asymptomatic Infections; Bacterial Load; Clarithromycin; Drug Combinations; Leprostatic Agents; Leprosy; Mice; Mice, Nude; Minocycline; Moxifloxacin; Mycobacterium leprae; Post-Exposure Prophylaxis; Rifampin

The pandemic prevalence of COVID-19 has become a very serious global health issue. Scientists all over the world have been seriously attempting in the discovery of a drug to combat SARS-CoV-2. It has been found that RNA-dependent RNA polymerase (RdRp) plays a crucial role in SARS-CoV-2 replication, and thus could be a potential drug target. Here, comprehensive computational approaches including drug repurposing and molecular docking were employed to predict an effective drug candidate targeting RdRp of SARS-CoV-2. This study revealed that Rifabutin, Rifapentine, Fidaxomicin, 7-methyl-guanosine-5'-triphosphate-5'-guanosine and Ivermectin have a potential inhibitory interaction with RdRp of SARS-CoV-2 and could be effective drugs for COVID-19. In addition, virtual screening of the compounds from ZINC database also allowed the prediction of two compounds (ZINC09128258 and ZINC09883305) with pharmacophore features that interact effectively with RdRp of SARS-CoV-2, indicating their potentiality as effective inhibitors of the enzyme. Furthermore, ADME analysis along with analysis of toxicity was also undertaken to check the pharmacokinetics and drug-likeness properties of the two compounds. Comparative structural analysis of protein-inhibitor complexes revealed that the amino acids Y32, K47, Y122, Y129, H133, N138, D140, T141, S709 and N781 are crucial for drug surface hotspot in the RdRp of SARS-CoV-2.

Topics: Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Repositioning; Fidaxomicin; Humans; Ivermectin; Molecular Docking Simulation; Pandemics; Pneumonia, Viral; Rifabutin; Rifampin; RNA-Dependent RNA Polymerase; SARS-CoV-2; Virus Replication

Aldosterone-producing adenoma (APA) is a main cause of primary aldosteronism (PA). Given that a large benign-appearing unilateral masse (>1 cm in diameter) may represent an aldosterone and cortisol-co-secreting adenoma, dexamethasone suppression testing is required in such patients to exclude or confirm the diagnosis of hypercortisolism. Tuberculosis is highly prevalent in China, and rifamycins are often used in these patients. Rifapentine belongs to the rifamycin family, and we herein for the first time report a case of misdiagnosis of hypercortisolism due to rifapentine use in a patient with APA. Thus, in patients treated with rifapentine, diagnosis of hypercortisolism based on dexamethasone suppression tests can be very misleading.

Topics: Cushing Syndrome; Diagnostic Errors; Humans; Hyperaldosteronism; Male; Middle Aged; Pituitary-Adrenal Function Tests; Rifampin

Preventive therapy is essential for reducing tuberculosis (TB) burden among people living with HIV (PLWH) in high-burden settings. Short-course preventive therapy regimens, such as three-month weekly rifapentine and isoniazid (3HP) and one-month daily rifapentine and isoniazid (1HP), may help facilitate uptake of preventive therapy for latently infected patients, but the comparative cost-effectiveness of these regimens under different conditions is uncertain.. We used a Markov state-transition model to estimate the incremental costs and effectiveness of 1HP versus 3HP in a simulated cohort of patients attending an HIV clinic in Uganda, as an example of a low-income, high-burden setting in which TB preventive therapy might be prescribed to PLWH. Our primary outcome was the incremental cost-effectiveness ratio, expressed as 2019 US dollars per disability-adjusted life year (DALY) averted. We estimated cost-effectiveness under different conditions of treatment completion and efficacy of 1HP versus 3HP, latent TB prevalence and rifapentine price.. Assuming equivalent clinical outcomes using 1HP and 3HP and a rifapentine price of $0.21 per 150 mg, 1HP would cost an additional $4.66 per patient treated. Assuming equivalent efficacy but 20% higher completion with 1HP versus 3HP, 1HP would cost $1,221 per DALY averted relative to 3HP. This could be reduced to $18 per DALY averted if 1HP had 5% greater efficacy than 3HP and the price of rifapentine were 50% lower. At a rifapentine price of $0.06 per 150 mg, 1HP would become cost-neutral relative to 3HP.. 1HP has the potential to be cost-effective under many realistic circumstances. Cost-effectiveness depends on rifapentine price, relative completion and efficacy, prevalence of latent TB and local willingness-to-pay.

Topics: Anti-HIV Agents; Antitubercular Agents; Cost-Benefit Analysis; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Quality-Adjusted Life Years; Rifampin; Tuberculosis; Uganda

Tuberculosis (TB) is a leading cause of death amongst infectious diseases. The poor response to antitubercular agents necessitates the long-term use of high drug doses, resulting in low patient compliance, which is the main reason for chemotherapy failure and contributes to the development of multidrug-resistant TB. Patient non-compliance has been a major obstacle in the successful management of TB. The aim of this work was to develop and characterise rifapentine (RPT)-loaded PLGA-based nanoparticles (NPs) for reducing dosing frequency.. RPT-loaded PLGA and PLGA-PEG NPs were prepared using premix membrane homogenisation combined with solvent evaporation method. The resulting NPs were characterised in terms of physicochemical characteristics, toxicity, cellular uptake and antitubercular activity. NPs were further evaluated for pharmacokinetic and biodistribution studies in mice.. The application of PLGA-based NPs as sustained-release delivery vehicles for RPT could prolong drug release, modify pharmacokinetics, increase antitubercular activity and diminish toxicity, thereby allowing low dosage and frequency.

Topics: Administration, Oral; Animals; Antitubercular Agents; Drug Carriers; Drug Delivery Systems; Drug Liberation; Hemolysis; Humans; Macrophages; Male; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nanoparticles; Particle Size; Polyesters; Polyethylene Glycols; Prostaglandins A; Rifampin; Tissue Distribution

Topics: Anti-Bacterial Agents; Biological Transport; Cell Membrane; DNA-Directed RNA Polymerases; Gram-Negative Bacteria; Hydrophobic and Hydrophilic Interactions; Models, Chemical; Molecular Conformation; Permeability; Rifampin; Rifamycins; Structure-Activity Relationship; Water

Topics: HIV; Humans; Isoniazid; Rifampin; Tuberculosis

Topics: HIV; Humans; Isoniazid; Rifampin; Tuberculosis

Weekly rifapentine and isoniazid therapy (3HP) is the most frequent treatment for latent tuberculosis infection (LTBI). However, the association between major adverse drug reactions (ADRs) and drug metabolic enzyme single-nucleotide polymorphisms (SNPs) remains unclear. In this study, 377 participants who received the 3HP regimen were recruited and examined for genotyping of CYP5A6, CYP2B6, CYP2C19, CYP2E1, and NAT2 SNPs. In our study, 184 participants (48.4%) developed ADRs. Moreover, CYP2C19 rs4986893 (TT vs. CC+CT, odds ratio [OR] [95% CI]: 2.231 [1.015-4.906]), CYP2E1 rs2070676 (CC vs. CG+GG, OR [95% CI]: 1.563 [1.022-2.389]), and CYP2E1 rs2515641 (CC vs. CT+TT, OR [95% CI]: 1.903 [1.250-2.898]) were associated with ADR development. In conclusion, CYP2C19 and CYP2E1 SNPs may provide useful information regarding ADRs in LTBI patients receiving the 3HP regimen.

Topics: Adult; Antitubercular Agents; Arylamine N-Acetyltransferase; Cytochrome P-450 Enzyme System; Drug Administration Schedule; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Odds Ratio; Polymorphism, Single Nucleotide; Rifampin

The consequences of once-weekly rifapentine plus isoniazid for 3 months (3HP) against latent tuberculosis infections in hemodialysis patients have not been studied before. This is the first study to evaluate the safety and tolerability of 3HP in this population and revealed a completion rate of 65.4%. The therapy was not associated with hepatotoxicity, but with high rates of adverse events (69.2%).

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Isoniazid; Kidney Failure, Chronic; Latent Tuberculosis; Male; Middle Aged; Renal Dialysis; Rifampin; Safety

Latent tuberculosis infection (LTBI) is a critical driver of the global burden of active TB, and therefore LTBI treatment is key for TB elimination. Treatment regimens for LTBI include self-administered daily isoniazid for 6 (6H) or 9 (9H) months, self-administered daily rifampicin plus isoniazid for 3 months (3RH), self-administered daily rifampicin for 4 months (4R) and weekly rifapentine plus isoniazid for 3 months self-administered (3HP-SAT) or administered by a healthcare worker as directly observed therapy (3HP-DOT). Data on the relative cost-effectiveness of these regimens are needed to assist policymakers and clinicians in selecting an LTBI regimen.. To evaluate the cost-effectiveness of all regimens for treating LTBI.. We developed a Markov model to investigate the cost-effectiveness of 3HP-DOT, 3HP-SAT, 4R, 3RH, 9H and 6H for LTBI treatment in a cohort of 10000 adults with LTBI. Cost-effectiveness was evaluated from a health system perspective over a 20 year time horizon.. Compared with no preventive treatment, 3HP-DOT, 3HP-SAT, 4R, 3RH, 9H and 6H prevented 496, 470, 442, 418, 370 and 276 additional cases of active TB per 10000 patients, respectively. All regimens reduced costs and increased QALYs compared with no preventive treatment. 3HP was more cost-effective under DOT than under SAT at a cost of US$27948 per QALY gained.. Three months of weekly rifapentine plus isoniazid is more cost-effective than other regimens. Greater recognition of the benefits of short-course regimens can contribute to the scale-up of prevention and achieving the 'End TB' targets.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Cost-Benefit Analysis; Decision Support Techniques; Drug Therapy, Combination; Female; Health Care Costs; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Rifampin; Young Adult

Poor-quality medicines undermine the treatment of infectious diseases, such as tuberculosis, which require months of treatment with rifampin and other drugs. Rifampin resistance is a critical concern for tuberculosis treatment. While subtherapeutic doses of medicine are known to select for antibiotic resistance, the effect of drug degradation products on the evolution of resistance is unknown. Here, we demonstrate that substandard drugs that contain degraded active pharmaceutical ingredients select for gene alterations that confer resistance to standard drugs. We generated drug-resistant

Topics: Antibiotics, Antitubercular; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Proteins; Humans; Microbial Sensitivity Tests; Mycobacterium smegmatis; Rifabutin; Rifampin; RNA Polymerase II; Substandard Drugs

Topics: Adolescent; Adult; Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Retrospective Studies; Rifampin; Risk; Treatment Outcome; Young Adult

Low drug concentration in the tuberculosis (TB) lesion and bone defects or nonunion after debridement are two major problems that occur in the course of treating osteo-articular TB. Thus, the combination of drug-delivery system and bone tissue repair appears to be the most promising option for osteoarticular TB treatment.. Herein, we report a novel anti-TB dual delivery system based on rifapentine polylactic acid microspheres (RPMs) to treat infections, with the addition of adipose-derived mesenchymal stem cells (ASCs) seeded in hydroxyapatite/tricalcium phosphate (HA/TCP) to promote bone formation. Cell proliferation, osteogenesis, and apoptosis were performed to investigate the effects of rifapentine on ASCs. The RPMs were synthesized by emulsion-solvent evaporation method, and then the monolayer composite (ASC + RPM) and three-dimensional (3D) composite scaffold (ASC + RPM + HA/TCP) were constructed, respectively. The alkaline phosphatase (ALP) activity and real-time PCR were used for determining the osteogenic differentiation. The concentrations of rifapentine resulting from the composites were detected.. The results showed that rifapentine has no influence on ASCs proliferation and osteogenesis when the drug concentration was below 20 µg/mL, which was significantly higher than minimal inhibitory concentration. The drug loading and encapsulation efficiency of RPMs were 40.56%±2.63% and 70.24%±2.18%, respectively. The proliferation of the cells in monolayer was higher than that in 3D composite, and the addition of RPMs slightly increased the proliferation. The ALP activity and gene expression of osteocalcin and osteopontin were higher in the 3D composite than those in the monolayer. Good biocompatibility was observed by microscopic image and H&E stain. The release tests revealed that the 3D composite exhibited sustained release profiles of rifapentine for 76 days. The dual delivery systems in 3D composite could moderate the burst release and extend the length of release time when compared to single delivery in monolayers.. In conclusion, such dual delivery antituberculotic scaffold represents a potential new strategy for TB infections and bone defects.

Topics: Adipocytes; Animals; Antitubercular Agents; Calcium Phosphates; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Drug Delivery Systems; Durapatite; Female; Microspheres; Particle Size; Rabbits; Rifampin; Structure-Activity Relationship; Surface Properties

Topics: HIV; Humans; Isoniazid; Rifampin; Tuberculosis

Topics: Aged; Antitubercular Agents; Humans; Isoniazid; Latent Tuberculosis; Rifampin

Clofazimine and high-dose rifapentine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of clofazimine and the replacement of rifampin with high-dose rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where rifapentine and clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose rifapentine and adding clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a rifapentine- and clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose rifapentine and clofazimine in clinical trials.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Clofazimine; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Rifampin; Tuberculosis

As part of the End TB Strategy, the World Health Organization calls for low-tuberculosis (TB) incidence settings to achieve pre-elimination (<10 cases per million) and elimination (<1 case per million) by 2035 and 2050, respectively. These targets require testing and treatment for latent tuberculosis infection (LTBI).. To estimate the ability and costs of testing and treatment for LTBI to reach pre-elimination and elimination targets in California.. We created an individual-based epidemic model of TB, calibrated to historical cases. We evaluated the effects of increased testing (QuantiFERON-TB Gold) and treatment (three months of isoniazid and rifapentine). We analyzed four test and treat targeting strategies: (1) individuals with medical risk factors (MRF), (2) non-USB, (3) both non-USB and MRF, and (4) all Californians. For each strategy, we estimated the effects of increasing test and treat by a factor of 2, 4, or 10 from the base case. We estimated the number of TB cases occurring and prevented, and net and incremental costs from 2017 to 2065 in 2015 U.S. dollars. Efficacy, costs, adverse events, and treatment dropout were estimated from published data. We estimated the cost per case averted and per quality-adjusted life year (QALY) gained.. In the base case, 106,000 TB cases are predicted to 2065. Pre-elimination was achieved by 2065 in three scenarios: a 10-fold increase in the non-USB and persons with MRF (by 2052), and 4- or 10-fold increase in all Californians (by 2058 and 2035, respectively). TB elimination was not achieved by any intervention scenario. The most aggressive strategy, 10-fold in all Californians, achieved a case rate of 8 (95% UI 4-16) per million by 2050. Of scenarios that reached pre-elimination, the incremental net cost was $20 billion (non-USB and MRF) to $48 billion. These had an incremental cost per QALY of $657,000 to $3.1 million. A more efficient but somewhat less effective single-lifetime test strategy reached as low as $80,000 per QALY.. Substantial gains can be made in TB control in coming years by scaling-up current testing and treatment in non-USB and those with medical risks.

Topics: Algorithms; Antitubercular Agents; Calibration; California; Computer Simulation; Cost-Benefit Analysis; Disease Eradication; Epidemics; Humans; Incidence; Isoniazid; Mass Screening; Quality-Adjusted Life Years; Rifampin; Risk Factors; Stochastic Processes; Tuberculin Test; Tuberculosis; World Health Organization

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Buruli Ulcer; Clarithromycin; Clofazimine; Disease Models, Animal; Drug Resistance, Bacterial; Drug Therapy, Combination; Electron Transport; Humans; Imidazoles; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium ulcerans; Piperidines; Pyridines; Rifampin; Streptomycin

In the province of Manitoba, Canada, given that latent tuberculosis infection (LTBI) treatment is provided at no cost to the patient, treatment completion rates should be optimal. The objective of this study was to estimate LTBI treatment completion using prescription drug administrative data and identify patient characteristics associated with completion.. Prescription drug data (1999-2014) were used to identify individuals dispensed isoniazid (INH) or rifampin (RIF) monotherapy. Treatment completion was defined as being dispensed INH for ≥ 180 days (INH180) or ≥ 270 days (INH270) or RIF for ≥ 120 days (RIF120). Logistic regression models tested socio-demographic and comorbidity characteristics associated with treatment completion.. The study cohort comprised 4985 (90.4%) persons dispensed INH and 529 (9.6%) RIF. Overall treatment completion was 60.2% and improved from 43.1% in 1999-2003 to 67.3% in 2009-2014. INH180 showed the highest completion (63.8%) versus INH270 (40.4%) and RIF120 (27.0%). INH180 completion was higher among those aged 0-18 years (68.5%) compared with those aged 19+ (61.0%). Sex, geography, First Nations status, income quintile, and comorbidities were not associated with completion.. Benchmark 80% treatment completion rates were not achieved in Manitoba. Factors associated with non-completion were older age, INH270, and RIF120. Access to shorter LTBI treatments, such as rifapentine/INH, may improve treatment completion.

Topics: Adolescent; Adult; Age Factors; Aged; Antitubercular Agents; Child; Child, Preschool; Databases, Factual; Female; Humans; Infant; Infant, Newborn; Isoniazid; Latent Tuberculosis; Male; Manitoba; Middle Aged; Prescription Drugs; Rifampin; Treatment Adherence and Compliance; Young Adult

A 76-year-old woman was admitted to the hospital four times from November 2007 to June 2009. In this complex case, the patient had silicosis complicated by broncholithiasis, oesophagobronchial fistulas, and relapsed tuberculosis. She had worked as a stone crusher for 3 years and was exposed to a large amount of quartz dust. Barium oesophagography, gastroesophageal endoscopy, and biopsy suggested oesophageal-related chronic inflammation and ulceration, which may have caused the repeated oesophagobronchial fistulas. Bronchoscopy revealed a free broncholithiasis in the left mainstem bronchus. The patient was admitted a fourth time because of silicotuberculosis relapse. After 9 months of antituberculosis treatment, the patient recovered and was still clinically well at the time of this writing.

Topics: Aged; Antibiotics, Antitubercular; Bronchial Fistula; Esophageal Fistula; Esophagoscopy; Female; Humans; Isoniazid; Lithiasis; Pyrazinamide; Rifampin; Silicotuberculosis; Stents; Treatment Outcome

The efficacy of rifapentine, an oral antibiotic used to treat tuberculosis, may be reduced due to degradation at gastric pH and low solubility at intestinal pH. We hypothesized that delivery properties would be improved in vitro by incorporating rifapentine into pH-responsive amorphous solid dispersions (ASDs) with cellulose derivatives including: hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate suberate (CASub), and 5-carboxypentyl hydroxypropyl cellulose (CHC). ASDs generally reduced rifapentine release at gastric pH, with CASub affording >31-fold decrease in area under the curve (AUC) compared to rifapentine alone. Critically, reduced gastric dissolution was accompanied by reduced degradation to 3-formylrifamycin. Certain ASDs also enhanced apparent solubility and stabilization of supersaturated solutions at intestinal pH, with HPMCAS providing nearly 4-fold increase in total AUC vs. rifapentine alone. These results suggest that rifapentine delivery via ASD with these cellulosic polymers may improve bioavailability in vivo.

Topics: Antibiotics, Antitubercular; Cellulose; Drug Carriers; Drug Delivery Systems; Humans; Hydrogen-Ion Concentration; Methylcellulose; Molecular Conformation; Rifampin; Solubility

Filarial parasites can be targeted by antibiotic treatment due to their unique endosymbiotic relationship with Wolbachia bacteria. This finding has led to successful treatment strategies in both, human onchocerciasis and lymphatic filariasis. A 4-6 week treatment course using doxycycline results in long-term sterility and safe macrofilaricidal activity in humans. However, current treatment times and doxycycline contraindications in children and pregnant women preclude widespread administration of doxycycline in public health control programs; therefore, the search for shorter anti-wolbachial regimens is a focus of ongoing research. We have established an in vivo model for compound screening, using mice infected with Litomosoides sigmodontis. We could show that gold standard doxycycline treatment did not only deplete Wolbachia, it also resulted in a larval arrest. In this model, combinations of registered antibiotics were tested for their anti-wolbachial activity. Administration of rifamycins in combination with doxycycline for 7 days successfully depleted Wolbachia by > 2 log (>99% reduction) and thus resulted in a significant reduction of the treatment duration. Using a triple combination of a tetracycline (doxycycline or minocycline), a rifamycin and a fluoroquinolone (moxifloxacin) led to an even greater shortening of the treatment time. Testing all double combinations that could be derived from the triple combinations revealed that the combination of rifapentine (15mg/kg) and moxifloxacin (2 x 200mg/kg) showed the strongest reduction of treatment time in intraperitoneal and also oral administration routes. The rifapentine plus moxifloxacin combination was equivalent to the triple combination with additional doxycycline (>99% Wolbachia reduction). These investigations suggest that it is possible to shorten anti-wolbachial treatment times with combination treatments in order to achieve the target product profile (TPP) requirements for macrofilaricidal drugs of no more than 7-10 days of treatment.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Therapy, Combination; Filariasis; Filarioidea; Fluoroquinolones; Mice; Moxifloxacin; Rifampin; Tetracyclines; Time Factors; Treatment Outcome; Wolbachia

The traditional treatment of tuberculosis (TB) infection (9 months of daily isoniazid [9H]) is safe but completion rates of <50% are reported. Shorter regimens (3 months of once-weekly isoniazid and rifapentine [3HP] or 4 months of daily rifampin [4R]) are associated with improved adherence in adults.. This was a retrospective cohort study (2014-2017) of children (0-18 years old) seen at a children's TB clinic in a low-incidence nation. We compared the frequency of completion and adverse events (AEs) in children receiving 3HP, 4R, and 9H; the latter 2 regimens could be administered by families (termed self-administered therapy [SAT]) or as directly observed preventive therapy (DOPT); 3HP was always administered under DOPT.. TB infection treatment was started in 667 children: 283 (42.4%) 3HP, 252 (37.8%) 9H, and 132 (19.8%) 4R. Only 52% of children receiving 9H via SAT completed therapy. Children receiving 3HP were more likely to complete therapy than the 9H (SAT) group (odds ratio [OR] 27.4, 95% confidence interval [CI]: 11.8-63.7). Multivariate analyses found receipt of medication under DOPT (OR: 5.72, 95% CI: 3.47-9.43), increasing age (OR: 1.09, 95% CI: 1.02-1.17), and the absence of any AE (OR: 1.70, 95% CI: 0.26-0.60) to be associated with completing therapy. AEs were more common in the 9H group (OR: 2.51, 95% CI: 1.48-4.32). Two (0.9%) children receiving 9H developed hepatotoxicity; no child receiving 3HP or 4R developed hepatotoxicity.. Shorter regimens are associated with increased completion rates and fewer AEs than 9H.

Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Isoniazid; Male; Medication Adherence; Retrospective Studies; Rifampin; Texas; Tuberculosis

A short-course regimen of 3 months of weekly rifapentine and isoniazid (3HP) has recently been recommended by the World Health Organization as an alternative to at least 6 months of daily isoniazid (isoniazid preventive therapy [IPT]) for prevention of tuberculosis (TB). The contexts in which 3HP may be cost-effective compared to IPT among people living with human immunodeficiency virus are unknown.. We used a Markov state transition model to estimate the incremental cost-effectiveness of 3HP relative to IPT in high-burden settings, using a cohort of 1000 patients in a Ugandan HIV clinic as an emblematic scenario. Cost-effectiveness was expressed as 2017 US dollars per disability-adjusted life year (DALY) averted from a healthcare perspective over a 20-year time horizon. We explored the conditions under which 3HP would be considered cost-effective relative to IPT.. Per 1000 individuals on antiretroviral therapy in the reference scenario, treatment with 3HP rather than IPT was estimated to avert 9 cases of TB and 1 death, costing $9402 per DALY averted relative to IPT. Cost-effectiveness depended strongly on the price of rifapentine, completion of 3HP, and prevalence of latent TB. At a willingness to pay of $1000 per DALY averted, 3HP is likely to be cost-effective relative to IPT only if the price of rifapentine can be greatly reduced (to approximately $20 per course) and high treatment completion (85%) can be achieved.. 3HP may be a cost-effective alternative to IPT in high-burden settings, but cost-effectiveness depends on the price of rifapentine, achievable completion rates, and local willingness to pay.

Topics: Anti-HIV Agents; Antitubercular Agents; Cost-Benefit Analysis; Drug Therapy, Combination; HIV Infections; Humans; Isoniazid; Markov Chains; Rifampin; Tuberculosis

Preclinical treatment outcome evaluation of tuberculosis (TB) occurs primarily in mice. Current designs compare relapse rates of different regimens at selected time points, but lack information about the correlation between treatment length and treatment outcome, which is required to efficiently estimate a regimens' treatment-shortening potential. Therefore we developed a new approach. BALB/c mice were infected with a Mycobacterium tuberculosis Beijing genotype strain and were treated with rifapentine-pyrazinamide-isoniazid-ethambutol (R

Topics: Administration, Oral; Animals; Antitubercular Agents; Disease Models, Animal; Drug Therapy, Combination; Ethambutol; Female; Genotype; Humans; Mice; Mice, Inbred BALB C; Models, Theoretical; Moxifloxacin; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

Topics: Aged; Antitubercular Agents; Arthritis, Rheumatoid; Drug Administration Schedule; Drug Therapy, Combination; Feasibility Studies; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Rifampin

In this work, we studied the effects of the N-alkyl group (methyl, cyclopentyl) in the piperazine ring of, respectively, rifampicin (RIF) and rifapentine (RPT) to correlate this substitution with their differential pharmacokinetic properties and overall clinical performance. Since this group is their only structural change, and given that they share the same pharmacological target, differences in their therapeutic behavior may respond to this asset, particularly in their interaction with lipid membranes across the organism. In this study, surface pressure-area isotherms, as well as spectroscopic and microscopic techniques of characterization of phospholipid monolayers at the air/water interface were used to gain insight into drug-membrane interactions. Differences in the affinity for lipid membranes for both drugs, given by the vibration frequency of characteristic chemical groups in the lipid, as well as by reflectivity and mean molecular area of the monolayer, seem to be due to the N-alkyl substituent and can contribute to provide a molecular explanation as why they pose different choices in the chemotherapy against the deadliest infectious disease, tuberculosis.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Membranes, Artificial; Microscopy; Piperazine; Piperazines; Pressure; Rifampin; Rifamycins; Spectrum Analysis; Temperature; Vibration

Treatment of latent tuberculosis infection (LTBI) is critical to the control and elimination of tuberculosis disease (TB) in the United States. In 2011, CDC recommended a short-course combination regimen of once-weekly isoniazid and rifapentine for 12 weeks (3HP) by directly observed therapy (DOT) for treatment of LTBI, with limitations for use in children aged <12 years and persons with human immunodeficiency virus (HIV) infection (1). CDC identified the use of 3HP in those populations, as well as self-administration of the 3HP regimen, as areas to address in updated recommendations. In 2017, a CDC Work Group conducted a systematic review and meta-analyses of the 3HP regimen using methods adapted from the Guide to Community Preventive Services. In total, 19 articles representing 15 unique studies were included in the meta-analysis, which determined that 3HP is as safe and effective as other recommended LTBI regimens and achieves substantially higher treatment completion rates. In July 2017, the Work Group presented the meta-analysis findings to a group of TB experts, and in December 2017, CDC solicited input from the Advisory Council for the Elimination of Tuberculosis (ACET) and members of the public for incorporation into the final recommendations. CDC continues to recommend 3HP for treatment of LTBI in adults and now recommends use of 3HP 1) in persons with LTBI aged 2-17 years; 2) in persons with LTBI who have HIV infection, including acquired immunodeficiency syndrome (AIDS), and are taking antiretroviral medications with acceptable drug-drug interactions with rifapentine; and 3) by DOT or self-administered therapy (SAT) in persons aged ≥2 years.

Topics: Adolescent; Antibiotics, Antitubercular; Centers for Disease Control and Prevention, U.S.; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Rifampin; United States

Anti-tuberculosis formulations necessitate uninterrupted treatment to cure tuberculosis (TB), but are characterised by suboptimal adherence, which jeopardises therapeutic efficacy. Long-acting injectable (LAI) formulations or implants could address these associated issues.. niazid, rifapentine, bedaquiline and delamanid-in adults for treatment for latent tuberculous infection (LTBI).. PBPK models were developed and qualified against available clinical data by integrating drug physicochemical properties and in vitro and population pharmacokinetic data into a mechanistic description of drug distribution. Combinations of optimal dose and release rates were simulated such that plasma concentrations were maintained over the epidemiological cut-off or minimum inhibitory concentration for the dosing interval.. The PBPK model identified 1500 mg of delamanid and 250 mg of rifapentine as sufficient doses for monthly intramuscular administration, if a formulation or device can deliver the required release kinetics of 0.001-0.0025 h-1 and 0.0015-0.0025 h-1, respectively. Bedaquiline and isoniazid would require weekly to biweekly intramuscular dosing.. We identified the theoretical doses and release rates of LAI anti-tuberculosis formulations. Such a strategy could ease the problem of suboptimal adherence provided the associated technological complexities for LTBI treatment are addressed.

Topics: Adolescent; Adult; Antitubercular Agents; Diarylquinolines; Drug Administration Schedule; Drug Liberation; Drug Therapy, Combination; Female; Humans; Injections, Intramuscular; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Nitroimidazoles; Oxazoles; Proof of Concept Study; Rifampin; Treatment Outcome; Young Adult

Successful treatment of latent tuberculosis infection (LTBI) is essential to reduce tuberculosis (TB) incidence rates in low-burden countries. This study measures treatment completion and determinants of non-completion of LTBI treatment in Norway in 2016.. This prospective cohort study included all individuals notified with LTBI treatment to the Norwegian Surveillance System for Infectious Diseases (MSIS) in 2016. We obtained data from MSIS and from a standardized form that was sent to health care providers at the time of patient notification to MSIS. We determined completion rates. Pearson's chi squared test was used to study associations between pairs of categorical variables and separate crude and multivariable logistic regression models were used to identify factors associated with treatment completion and adverse drug effects.. We obtained information on treatment completion from 719 of the 726 individuals notified for LTBI treatment in 2016. Overall, 91% completed treatment. Treatment completion was highest in the foreign-born group [foreign-born, n = 562 (92%) vs Norwegian-born, n = 115 (85%), p = 0.007]. Treatment completion did not differ significantly between prescribed regimens (p = 0.124). Adverse events were the most common reason for incomplete treatment. We found no significant differences in adverse events when comparing weekly rifapentine (3RPH) with three months daily isoniazid and rifampicin (3RH). However, there were significantly fewer adverse events with 3RPH compared to other regimens (p = 0.037). Age over 35 years was significantly associated with adverse events irrespective of regimen (p = 0.024), whereas immunosuppression was not significantly associated with adverse events after adjusting for other variables (p = 0.306). Treatment under direct observation had a significant effect on treatment completion for foreign-born (multivariate Wald p-value = 0.017), but not for Norwegian-born (multivariate Wald p-value = 0.408) individuals.. We report a very high treatment completion rate, especially among individuals from countries with high TB incidence. The follow-up from tuberculosis-coordinators and the frequent use of directly observed treatment probably contributes to this. Few severe adverse events were reported, even with increased age and in individuals that are more susceptible. While these results are promising, issues of cost-effectiveness and targeting treatment to individuals at highest risk of TB are important components of public health impact.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Child; Child, Preschool; Female; Humans; Incidence; Isoniazid; Latent Tuberculosis; Male; Medication Adherence; Middle Aged; Norway; Prospective Studies; Rifampin; Young Adult

Since January 2013, the New York City (NYC) Health Department Tuberculosis (TB) Program has offered persons diagnosed with latent TB infection (LTBI) the 3-month, once-weekly isoniazid and rifapentine (3HP) treatment regimen. Patients on this treatment are monitored in-person under directly observed therapy (DOT). To address patient and provider barriers to in-person DOT, we piloted the use of a videoconferencing software app to remotely conduct synchronous DOT (video directly observed therapy; VDOT) for patients on 3HP.. The objective of our study was to evaluate the implementation of VDOT for patients on 3HP and to assess whether treatment completion for these patients increased when they were monitored using VDOT compared with that using the standard in-person DOT.. Between February and October 2015, patients diagnosed with LTBI at any of the four NYC Health Department TB clinics who met eligibility criteria for treatment with 3HP under VDOT (V3HP) were followed until 16 weeks after treatment initiation, with treatment completion defined as ingestion of 11 doses within 16 weeks. Treatment completion of patients on V3HP was compared with that of patients on 3HP under clinic-based, in-person DOT who were part of a prior study in 2013. Furthermore, outcomes of video sessions with V3HP patients were collected and analyzed.. During the study period, 70% (50/71) of eligible patients were placed on V3HP. Treatment completion among V3HP patients was 88% (44/50) compared with 64.9% (196/302) among 3HP patients on clinic DOT (P<.001). A total of 360 video sessions were conducted for V3HP patients with a median of 8 (range: 1-11) sessions per patient and a median time of 4 (range: 1-59) minutes per session. Adherence issues (eg, >15 minutes late) during video sessions occurred 104 times. No major side effects were reported by V3HP patients.. The NYC TB program observed higher treatment completion with VDOT than that previously seen with clinic DOT among patients on 3HP. Expanding the use of VDOT may improve treatment completion and corresponding outcomes for patients with LTBI.

Topics: Adult; Ambulatory Care Facilities; Antitubercular Agents; Data Collection; Directly Observed Therapy; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Rifampin; Telemedicine; Videoconferencing; Young Adult

Topics: Aged; Antitubercular Agents; Humans; Isoniazid; Latent Tuberculosis; Rifampin

Tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis and is spread from person to person through the air. TB can be spread in congregate settings, such as school environments, to varying degrees, based on factors including duration of contact and air ventilation (1); therefore, evaluating potential contacts and exposures can be challenging. In February 2015, a student at a Kansas high school received a diagnosis of active pulmonary TB disease. Screening of 385 (91%) school contacts, four (100%) household contacts, and 19 (90%) social contacts resulted in the identification of 50 persons with latent TB infection. Johnson County Department of Health and Environment (JCDHE) Public Health Emergency Preparedness personnel used their experience with points of distribution logistics to optimize testing clinic layouts and implement the incident command structure. Open communication with students, school staff members, the public, and the media about the investigation from the outset was imperative to reduce rumors and unease that can accompany a large communicable disease investigation. The large number of persons needing treatment for latent TB overwhelmed JCDHE's two TB nurses. As a result, JCDHE developed a policy and procedure to allow persons who met eligibility requirements to complete 12 weekly doses of isoniazid and rifapentine treatment using video directly observed therapy (VDOT) rather than traditional in-person directly observed therapy (DOT). This procedure facilitated treatment compliance and completion; among the eligible 15 persons who chose the 12-week VDOT option, 14 (93%) completed treatment. State and local health departments might consider use of VDOT to monitor treatment of persons with latent TB infection.

Topics: Antitubercular Agents; Contact Tracing; Directly Observed Therapy; Humans; Isoniazid; Kansas; Latent Tuberculosis; Mycobacterium tuberculosis; Patient Compliance; Rifampin; Schools; Telemedicine; Treatment Outcome; Videoconferencing

In this study, we aimed to design controlled-release microspheres for the treatment of cavitary pulmonary tuberculosis (TB) for solving the issues of poor drug delivery and short duration maintained at effective drug concentration during bronchoscopic interventional therapy. We fabricated rifapentine-linezolid-loaded poly(lactic acid-co-glycolic acid) microspheres (RLPMs) using the oil-in-water emulsion solvent evaporation method and assessed their in vitro release as well as the bronchial mucosal retention characteristics. The microspheres are spherical in shape with a circular concave on the surface. The particle size of RLPMs was 27.38±1.28 μm. The drug loading of rifapentine and linezolid was 18.51±0.26 and 8.42%±0.24%, respectively, while the encapsulation efficiencies were 55.53±0.78 and 16.87%±0.47%, respectively (n=3). During the burst release phase of the in vitro release test, 21.37%±0.68% rifapentine was released in 3 days and 43.56%±2.54% linezolid was released in 1 day. Then, both the drugs entered the sustained release phase. Finally, the cumulative percentage release of rifapentine and linezolid in 14 days was 27.61±1.52 and 51.01%±3.31%, respectively (n=3). Bronchoscopic observation revealed that the controlled-release microspheres could slowly release the drugs and retain them on the surface of bronchial mucosa of canines for 20 days. These results indicated that the fabricated microspheres exhibited a significant sustained release effect and could effectively retain the drugs on the surface of bronchial mucosa. Therefore, this study provides a theoretical and practical foundation for the development of fabricated microspheres loaded with multiple anti-TB drugs in the bronchoscopic interventional therapy of cavity pulmonary TB.

Topics: Animals; Bronchoscopy; Dogs; Female; Lactic Acid; Linezolid; Microspheres; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rifampin; Surface Properties; Tuberculosis, Pulmonary

Randomized controlled trials have demonstrated that the newest latent tuberculosis (LTBI) regimen, 12 weekly doses of directly observed isoniazid and rifapentine (3HP), is as efficacious as 9 months of isoniazid, with a greater completion rate (82% vs 69%); however, 3HP has not been assessed in routine healthcare settings.. Observational cohort of LTBI patients receiving 3HP through 16 US programs was used to assess treatment completion, adverse drug reactions, and factors associated with treatment discontinuation.. Of 3288 patients eligible to complete 3HP, 2867 (87.2%) completed treatment. Children aged 2-17 years had the highest completion rate (94.5% [155/164]). Patients reporting homelessness had a completion rate of 81.2% (147/181). In univariable analyses, discontinuation was lowest among children (relative risk [RR], 0.44 [95% confidence interval {CI}, .23-.85]; P = .014), and highest in persons aged ≥65 years (RR, 1.72 [95% CI, 1.25-2.35]; P < .001). In multivariable analyses, discontinuation was lowest among contacts of patients with tuberculosis (TB) disease (adjusted RR [ARR], 0.68 [95% CI, .52-.89]; P = .005) and students (ARR, 0.45 [95% CI, .21-.98]; P = .044), and highest with incarceration (ARR, 1.43 [95% CI, 1.08-1.89]; P = .013) and homelessness (ARR, 1.72 [95% CI, 1.25-2.39]; P = .001). Adverse drug reactions were reported by 1174 (35.7%) patients, of whom 891 (76.0%) completed treatment.. Completion of 3HP in routine healthcare settings was greater overall than rates reported from clinical trials, and greater than historically observed using other regimens among reportedly nonadherent populations. Widespread use of 3HP for LTBI treatment could accelerate elimination of TB disease in the United States.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Ill-Housed Persons; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Students; United States; Young Adult

Bone-like hydroxyapatite/poly amino acid (BHA/PAA) is a potential bone repair material. Rifapentine-loaded poly(lactic‑co‑glycolic acid) microspheres (RPMs) are bioactive and efficient controlled‑release delivery systems used in vitro. The aim of the present study was to investigate the in vivo drug release characteristics of RPM‑loaded BHA/PAA on a rabbit model of bone defect. RPM was combined with BHA/PAA to obtain the drug‑loaded, slow‑releasing bioactive material. Bone defects were generated in New Zealand white rabbits and the rabbits were then implanted with RPM‑loaded BHA/PAA. High‑performance liquid chromatography (HPLC) was used to determine the concentrations of rifapentine in the plasma and the local muscle tissues of the treated rabbits. Hematoxylin and eosin (H&E) staining and biochemical analyses were performed to elucidate potential side effects of RPM‑loaded BHA/PAA on the heart, liver and kidney histopathology and functions of the treated rabbits. The biocompatibility and osteogenic ability of RPM‑loaded BHA/PAA was evaluated by H&E staining. The results demonstrated that the material was completely degraded and absorbed at 12 weeks following implantation and new trabecular bone and cartilage tissues had formed. The in vivo release tests revealed that RPM‑loaded BHA/PAA exhibited sustained release profiles of rifapentine and the drug concentration in the muscle tissues remained higher than the minimum inhibitory concentration of rifapentine against Mycobacterium tuberculosis for as long as 12 weeks. In addition, RPM‑loaded BHA/PAA had no long‑term side effects to the heart, liver and kidney of the treated rabbits. In conclusion, the present study demonstrated that RPM‑loaded BHA/PAA slowly and continuously released rifapentine in vivo and exhibited no side effects on heart, liver and kidney tissues and function. Furthermore, RPM‑loaded BHA/PAA promoted new bone formation, while it was gradually degraded and absorbed. The present study provided a theoretical basis for the potential advancement in developing novel treatments for osteoarticular tuberculosis.

Topics: Alanine Transaminase; Amino Acids; Animals; Aspartate Aminotransferases; Blood Urea Nitrogen; Bone and Bones; Creatinine; Disease Models, Animal; Durapatite; Male; Microspheres; Organ Specificity; Rabbits; Rifampin

During active TB in humans a spectrum of pulmonary granulomas with central necrosis and hypoxia exists. BALB/c mice, predominantly used in TB drug development, do not reproduce this complex pathology thereby inaccurately predicting clinical outcome. We found that Nos2

Topics: Animals; Antitubercular Agents; Disease Models, Animal; Fibrosis; Foam Cells; Humans; Hypoxia; Isoniazid; Mice; Mice, Knockout; Necrosis; Nitric Oxide Synthase Type II; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

There are 8.6 million cases of active tuberculosis (TB) worldwide, and an estimated one-third of the world population has latent tuberculosis infection (LTBI). In the United States, up to 80% of active cases may be caused by untreated reactivated latent infection. A case of TB can spread rapidly impacting the readiness of a unit. To prevent the development of TB, it is critical that active duty service members with LTBI complete treatment. The use of isoniazid (INH) and rifapentine (RPT) as a directly observed therapy (DOT) treatment option was recommended by the Centers for Disease Control and Prevention in late 2011. Since then, there have been limited studies on the use of this treatment regimen in a civilian clinic setting and to our knowledge no studies within a military setting.. This study compares the completion rate of LTBI treatment in 2 military public health clinics, using a retrospective chart review of 179 subjects who attempted treatment with INH/RPT DOT and 186 with the non-INH/RPT non-DOT regimen.. When compared to other LTBI regimens completed or attempted in this period, completion rates were higher in INH/RPT DOT regimens. The INH/RPT DOT treatment regimen allowed enough flexibility with completion between 11 and 16 weeks for active duty service members to increase completion to 94.6%, compared to 73% in the non-INH/RPT regimen.. This project demonstrated the feasibility of INH/RPT DOT treatment within the military population resulting in a higher completion rate than the non-INH/RPT non-DOT regimen. The use of the INH/RPT DOT regimen should be considered for use in all military or similar populations.

Topics: Adolescent; Adult; Ambulatory Care Facilities; Antitubercular Agents; Directly Observed Therapy; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Military Personnel; Retrospective Studies; Rifampin; United States

The risk of infection with Mycobacterium tuberculosis among healthcare workers (HCWs) is estimated to be higher than the general population. However, HCW acceptance and compliance with available latent tuberculosis infection (LTBI) treatment regimens has been problematic. Recently, regimens have become available that might improve HCW acceptance and compliance with LTBI treatment.. A retrospective single-center review of Employee Health and Wellness Services records of all HCWs diagnosed with LTBI was conducted. HCWs diagnosed with LTBI were offered 9-month isoniazid (INH), 4-month rifampin (RIF), weekly rifapentine/isoniazid (RPT/INH) for 12 weeks, or no treatment. Acceptance, completion rates, and side effects were reported for each regimen. Comparisons of regimens were assessed using Fisher exact test.. Between 2005 and 2014, 363 of 927 (39%) HCWs diagnosed with LTBI accepted treatment. Of 363, 202 chose INH, 106 RIF, and 55 RPT/INH. Completion rates for each regimen were 58%, 80%, and 87%, respectively. HCWs were significantly more likely to have completed treatment with RIF (P < .0001) or RPT/INH (P < .0001) than INH. Rates of discontinuation owing to side effects were 35% for INH, 21% for RIF, and 10% for RPT/INH. Discontinuation of therapy due to side effects was significantly more frequent in the INH than the RPT/INH group (P = .0042).. Completion of RIF and RPT/INH for LTBI in an HCW population is more likely than INH. Rates of discontinuation due to side effects were lower among those taking RPT/INH. Shorter LTBI treatment regimens should be more widely considered for HCWs in the United States.

Topics: Adult; Antitubercular Agents; Disease Management; Drug Therapy, Combination; Female; Health Personnel; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Retrospective Studies; Rifampin

The primary role of any tuberculosis (TB) control program is to ensure the prompt identification and effective treatment of active disease. The host immune system often succeeds in containing the initial (or primary) infection with Mycobacterium tuberculosis (Mtb), but may fail to eliminate the pathogen. The persistence of viable organisms explains the potential for the development of active disease years or even decades after infection. This is known as latent tuberculosis infection (LTBI) although, rather than a distinct entity, this probably represents part of a dynamic spectrum. Individuals with LTBI are asymptomatic and it is therefore clinically undetectable. The World Health Organization (WHO) estimates that one-third of the global population has been infected with Mtb, with highest prevalence of LTBI in countries/regions with the highest prevalence of active disease. In 2013, 88% of 1322 notifications in Australia were in the overseas-born population (incidence 19.5 per 100,000 v. 1.0 per 100,000), with this proportion rising over the course of the last decade. Combined with epidemiological evidence of low local transmission, this strongly implies that the vast majority resulted from reactivation of latent infection acquired prior to immigration. Contrasting trends in TB incidence in other developed countries probably reflect differences in policy regarding LTBI.. The diagnosis and treatment of LTBI represents an important opportunity for intervention by jurisdictional TB control programs.

Topics: Antitubercular Agents; Australia; Chemoprevention; Communicable Disease Control; Disease Notification; Drug Combinations; Emigration and Immigration; Humans; Interferon-gamma Release Tests; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Prevalence; Rifampin; Transients and Migrants; Tuberculin Test; Tuberculosis, Pulmonary

Renal transplant candidates (RTC) with latent tuberculosis infection (LTBI) are at significant risk for tuberculosis reactivation. Twelve-week rifapentine (RPT)/isoniazid (INH) is effective for LTBI but clinical experience in RTC is scarce.. We conducted a retrospective study of RTC with LTBI treated with either 12-week RPT/INH or 9-month INH from March 1, 2012, through February 28, 2014. We evaluated both groups for differences in rates of treatment completion, monthly follow-up visit compliance, transaminase elevations, and adverse reactions leading to discontinuation of LTBI treatment. The utility of weekly reminders was also evaluated in the 12-week regimen. Direct observed therapy was not performed in our study.. Of 153 patients, 43 (28%) and 110 (72%) were started on 12-week RPT/INH and 9-month INH, respectively. The treatment completion and monthly follow-up visit compliance rates were higher in the 12-week RPT/INH group (40 [93%] vs 52 [47%], P < 0.001) and (11/40 [28%] vs 13/104 [13%], P = 0.03), respectively. Transaminase elevations were not observed in the RPT/INH group, but occurred in 6 (5%) of the INH group. There were no differences in adverse reactions leading to discontinuation of LTBI treatment.. Twelve-week RPT/INH appears to be an excellent choice for LTBI in RTC. It has a higher treatment completion rate and causes less transaminase elevations, and weekly reminders may be an alternative when direct observed therapy is not feasible.

Topics: Adult; Aged; Antitubercular Agents; Biomarkers; Chemical and Drug Induced Liver Injury; Choice Behavior; Drug Therapy, Combination; Female; Humans; Isoniazid; Kidney Diseases; Kidney Transplantation; Latent Tuberculosis; Male; Medication Adherence; Middle Aged; Reminder Systems; Retrospective Studies; Rifampin; Time Factors; Transaminases; Treatment Outcome; Treatment Refusal; Up-Regulation; Waiting Lists

Rifapentine is an anti-tuberculosis (anti-TB) drug with a prolonged half-life, but oral delivery results in low concentrations in the lungs because of its high binding (98%) to plasma proteins. We have shown that inhalation of crystalline rifapentine overcomes the limitations of oral delivery by significantly enhancing and prolonging the drug concentration in the lungs. The delivery of crystalline particles to the lungs may promote inflammation. This in vivo study characterizes the inflammatory response caused by pulmonary deposition of the rifapentine particles. The rifapentine powder was delivered to BALB/c mice by intratracheal insufflation at a dose of 20 mg/kg. The inflammatory response in the lungs and bronchoalveolar lavage (BAL) was examined at 12 h, 24 h, and 7 days post-treatment by flow cytometry and histopathology. At 12 and 24 h post-treatment, there was a significant influx of neutrophils into the lungs, and this returned to normal by day 7. A significant recruitment of macrophages occurred in the BAL at 24 h. Consistent with these findings, histopathological analysis demonstrated pulmonary vascular congestion and significant macrophage recruitment at 12 and 24 h post-treatment. In conclusion, the pulmonary delivery of crystalline rifapentine caused a transient neutrophil-associated inflammatory response in the lungs that resolved over 7 days. This observation may limit pulmonary delivery of rifapentine to once a week at a dose of 20 mg/kg or less. The effectiveness of weekly dosing with inhalable rifapentine will be assessed in murine Mycobacterium tuberculosis infection.

Topics: Administration, Inhalation; Animals; Antibiotics, Antitubercular; Female; Half-Life; Lung; Macrophages; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Neutrophils; Pneumonia; Powders; Rifampin; Tuberculosis

The activities of rifampin, rifapentine, bedaquiline, PA-824, clofazimine, nitazoxanide, isoniazid, amikacin, moxifloxacin, niclosamide, thioridazine, and pyrazinamide were tested against nonreplicating (dormant)

Topics: Anaerobiosis; Antitubercular Agents; Hydrogen-Ion Concentration; Isonicotinic Acids; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Phenazines; Quinolines; Rifampin; Thiazoles

Topics: Adult; Aged; Antitubercular Agents; Blood Pressure; Cohort Studies; Drug Therapy, Combination; Humans; Hypertension; Isoniazid; Kidney Transplantation; Latent Tuberculosis; Middle Aged; Rifampin; Time Factors; Transplant Recipients

Rifapentine-loaded poly(lactic-co-glycolic acid) microspheres (RPMs)-loaded bone-like hydroxyapatite/poly amino acid (BHA/PAA) is effective in curing Staphylococcus aureus-induced chronic osteomyelitis. This study continues to investigate the effect of RPM-loaded BHA/PAA on the bacterial growth of Mycobacterium tuberculosis (MTB), cell proliferation and differentiation in MTB H37Rv-infected MG63 cells. Furthermore, whether Wnt/β-catenin signaling pathway was activated by RPM-loaded BHA/PAA was explored. We found the bactec growth index of H37Rv was significantly inhibited by RPM-loaded BHA/PAA. The MTT assay showed that RPM-loaded BHA/PAA could promote the cell proliferation of H37Rv-infected MG63 cells, as determined by MTT assay. The alkaline phosphatase (ALP) activity and the expression of runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) was examined by commercial kit and Western blot analysis to determine the effect of RPM-loaded BHA/PAA on MTB H37Rv-infected MG63 cell differentiation. It was revealed that RPM-loaded BHA/PAA could promote cell differentiation of H37Rv-infected MG63 cells. Furthermore, we found the expression of Wnt1, LDL receptor related protein 6 (Lrp6) and β-catenin was significantly increased in H37Rv-infected MG63 cells following treatment with RPM-loaded BHA/PAA, as determined by Western blot analysis. In conclusion, this study demonstrated that RPM-loaded BHA/PAA has an effective activity against MTB. RPM-loaded BHA/PAA promoted cell proliferation and cell differentiation of H37Rv-infected MG63 cells. Wnt/β-catenin signaling could be activated by RPM-loaded BHA/PAA in MG63 cells infected with H37Rv. This study demonstrated the potential value of RPM-loaded BHA/PAA in treating bone and joint TB, and suggested Wnt/β-catenin signaling may be an important pathway underlying its function.

Topics: Cell Differentiation; Cell Line, Tumor; Drug Carriers; Durapatite; Humans; Lactic Acid; Microbial Sensitivity Tests; Microspheres; Mycobacterium tuberculosis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rifampin; Tuberculosis, Osteoarticular; Wnt Signaling Pathway

The U.S. Centers for Disease Control and Prevention (CDC) recommended a new regimen for treatment of latent tuberculosis (three months of weekly isoniazid and rifapentine) in late 2011. While completion rates of this regimen were reported to be higher than nine months of isoniazid, little is known about the completion rates of three months of isoniazid and rifapentine compared to nine months of isoniazid or four months of rifampin in actual use scenarios.. We conducted a retrospective cohort study comparing treatment completion for latent tuberculosis (TB) infection in patients treated with nine months of isoniazid, three months of isoniazid and rifapentine or four months of rifampin in outpatient clinics and a public health TB clinic in Seattle, Washington. The primary outcome of treatment completion was defined as 270 doses of isoniazid within 12 months, 120 doses of rifampin within six months and 12 doses of isoniazid and rifapentine within four months.. Three hundred ninety-three patients were included in the study. Patients were equally likely to complete three months of weekly isoniazid and rifapentine or four months of rifampin (85% completion rate of both regimens), as compared to 52% in the nine months of isoniazid group (p < 0.001). These associations remained statistically significant even after adjusting for clinic location and type of monitoring. Monitoring type (weekly versus monthly versus less often than monthly) had less impact on treatment completion than the type of treatment offered.. Patients were equally as likely to complete the three months of isoniazid and rifapentine as four months of rifampin. Four months of rifampin is similar in efficacy compared to placebo as isoniazid and rifapentine but does not require directly observed therapy (DOT), and is less expensive compared to combination therapy with isoniazid and rifapentine, and thus can be the optimal treatment regimen to achieve the maximal efficacy in a community setting.

Topics: Adult; Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Patient Compliance; Retrospective Studies; Rifampin; United States; Washington

The treatment of latent tuberculous infection (TBI) is a productive and meaningful approach to tuberculosis (TB) control, and an important component of the World Health Organization's (WHO's) new End TB Strategy, especially in high-risk contacts. Unfortunately, although recognized and recommended by the WHO, it continues to be underutilized, and has even been ignored for decades in some high-risk groups, as though it were a taboo. Historical approaches to treating TBI in contacts of drug-susceptible and drug-resistant TB are presented and discussed as compelling experiences. In the United States, the Centers for Disease Control and Prevention have recently shown that a directly observed or even self-administered 12-month regimen to treat TBI with once-weekly isoniazid (INH) and rifapentine is as effective as 9 months of daily INH. Treating TBI in drug-susceptible cases and their contacts should not still be considered taboo-such a short, effective regimen is more akin to the Holy Grail. While not yet confirmed in a clinical trial, treating contacts of drug-resistant TB with the same drugs that are effective in the source case would be expected intuitively and practically to prevent TB in contacts and should be introduced now instead of waiting until clinical trials are completed.

Topics: Antitubercular Agents; Contact Tracing; Drug Therapy, Combination; Global Health; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Taboo; Time Factors; Tuberculosis; World Health Organization

Isoniazid daily for 9 months is the recommended regimen for latent tuberculosis infection (LTBI) in solid organ transplant (SOT) candidates, but its use is controversial, due to reports of hepatotoxicity and low treatment completion rates. A 12-week course of once weekly directly observed therapy (DOT) with isoniazid plus rifapentine (3HP) is a new LTBI treatment regimen. Tolerability and safety data of 3HP LTBI treatment in SOT candidates are limited.. Twelve consecutive SOT candidates who underwent DOT with 3HP for LTBI at Westchester Medical Center, Valhalla, New York, USA, between January 2013 and August 2016 were prospectively evaluated for tolerability and safety of 3HP. The diagnosis of LTBI was made in a person with a positive interferon-gamma release test, without a history of previously treated active or latent tuberculosis infection, and without signs, symptoms, or radiographic evidence of active tuberculosis. Patients were followed up 1 month after treatment completion and at routine follow-up visits with their transplant providers.. Eleven patients were men, and the median age was 60 years (range 44-72). Eight patients were liver, and four kidney transplant candidates. The median Model for End-Stage Liver Disease (MELD score) was 17 (range 10-31). All patients completed treatment. Only a single patient developed transaminitis greater than twice the baseline value. Three patients underwent liver transplantation. None of them developed tuberculosis at 9, 22, or 40 months following transplantation.. Directly observed 3HP LTBI treatment was not associated with hepatotoxicity, even in patients with higher MELD scores. Further studies are needed to confirm the safety and efficacy of this LTBI treatment regimen in the SOT population.

Topics: Adult; Aged; Antibiotics, Antitubercular; Directly Observed Therapy; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; New York; Rifampin

Completion of treatment for tuberculosis infection (TBI) with 9 months of self-administered daily isoniazid (9H) has historically been low (<50%) among New York City (NYC) Health Department tuberculosis clinic patients. Treatment of TBI with 3 months of once-weekly isoniazid and rifapentine (3HP) administered under directly observed therapy (DOT) might increase treatment acceptance and completion.. The study population included patients diagnosed with TBI at 2 NYC Health Department tuberculosis clinics from January 2013 through November 2013. Treatment acceptance and completion with 3HP were compared with historical estimates. Treatment outcomes, side effects, and reasons for refusing 3HP were described.. Among 631 patients eligible for TBI treatment, 503 (80%) were offered 3HP; 302 (60%) accepted, 92 (18%) chose other treatment, and 109 (22%) refused treatment. The most common reason for refusing 3HP was the clinic-based DOT requirement. Forty (13%) patients treated with 3HP experienced side effects--9 were restarted on 3HP, 18 switched treatment regimens, and 13 discontinued. Although treatment acceptance did not differ from historical estimates (78% vs 79%, P = .75), treatment completion increased significantly (65% vs 34%, P < .01).. Implementation of 3HP in 2 NYC Health Department tuberculosis clinics increased TBI treatment completion by 31 percentage points compared with historical estimates. More flexible DOT options may improve acceptance of 3HP. Wider use of 3HP may substantially improve TBI treatment completion in NYC and advance progress toward tuberculosis elimination.

Topics: Adult; Ambulatory Care Facilities; Antitubercular Agents; Directly Observed Therapy; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; New York City; Patient Compliance; Public Health; Rifampin; Young Adult

1. Interspecies allometry scaling for prediction of human excretory amounts in urine or feces was performed for numerous antibacterials. Antibacterials used for urinary scaling were: rifapentine, pefloxacin, trovafloxacin (Gr1/low; <10%); miloxacin, linezolid, PNU-142300 (Gr2/medium; 10-40%); aztreonam, carumonam, cefozopran, doripenem, imipenem, and ceftazidime (Gr3/high; >50%). Rifapentine, cabotegravir, and dolutegravir was used for fecal scaling (high; >50%). 2. The employment of allometry equation: Y = aW(b) enabled scaling of urine/fecal amounts from animal species. Corresponding predicted amounts were converted into % recovery by considering the respective human dose. Comparison of predicted/observed values enabled fold difference and error calculations (mean absolute error [MAE] and root mean square error [RMSE]). Comparisons were made for urinary/fecal data; and qualitative assessment was made amongst Gr1/Gr2/Gr3 for urine. 3. Average correlation coefficient for the allometry scaling was >0.995. Excretory amount predictions were largely within 0.75- to 1.5-fold differences. Average MAE and RMSE were within ±22% and 23%, respectively. Although robust predictions were achieved for higher urinary/fecal excretion (>50%), interspecies scaling was applicable for low/medium excretory drugs. 4. Based on the data, interspecies scaling of urine or fecal excretory amounts may be potentially used as a tool to understand the significance of either urinary or fecal routes of elimination in humans in early development.

Topics: Animals; Anti-Bacterial Agents; Aztreonam; Carbapenems; Cefozopran; Ceftazidime; Cephalosporins; Doripenem; Feces; Fluoroquinolones; Heterocyclic Compounds, 3-Ring; Humans; Imipenem; Linezolid; Naphthyridines; Oxazines; Oxolinic Acid; Pefloxacin; Piperazines; Pyridones; Retrospective Studies; Rifampin

Recent studies have demonstrated that efflux pumps of Mycobacterium tuberculosis (M. tb) provide a crucial mechanism in the development of drug resistant to antimycobacterial drugs. Drugs that inhibit these efflux pumps, such as verapamil, have shown the potential in enhancing the treatment success. We therefore hypothesized that the combined inhaled administration of verapamil and a first-line rifamycin antibiotic will further improve the treatment efficacy. An inhalable dry powder consisting of amorphous verapamil and crystalline rifapentine with l-leucine as an excipient was produced by spray drying. The in vitro aerosol characteristic of the powder, its microbiological activity and stability were assessed. When the powder was dispersed by an Osmohaler, the total fine particle fraction (FPFtotal, wt % of particles in aerosol <5 μm) of verapamil and rifapentine was 77.4 ± 1.1% and 71.5 ± 2.0%, respectively. The combination drug formulation showed a minimum inhibitory concentration (MIC90) similar to that of rifapentine alone when tested against both M. tb H37Ra and M. tb H37Rv strains. Importantly, the combination resulted in increased killing of M. tb H37Ra within the infected macrophage cells compared to either verapamil or rifapentine alone. In assessing cellular toxicity, the combination exhibited an acceptable half maximal inhibitory concentration (IC50) values (62.5 μg/mL) on both human monocytic (THP-1) and lung alveolar basal epithelial (A549) cell lines. Finally, the powder was stable after 3 months storage in 0% relative humidity at 20 ± 3 °C.

Topics: Adenocarcinoma; Administration, Inhalation; Aerosols; Anti-Arrhythmia Agents; Antibiotics, Antitubercular; Cell Survival; Chemistry, Pharmaceutical; Humans; In Vitro Techniques; Lung Neoplasms; Microbial Sensitivity Tests; Monocytes; Mycobacterium tuberculosis; Particle Size; Rifampin; Tuberculosis; Verapamil

In clinical practice, rifampicin exposure is estimated from its concentration in venous blood samples. In this study, we hypothesized that differences in rifampicin concentration may exist between arterial and venous plasma. An HPLC-UV method for determining rifampicin concentration in plasma using rifapentine as an internal standard was validated. The method, which requires a simple protein precipitation procedure as sample preparation, was performed to compare venous and arterial plasma kinetics after a single therapeutic dose of rifampicin (8.6 mg/kg i.v, infused over 30 min) in baboons (n=3). The method was linear from 0.1 to 40 μg mL(-1) and all validation parameters fulfilled the international requirements. In baboons, rifampicin concentration in arterial plasma was higher than in venous plasma. Arterial Cmax was 2.1±0.2 fold higher than venous Cmax. The area under the curve (AUC) from 0 to 120 min was ∼80% higher in arterial plasma, indicating a significant arteriovenous concentration gradient in early rifampicin pharmacokinetics. Arterial and venous plasma concentrations obtained 6h after rifampicin injection were not different. An important arteriovenous equilibration delay for rifampicin pharmacokinetics is reported. Determination in venous plasma concentrations may considerably underestimate rifampicin exposure to organs during the distribution phase.

Topics: Animals; Area Under Curve; Arteries; Chromatography, High Pressure Liquid; Kinetics; Male; Papio; Plasma; Reproducibility of Results; Rifampin; Spectrophotometry, Ultraviolet; Veins

Inhaled delivery of drugs incorporated into poly (lactic-co-glycolic acid) (PLGA) microparticles allows a sustained lung concentration and encourages phagocytosis by alveolar macrophages that harboring Mycobacterium tuberculosis. However, limited data are available on the effects of physicochemical properties of PLGA, including the monomer ratio (lactide:glycide) and molecular weight (MW) on the aerosol performance, macrophage uptake, and toxicity profile. The present study aims to address this knowledge gap, using PLGAs with monomer ratios of 50:50, 75:25 and 85:15, MW ranged 24 - 240kDa and an anti-tuberculosis (TB) drug, rifapentine. The PLGA-rifapentine powders were produced through a solution spray drying technique. The particles were spherical with a smooth surface and a volume median diameter around 2μm (span ~2). When the powders were dispersed using an Osmohaler(®) at 100L/min for 2.4s, the fine particle fraction (FPFtotal, wt.% particles in aerosol <5μm relative to the total recovered drug mass) was ranged between 52 and 57%, with no significant difference between the formulations. This result suggests that the monomer ratio and MW are not crucial parameters for the aerosol performance of PLGA. The phagocytosis analysis was performed using Thp-1 monocyte-derived macrophages. The highest rate of uptake was observed in PLGA 85:15 followed by 75:25 and 50:50 with about 90%, 80% and 70%, respectively phagocytosis over 4h of exposure. Furthermore, the cytotoxicity analysis on Thp-1 and human lung adenocarcinoma epithelial cells demonstrated that PLGA concentration up to 1.5mg/mL, regardless of the monomer composition and MW, were non-toxic. In conclusion, the monomer ratio and MW are not crucial in determining the aerosol performance and cytotoxicity profile of PLGA however, the particles with high lactide composition have a superior tendency for macrophage uptake.

Topics: Administration, Inhalation; Aerosols; Antitubercular Agents; Cell Line; Cell Survival; Chemistry, Pharmaceutical; Drug Delivery Systems; Humans; Lactic Acid; Lung; Microscopy, Electron, Scanning; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rifampin

Screening for and treating tuberculosis (TB) infection in children and adolescents is an effective way of decreasing future TB cases. However, current approaches leave many children at risk for TB unidentified.. We recruited adolescent students from 2 public high schools (a magnet and a low-income) in the Houston Independent School District. Compared with the magnet school, the student population at the low-income school was larger, primarily Hispanic and economically disadvantaged. Students were educated about TB, and parents completed a risk factor questionnaire. Students with TB risk factors were tested using 2 interferon gamma release assays (IGRAs). Those with a positive IGRA received a 12-dose regimen of weekly isoniazid/rifapentine (3HP) administered via direct observation at school.. Nine hundred twenty-five students received TB education; 73% of their parents submitted the TB questionnaire. Eighty-six percent of students (n = 415) with a TB risk factor identified on the study questionnaire agreed to IGRA testing. Sixteen students had at least one positive IGRA (1% [magnet], 4.1% [low-income]; P = 0.005). Recent student travel to a high-risk country (7) or contact with TB disease (2) were associated with IGRA positivity (P < 0.05). All students with a positive IGRA accepted, tolerated and completed 3HP treatment at school.. School-based TB education, screening, testing using IGRAs and administration of 3HP treatment is feasible to improve the identification and treatment of adolescent students at risk for TB.

Topics: Adolescent; Antitubercular Agents; Directly Observed Therapy; Drug Combinations; Female; Humans; Isoniazid; Male; Mass Screening; Mycobacterium tuberculosis; Poverty; Rifampin; Risk Factors; School Health Services; Students; Surveys and Questionnaires; Texas; Tuberculin Test; Tuberculosis

Traditional treatment of tuberculosis infection (TBI) is efficacious, but adherence is low. Eighty children with TBI received a 12-dose once-weekly isoniazid/rifapentine regimen; 79 (99%) completed therapy, 94% reported no adverse events, 1 child had mildly elevated transaminases but 1 adolescent later developed pulmonary TB. Isoniazid/rifapentine is safe, is well tolerated and has much higher completion rates than traditional TBI regimens.

Topics: Adolescent; Antibiotics, Antitubercular; Antitubercular Agents; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Isoniazid; Male; Medication Adherence; Rifampin; Skin Tests; Treatment Outcome; Tuberculosis; Tuberculosis, Pulmonary; Young Adult

Rifapentine (RPT) is a rifamycin antimycobacterial and, as part of a combination therapy, is indicated for the treatment of pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis Although the results from a number of studies indicate that rifapentine has the potential to shorten treatment duration and enhance completion rates compared to other rifamycin agents utilized in antituberculosis drug regimens (i.e., regimens 1 to 4), its optimal dose and exposure in humans are unknown. To help inform such an optimization, a physiologically based pharmacokinetic (PBPK) model was developed to predict time course, tissue-specific concentrations of RPT and its active metabolite, 25-desacetyl rifapentine (dRPT), in humans after specified administration schedules for RPT. Starting with the development and verification of a PBPK model for rats, the model was extrapolated and then tested using human pharmacokinetic data. Testing and verification of the models included comparisons of predictions to experimental data in several rat tissues and time course RPT and dRPT plasma concentrations in humans from several single- and repeated-dosing studies. Finally, the model was used to predict RPT concentrations in the lung during the intensive and continuation phases of a current recommended TB treatment regimen. Based on these results, it is anticipated that the PBPK model developed in this study will be useful in evaluating dosing regimens for RPT and for characterizing tissue-level doses that could be predictors of problems related to efficacy or safety.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Lung; Mycobacterium tuberculosis; Rats; Rifampin; Rifamycins; Tuberculosis, Pulmonary

In order to detect the in vitro synergistic effect of 4 drugs-pasiniazid (PA), moxifloxacin, rifabutin and rifapentini on multidrug-resistant mycobacterium tuberculosis (MDR-MTB) and extensively drug-resistant mycobacterium tuberculosis(XDR-MTB), which were core drugs of"The program of retreatment research of tuberculosis".. The checkerboard method was used to detect the minimum inhibitory concentration (MIC) of antituberculosis drug combination schemes (moxifloxacin-PA, moxifloxacin-PA-rifabutin and moxifloxacin-PA-rifapentini) to 40 strains of clinical drug resistant MTB(20 strains of MDR-MTB and 20 XDR-MTB) and the standard strain H37Rv, by calculating the fractional inhibitory concentration index of joint action in vitro to judge the combined effect, with fractional inhibitory concentration index(FICI)≤0.5 and FICI≤0.75 as the basis of 2 drugs and 3 drugs showing synergy.. The FICI of moxifloxacin-PA scheme for DR-MTB was 0.125 to 1.000, only 5 strains with a FICI ≤0.5, showing synergistic effect. The FICI of moxifloxacin-Pa-rifabutin scheme with 20 strains of MDR-MTB ranged from 0.310 to 1.260, 10 strains with a FICI≤0.75, showing synergistic effect. The FICI of moxifloxacin-PA-rifabutin scheme with 20 strains of XDR-MTB ranged from 0.215 to 1.250, 11 strains with a FICI≤0.75, showing synergistic effect. The FICI of moxifloxacin-PA-rifapentini scheme with 20 strains of MDR-MTB ranged from 0.150 to 0.780, 19 strains with a FICI≤0.75, showing synergistic effect. The FICI of moxifloxacin-PA-rifapentini scheme with 20 strains of XDR-MTB ranged from 0.200 to 1.280, 16 strains with a FICI≤0.75, showing synergistic effect.. The synergistic effect of moxifloxacin-PA scheme was poor, but showing better synergy when further combined with rifabutin or rifapentini. Rifabutin showed better effect than rifapentini, but the synergistic effect of moxifloxacin-PA-rifabutin combination scheme was poor than that of moxifloxacin-PA-rifapentini combination scheme.

Topics: Aminosalicylic Acids; Antibiotics, Antitubercular; Drug Synergism; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Fluoroquinolones; Isoniazid; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium tuberculosis; Retreatment; Rifabutin; Rifampin; Tuberculosis, Multidrug-Resistant

Thioridazine is an orally administered antipsychotic drug with potential for treatment of drug-resistant tuberculosis (TB). However, drug-induced adverse cardiac effects have been reported when thioridazine was used at an efficacious oral dose of 200mg/day to treat TB. Pulmonary delivery of thioridazine could be a rational approach to reduce dose-related side effects while enabling high drug concentrations at the primary site of infection. The present study compares in vitro aerosol performance, storage stability, and in vitro antimicrobial activity and cytotoxicity of two inhalable powders composed of thioridazine and a first-line anti-TB drug, rifapentine. Formulation 1 is a combination of amorphous thioridazine and crystalline rifapentine, while Formulation 2 consisted of both drugs as amorphous forms. Both thioridazine-rifapentine formulations were found suitable for inhalation with a total fine particle fraction (<5μm) of 68-76%. The two powders had similar MIC90 to rifapentine alone, being 0.000625μg/mL and 0.005μg/ml against Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv, respectively. In contrast, thioridazine alone had a MIC90 of 12.5μg/mL and 500μg/mL, against M. tuberculosis H37Ra and M. tuberculosis H37Rv, respectively, demonstrating no synergistic anti-TB activity. However, thioridazine and rifapentine in a ratio of 1:3 enhanced the killing of M. tuberculosis H37Ra within the human monocyte-derived macrophages (THP-1) compared to the single drug treatments. Both powders showed an acceptable half maximal inhibitory concentration (IC50) of 31.25μg/mL on both THP-1 and human lung epithelial (A549) cells. However, Formulation 1 showed greater chemical stability than Formulation 2 after three months of storage under low humidity (vacuum) at 20±3°C. In conclusion, we have demonstrated a novel inhalable powder consisted of amorphous thioridazine and crystalline rifapentine (Formulation 1) with a good aerosol performance, potent anti-TB activity and storage stability, which deserves further in vivo investigations.

Topics: Administration, Inhalation; Antitubercular Agents; Humans; In Vitro Techniques; Powder Diffraction; Powders; Rifampin; Thioridazine; Tuberculosis

Treatment of latent tuberculosis infection (LTBI) is essential for eradicating tuberculosis (TB). Moreover, the patient adherence is crucial in determining the effectiveness of TB control. Isoniazid given by DOTS daily for 9 months (9H) is the standard treatment for LTBI in Taiwan. However, the completion rate is low due to the long treatment period and its side effects. The combined regimen using a high dose of rifapentine/isoniazid once weekly for 12 weeks (3HP) has been used as an alternative treatment option for LTBI in the United States. This may result in a higher completion rate. In this pilot study, patient adherence and cost of these 2 treatment regimens were investigated. Thus, we aimed to assess the treatment completion rate and costs of 3HP and compare to those with 9H.Data from 691 cases of LTBI treatments including 590 cases using the conventional regimen and 101 cases with rifapentine/Isoniazid were collected. The cost was the sum of the cost of treatment with Isoniazid for 9 months or with rifapentin/Isoniazid for 3 months of all contacts. The effectiveness was the cost of cases of tuberculosis avoided.In this study, the treatment completion rate for patients prescribed with the 3 months rifapentine/isoniazid regimen (97.03%) was higher than those given the conventional 9-month isoniazid regimen (87.29%) (P <0.001). The cost of 3HP and 9H was US$261.24 and US$717.3, respectively. The cost-effectiveness ratio with isoniazid for 9 months was US$ 15392/avoided 1 case of tuberculosis and US$ 5225/avoided 1 case of tuberculosis with 3HP. In addition, when compared with the conventional regimen, there were fewer patients discontinued with rifapentine/isoniazid regimen due to undesirable side effects.This was the first study to compare the 2 treatment regimens in Taiwan, and it showed that a short-term high-dosage rifapentine/isoniazid treatment regimen reduced costs and resulted in higher treatment completion than the standard LTBI isoniazid treatment.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Cost-Benefit Analysis; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Medication Adherence; Middle Aged; Pilot Projects; Rifampin; Taiwan; Time Factors; Tuberculosis, Pulmonary; Young Adult

The treatment of Buruli ulcer (BU) that is caused by Mycobacterium ulcerans, is currently based on a daily administration of rifampin and streptomycin (RIF-STR). A fully oral intermittent regimen would greatly simplify its treatment on the field.. The objective of this study was to assess the bactericidal and sterilizing activities of intermittent oral regimens in a murine model of established M. ulcerans infection. Regimens combining rifapentine (RFP 20 mg/kg) with either moxifloxacin (MXF 200 mg/kg), clarithromycin (CLR 100 mg/kg) or bedaquiline (BDQ 25 mg/kg) were administrated twice (2/7) or three (only for RFP-CLR 3/7) times weekly during 8 weeks. The bactericidal but also the sterilizing activities of these four intermittent oral regimens were at least as good as those obtained with control weekdays regimens, i.e. RFP-CLR 5/7 or RIF-STR 5/7. A single mouse from the RFP-MFX 2/7 group had culture-positive relapse at the end of the 28 weeks following treatment completion among the 157 mice treated with one of the four intermittent regimens (40 RFP-CLR 2/7, 39 RFP-CLR 3/7, 39 RFP-MXF 2/7, 39 RFP-BDQ 2/7).. These results open the door for a fully intermittent oral drug regimen for BU treatment avoiding intramuscular injections and facilitating supervision by health care workers.

Topics: Animals; Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Diarylquinolines; Drug Therapy, Combination; Female; Fluoroquinolones; Humans; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium ulcerans; Rifampin

Hen egg low-density lipoprotein (heLDL), which is present in large quantities in egg yolk, share a high identity with human apolipoprotein B-100 precursor.. This study investigated the use of heLDL as a macrophage-targeted drug delivery carrier against intracellular Staphylococcus aureus.. Rifapentine (RPT) was incorporated into heLDL (RPT-heLDL). Staphylococcus aureus ATCC 29740 and human U937 macrophage were used as intracellular infection models.. The loading efficiency of RPT into the heLDL was 66.10 ± 2.28 μg RPT/mg heLDL. Fluorescence microscopy and oil red O staining results indicated RPT-heLDL can be taken up by U937 macrophages. The cell viability (MTT assay) was increased when the concentration of heLDL was <150 μg/mL. Unloaded heLDL (100 μg/mL) can inhibit the growth of intracellular S. aureus compared with the untreated control group after 18 h incubation. RPT-heLDL (6.6 μg/mL RPT, 100 μg/mL heLDL) eliminated 94% of intracellular S. aureus, whereas the corresponding dose of free RPT (6.6 μg/mL) induced an 87% reduction. The in vitro results of the current study indicated that heLDL might be used as a suitable drug carrier for targeting human macrophages.

Topics: Animals; Anti-Bacterial Agents; Cell Survival; Chickens; Drug Carriers; Drug Delivery Systems; Egg Proteins; Egg Yolk; Humans; Lipoproteins; Macrophages; Microscopy, Fluorescence; Rifampin; Staphylococcus aureus

Colistin has been increasingly used for the treatment of respiratory infections caused by Gram-negative bacteria. Unfortunately parenteral administration of colistin can cause severe adverse effects. This study aimed to develop an inhaled combination dry powder formulation of colistin and rifapentine for the treatment of respiratory infections. The combination formulation was produced by spray-drying rifapentine particles suspended in an aqueous colistin solution. The combination dry powder had enhanced antimicrobial activities against planktonic cells and biofilm cultures of Pseudomonas aeruginosa, with both minimum inhibitory concentration (MIC) and minimum biofilm inhibitory concentration (MBIC) values (2 and 4 mg/L, respectively) being half that of pure colistin (MIC 4 mg/L and MBIC 8 mg/L) and 1/16th that of pure rifapentine (MIC 32 mg/L and MBIC 64 mg/L). High aerosol performance, as measured via an Aerolizer device, was observed with emitted doses>89% and fine particle fraction (FPF) total>76%. The proportion of submicron particles of rifapentine particles was minimized by the attachment of colistin, which increased the overall particle mass and aerodynamic size distribution. Using the spray-drying method described here, stable particles of amorphous colistin and crystalline rifapentine were distributed homogeneously in each stage of the impinger. Unlike the colistin alone formulation, no deterioration in aerosol performance was found for the combination powder when exposed to a high relative humidity of 75%. In our previous study, surface coating by rifampicin contributed to the moisture protection of colistin. Here, a novel approach with a new mechanism was proposed whereby moisture protection was attributed to the carrier effect of elongated crystalline rifapentine particles, which minimized contact between hygroscopic colistin particles. This inhaled combination antibiotic formulation with enhanced aerosol dispersion efficiency and in vitro efficacy could become a superior treatment for respiratory infections.

Topics: Administration, Inhalation; Anti-Infective Agents; Biofilms; Colistin; Drug Combinations; Drug Synergism; Dry Powder Inhalers; Humans; Microbial Sensitivity Tests; Nanoparticles; Nasal Sprays; Particle Size; Plankton; Powders; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Rifampin

A novel assay using high pressure liquid chromatography (HPLC) coupled to mass spectrometer (MS) detection was developed and validated for the rifamycin anti-tuberculosis antibiotics rifampicin (RIF), rifabutin (RBT), rifapentine (RPT) and their active desacetyl metabolites (dRIF, dRBT and dRPT, respectively) in human plasma. The assay uses 50 μL of human plasma with a quick and simple protein-precipitation extraction to achieve a dynamic range of 75-30,000 ng/mL for RIF, RBT and RPT and 37.5-15,000 ng/mL for dRIF, dRBT and dRPT, respectively. The average %CV and %deviation were less than 20% at the lower limit of quantitation and less than 15% over the range of the curve. The method was fully validated according to FDA criteria for bioanalytical assays and has successfully been used to support three large international tuberculosis trials.

Topics: Antibiotics, Antitubercular; Chemical Precipitation; Chromatography, Liquid; Humans; Reproducibility of Results; Rifabutin; Rifampin; Rifamycins; Tandem Mass Spectrometry

A novel inhalable rifapentine dry powder formulation could improve pulmonary rifapentine concentrations resulting in a significantly shorter time to treat tuberculosis infection. The pharmacokinetics of rifapentine (20mg/kg) in healthy mice was compared following intratracheal (IT) and intraperitoneal (IP) administration. Plasma, bronchoalveolar lavage (BAL) and tissue samples were collected and drug levels were quantified at time points up to 24h. Concentration-time data were analysed using a mixed-effects modelling approach to provide model-based estimates of area under the concentration-time curve from time 0 to infinity (AUC0-∞). IT delivery had considerably higher peak rifapentine lung and BAL concentrations and associated AUC0-∞ compared with IP delivery. The plasma AUC0-∞ following IT dry powder delivery was ca. four-fold smaller than the value for IP delivery. Inhaled delivery of rifapentine has the potential to selectively enhance therapeutic efficacy at the pulmonary site of infection whilst minimising systemic exposure and related toxicity.

Topics: Administration, Inhalation; Aerosols; Animals; Antibiotics, Antitubercular; Bronchoalveolar Lavage Fluid; Female; Lung; Mice, Inbred BALB C; Models, Animal; Models, Statistical; Plasma; Powders; Rifampin

Topics: Antitubercular Agents; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Rifampin

Topics: Antibiotics, Antitubercular; Female; Humans; Male; Rifampin; Tuberculosis, Pulmonary

The study was to develop and evaluate the rifapentine-loaded poly(lactic acid-co-glycolic acid) (PLGA) microspheres (RPMs) for the treatment of osteoarticular tuberculosis to avoid critical side effects caused by oral regimens of antibiotics or intravenous antibiotics. The RPMs were spherical with rough surfaces, and elevated amounts of rifapentine in the formulation markedly increased the particle size and drug loading, while decreased the size distribution and entrapment efficiency. The highest drug loading and encapsulation efficiency of RPMs were 23.93%±3.93% and 88.49%±8.49%, respectively. After the initial rapid drug release, the release rate gradually decreased, and approximately 80% of the encapsulated rifapentine was released after 30 days of incubation. Moreover, RPMs could effectively inhibit the growth of Staphylococcus aureus. With increasing rifapentine content, the inhibition zones were continuously enlarged while the minimal inhibitory concentration values decreased. These results suggested that RPMs were bioactive and controlled release delivery systems for the treatment of osteoarticular tuberculosis.

Topics: Drug Delivery Systems; Lactic Acid; Microbial Sensitivity Tests; Microspheres; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rifampin; Staphylococcus aureus; Surface Properties; Tuberculosis, Osteoarticular

A 25-year-old male state-prisoner presented with altered mental status, right neck pain, and uncontrolled hypertension.

Topics: Adult; Antibiotics, Antitubercular; Cervical Vertebrae; Drug Therapy, Combination; Humans; Isoniazid; Magnetic Resonance Imaging; Male; Neurosurgical Procedures; Orthopedic Procedures; Radiography; Rifampin; Tomography, X-Ray Computed; Treatment Outcome; Tuberculosis, Spinal

The purpose of this study was to investigate the curative effect of bone-like hydroxyapatite/poly amino acid (BHA/PAA) as a carrier for poly(lactic-co-glycolic acid)-coated rifapentine microsphere (RPM) in the treatment of rabbit chronic osteomyelitis induced by Staphylococcus aureus.. RPM was prepared through an oil-in-water emulsion solvent evaporation method, and RPM was combined with BHA/PAA to obtain drug-loaded, slow-releasing materials. Twenty-six New Zealand white rabbits were induced to establish the animal model of chronic osteomyelitis. After debridement, the animals were randomly divided into three groups (n=8): the experimental group (with RPM-loaded BHA/PAA), the control group (with BHA/PAA), and the blank group. The RPM-loaded BHA/PAA was evaluated for antibacterial activity, dynamics of drug release, and osteogenic ability through in vitro and in vivo experiments.. In vitro, RPM-loaded BHA/PAA released the antibiotics slowly, inhibiting the bacterial growth of S. aureus for up to 5 weeks. In vivo, at week 4, the bacterial colony count was significantly lower in the experimental group than in the control and blank groups (P<0.01). At week 12, the chronic osteomyelitis was cured and the bone defect was repaired in the experimental group, whereas the infection and bone defect persisted in the control and blank groups.. In vitro and in vivo experiments demonstrated that RPM-loaded BHA/PAA effectively cured S. aureus-induced chronic osteomyelitis. Therefore, BHA/PAA has potential value as a slow-releasing material in clinical setting. Further investigation is needed to determine the optimal dosage for loading rifapentine.

Topics: Amino Acids; Animals; Anti-Bacterial Agents; Chronic Disease; Delayed-Action Preparations; Drug Carriers; Durapatite; Lactic Acid; Microspheres; Osteomyelitis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rabbits; Rifampin; Staphylococcal Infections; Staphylococcus aureus

By lyophilization of rifampicin (RIF) solution in TBA/water with various solvent compositions, uniform and amorphous rifampicin (RIF) microspheres were produced. Using 55% TBA solution, the obtained RIF microspheres have a mono-dispersive size distribution with diameters range from 1 to 3 μm. The RIF microspheres are found to be amorphous by X-ray diffraction, and are expected to dissolve much faster than the crystalline RIF upon inhalation. Mechanistic investigation revealed that the amorphous RIF microspheres were formed due to liquid-liquid phase separation (LLPS) occurred during the freezing of the TBA/water solution. We also observed that the RIF microspheres can be readily phagocytized by activated THP-1 cells within 15 min. The suitable size distribution, high solubility, and readiness for phagocytosis by macrophages, all suggest that the lyophilized amorphous RIF microspheres could be potentially used as an anti-tuberculosis inhalation therapy. In addition, similar process was used to lyophilize TBA/water solutions of several other drugs, including rifaximin, rifapentine, paclitaxel, and isoniazid. We found that for drugs with appropriate physiochemical properties, such as paclitaxel and rifaximin, mono-dispersive microspheres could be obtained as well, which demonstrated that freezing induced LLPS could be utilized as a novel particle engineering methodology to produce drug microspheres by lyophilization.

Topics: Administration, Inhalation; Cell Line; Chemistry, Pharmaceutical; Drug Carriers; Dynamic Light Scattering; Freeze Drying; Humans; Isoniazid; Macrophages; Microscopy, Electron, Scanning; Microspheres; Paclitaxel; Particle Size; Phagocytosis; Rifampin; Solubility; tert-Butyl Alcohol; Water; X-Ray Diffraction

In the last century, the United States has transitioned from a high to a low tuberculosis (TB) incidence country. A major factor in this decline has been the emphasis on identification and treatment of patients with tuberculous infection. While identification, testing, and preventive therapy pose challenges, recent developments in childhood TB offer more options for effective strategies that are acceptable to both children and their families. These include screening and testing in non-traditional settings, use of more specific assays (interferon-gamma release assays) for testing, and implementation of shorter-course preventive regimens.

Topics: Antibiotics, Antitubercular; Child; Humans; Incidence; Interferon-gamma Release Tests; Isoniazid; Mass Screening; Rifampin; Tuberculosis; United States

Quality by Design (QbD) is a systematic approach to develop drug products which includes evaluation of formulation parameters to achieve defined final product quality. In the present study principles of QbD were extended to the preparation, in-vitro and in-vivo performance of rifapentine-loaded proliposomes for pulmonary inhalation where final product needs to comply with specific properties. The rifapentine-loaded proliposomes for the treatment of tuberculosis were prepared in single step by spray drying method and independent variables were optimized using factorial design approach. Contour plots and multiple regression analysis were used to study the effect of selected independent variables on dependent variables. The effect of presence of drug: hydrogenated soya phosphatidylcholine (HSPC) and type of charged lipid in the formulation at three levels were studied on mass median diameter (MMD), liposomal vesicle size, % encapsulation efficiency (% EE), mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF) as critical quality attributes. Optimized formulation (R-LDPI-7) with drug: HSPC ratio of 1:2 and stearyl amine as charged lipid were found to give respirable proliposomes with MMAD of 1.56 ± 0.16 μm and FPF of 92.5 ± 1.5%. Sustained drug release with Higuchi diffusion kinetics was achieved from liposomally encapsulated rifapentine. Pulmonary pharmacokinetics of optimized batch R-LDPI-7 revealed longer retention of drug in lungs with 7 fold increase in both, the mean residence time and t1/2 as compared to R-DPI-0. The study results demonstrated the application of QbD principles and design of experiment (DOE) approach to develop drug encapsulated proliposomes for inhalation by spray drying in single step.

Topics: Administration, Inhalation; Amines; Animals; Antibiotics, Antitubercular; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Liberation; Female; Glycine max; Half-Life; Liposomes; Lung; Male; Particle Size; Phosphatidylcholines; Rats; Regression Analysis; Rifampin; Tissue Distribution

Short-course directly observed isoniazid plus rifapentine (INH/RPT) combination could have potential advantages over a standard 9-month INH regimen for the treatment of latent tuberculosis infection in solid-organ transplant (SOT) candidates.. We prospectively assessed the safety and tolerability of 12 weeks of INH/RPT given directly observed therapy in 17 consecutive SOT candidates with latent tuberculosis infection.. The median age was 57 years and 82% were men. Of the 17 patients, 13 (76%) successfully completed therapy and 4 (24%) eventually underwent SOT. Treatment was prematurely discontinued in four patients. One of these patients underwent a kidney transplant. The overall dose compliance was 83% (169/204 scheduled doses), and 12 (71%) of 17 patients received 100% of scheduled doses. No patient developed transaminase elevations greater than twice baseline or greater than four times the upper limit of normal or clinical hepatotoxicity. No cases of TB developed during 20.4 months after transplant among INH/RPT-treated recipients.. For carefully selected SOT candidates, combination INH/RPT weekly given as directly observed therapy seems to be reasonably well tolerated and is associated with a relatively high completion rate. Future larger prospective studies to confirm the safety and high completion rates reported here and to identify the most appropriate SOT candidates for this regimen are warranted.

Topics: Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Directly Observed Therapy; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Organ Transplantation; Prospective Studies; Rifampin

The potential for rifapentine-containing oral therapeutic regimens to significantly shorten the current six-month anti-tubercular treatment regimen is confounded by high plasma protein binding of rifapentine. Inhaled aerosol delivery of rifapentine, a more potent anti-tubercular antibiotic drug, in combination with other first-line antibiotics may overcome this limitation to deliver a high drug dose at the pulmonary site of infection.. A formulation consisting of rifapentine, moxifloxacin and pyrazinamide, with and without leucine, was prepared by spray-drying. This formulation was assessed for its physico-chemical properties, in vitro aerosol performance and antimicrobial activity.. The antibiotic powders, with and without leucine, had similar median aerodynamic diameters of 2.58 ± 0.08 μm and 2.51 ± 0.06 μm, with a relatively high fine particle fraction of 55.5 ± 1.9% and 63.6 ± 2.0%, respectively. Although the powders were mostly amorphous, some crystalline peaks associated with the δ polymorph for the spray-dried crystalline pyrazinamide were identified.. Stabilisation of the powder with 10% w/w leucine and protection from moisture ingress was found to be necessary to prevent overt crystallisation of pyrazinamide after long-term storage. In vitro biological assays indicated antimicrobial activity was retained after spray-drying. Murine pharmacokinetic studies are currently underway.

Topics: Administration, Inhalation; Aerosols; Animals; Antibiotics, Antitubercular; Humans; Mice; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Particle Size; Powder Diffraction; Powders; Rifampin; Tuberculosis

for assessing the level of understanding of trial-related information during the informed consent (IC) process in developing countries are lacking.. To assess the understanding and retention of trial-related information presented in the IC process by administering an informed consent assessment instrument (ICAI) to participants in a clinical trial for a new tuberculosis (TB) regimen being conducted in Rio de Janeiro (Brazil). Methods The format of the ICAI was based on the language and structure of the United States National Cancer Institute's IC comprehension checklist. The ICAI was designed to assess points of the RioMAR study IC process that addressed the principles of research ethics requested by Brazilian Regulatory Authority: autonomy, beneficence, non-maleficence, and justice. Briefly, (1) Is the respondent participating in a clinical trial? (2) Are two different treatments being evaluated? (3) Is the treatment arm chosen by chance? (4) Is an HIV test required? (5) Are liver function tests required? (6) Can participants leave the study at any time? (7) Are the risks and benefits of taking part in the study clear? (8) May pregnant women participate in the study? (9) Can one of the study drugs reduce the effectiveness of contraceptives? (10) Are patients paid to participate in the study? The ICAI was applied at two time points: immediately after enrollment in the clinical trial and 2 months later.. A total of 61 patients who enrolled in the RioMAR study participated in this study. The percentage of correct answers to all questions was 82% at the time of the first ICAI; 31 participants (51%) did not recall that an HIV test was required (question 4) and 43 (70%) did not know that they could leave the study (question 6). Other individual questions were answered correctly by at least 76% of participants. There was no association between incorrect answers and age, gender, monthly family income, neighborhood, or level of education (p > 0.07). When the responses to the first and the second ICAI questions were compared, 15% or more of participants had conflicting answers to 5 of the 10 questions.. The ICAI uses dichotomous responses, leading to a 50% chance of guessing the correct answers. Two questions were asked only of women. Finally, only 6 of the 10 questions on the current version of the ICAI apply to most trials; others are trial-specific.. The ICAI may be adapted to an individual trial and may prove to be a useful tool following a consent discussion to identify issues not fully understood by the research participants, thus prompting study staff to re-explain topics, possibly in a more elementary manner.

Topics: Adult; Antitubercular Agents; Brazil; Comprehension; Developing Countries; Drug Therapy, Combination; Female; Fluoroquinolones; Humans; Informed Consent; Male; Middle Aged; Moxifloxacin; Randomized Controlled Trials as Topic; Retention, Psychology; Rifampin; Surveys and Questionnaires; Tuberculosis, Pulmonary

Recent murine studies found that rifapentine, dosed daily, at least halved tuberculosis treatment times compared with standard rifampicin and isoniazid-containing regimens. However, in humans, an inhalable form of rifapentine may be necessary to considerably shorten treatment duration because of the physiological barriers associated with oral therapy. The current study compares two inhalable rifapentine dry powders-a novel pure crystalline form and an amorphous form-by a series of in vitro tests. The crystalline and amorphous powders had a mass median aerodynamic size of 1.68 ± 0.03 and 1.92 ± 0.01 μm, respectively, associated with a fine particle fraction of 83.2 ± 1.2% and 68.8 ± 2.1%, respectively. A quinone degradation product was identified in the amorphous powder stored for 1 month, whereas the crystalline form remained chemically stable after storage at both 0% and 60% relative humidity, 25°C, for at least 3 months. Solubilized rifapentine was well tolerated by pulmonary tissue and macrophage cells up to approximately 50 μM. The accumulation of rifapentine within alveolar macrophage cells was significantly higher than for rifampicin, indicating enhanced delivery to infected macrophages. The novel inhalable crystalline form of rifapentine is suitable for targeted treatment of tuberculosis infection and may radically shorten treatment duration.

Topics: Administration, Inhalation; Aerosols; Antibiotics, Antitubercular; Cell Line; Dry Powder Inhalers; Humans; Lung; Macrophages, Alveolar; Mycobacterium tuberculosis; Particle Size; Powders; Rifampin

Rifapentine is highly protein bound in blood, but the free, unbound drug is the microbiologically active fraction. In this exploratory study, we characterized the free plasma fraction of rifapentine in 41 patients with tuberculosis. We found a lower total rifapentine concentration but significantly higher free rifapentine levels in African patients of black race compared to non-Africans. These data support larger pharmacokinetic/pharmacodynamic studies to confirm these findings and assess free rifapentine in relation to microbiological and clinical outcomes.

Topics: Adult; Antibiotics, Antitubercular; Biotransformation; Black People; Blood Proteins; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Protein Binding; Rifampin; Tuberculosis, Pulmonary; White People

Topics: Antitubercular Agents; Female; Fluoroquinolones; Gatifloxacin; Humans; Male; Moxifloxacin; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Pulmonary

Since 2004, treatment of Mycobacterium ulcerans disease, or Buruli ulcer, has shifted from surgery to daily treatment with streptomycin (STR) + rifampin (RIF) for 8 weeks. For shortening treatment duration, we tested the potential of daily rifapentine (RPT), a long-acting rifamycin derivative, as a substitute for RIF.. BALB/c mice were infected with M. ulcerans in the right hind footpad and treated either daily (7/7) with STR+RIF or five days/week (5/7) with STR+RIF or STR+RPT for 4 weeks, beginning 28 days after infection when CFU counts were 4.88±0.51. The relative efficacy of the drug treatments was compared by footpad CFU counts during treatment and median time to footpad swelling after treatment cessation as measure of sterilizing activity. All drug treatments were bactericidal. After 1 week of treatment, the decline in CFU counts was significantly greater in treated mice but not different between the three treated groups. After 2 weeks of treatment, the decline in CFU was greater in mice treated with STR+RPT 5/7 than in mice treated with STR+RIF 7/7 and STR+RIF 5/7. After 3 and 4 weeks of treatment, CFU counts were nil in mice treated with STR+RPT and reduced by more than 3 and 4 logs in mice treated with STR+RIF 5/7 and STR+RIF 7/7, respectively. In sharp contrast to the bactericidal activity, the sterilizing activity was not different between all drug regimens although it was in proportion to the treatment duration.. The better bactericidal activity of daily STR+RIF and especially of STR+RPT did not translate into better prevention of relapse, possibly because relapse-freecure after treatment of Buruli ulcer is more related to the reversal of mycolactone-induced local immunodeficiency by drug treatment rather than to the bactericidal potency of drugs.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Buruli Ulcer; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Female; Mice; Mice, Inbred BALB C; Microbial Viability; Mycobacterium ulcerans; Rifampin; Secondary Prevention; Streptomycin; Treatment Outcome

Rifampin is a potent inducer of cytochrome P450 (CYP) enzymes and transporters. Drug-drug interactions during tuberculosis treatment are common. Induction by rifapentine and rifabutin is understudied. Rifampin and rifabutin significantly induced CYP3A4 (80-fold and 20-fold, respectively) in primary human hepatocytes. The induction was concentration dependent. Rifapentine induced CYP3A4 in hepatocytes from 3 of 6 donors. Data were also generated for ABCB1, ABCC1, ABCC2, organic anion-transporting polypeptide 1B1 (OATP1B1), and OATP1B3. This work serves as a basis for further study of the extent to which rifamycins induce key metabolism and transporter genes.

Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cells, Cultured; Cytochrome P-450 CYP3A; Hepatocytes; Humans; Membrane Transport Proteins; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Rifabutin; Rifampin

Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), is spread from person to person by the airborne route. It can be transmitted extensively in congregate settings, making investigating exposures and treating infected contacts challenging. In December 2011, a student at a Colorado high school with 1,381 students and school personnel received a diagnosis of pulmonary TB disease. One of five household contacts had TB disease, and the other four had latent M. tuberculosis infection (LTBI). Screening of 1,249 school contacts (90%) found one person with pulmonary TB disease, who was fully treated, and 162 with LTBI, of whom 159 started an LTBI treatment regimen for preventing progression to TB disease and 153 completed a regimen. Only the index patient required inpatient care for TB, and TB caused no deaths. Use of short-course treatment regimens, either 12-dose weekly isoniazid and rifapentine directly observed at school or 4 months of self-supervised rifampin daily, facilitated treatment completion. State and county incident command structures led by county TB control authorities guided a response team from multiple jurisdictions. News media reports brought public scrutiny, but meetings with the community addressed the concerns and enhanced public participation. Two contacts of the index patient outside of the school had TB disease diagnosed after the school investigation. As of July 2013, no additional TB disease associated with in-school exposure had been found. An emergency plan for focusing widespread resources, an integral public communications strategy, and new, efficient interventions should be considered in other large TB contact investigations.

Topics: Antitubercular Agents; Capacity Building; Colorado; Communication; Community-Institutional Relations; Contact Tracing; Drug Therapy, Combination; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; School Health Services; Tuberculosis

Topics: Antitubercular Agents; Drug Costs; Humans; Isoniazid; Latent Tuberculosis; Rifampin

A large randomized controlled trial recently showed that for treating latent tuberculous infection (LTBI) in persons at high risk of progression to tuberculosis (TB) disease, a 12-dose regimen of weekly rifapentine plus isoniazid (3HP) administered as directly observed treatment (DOT) can be as effective as 9 months of daily self-administered isoniazid (9H).. To assess the cost-effectiveness of 3HP compared to 9H.. A computational model was designed to simulate individuals with LTBI treated with 9H or 3HP. Costs and health outcomes were estimated to determine the incremental costs per active TB case prevented and per quality-adjusted life year (QALY) gained by 3HP compared to 9H.. Over a 20-year period, treatment of LTBI with 3HP rather than 9H resulted in 5.2 fewer cases of TB and 25 fewer lost QALYs per 1000 individuals treated. From the health system and societal perspectives, 3HP would cost respectively US$21,525 and $4294 more per TB case prevented, and respectively $4565 and $911 more per QALY gained.. 3HP may be a cost-effective alternative to 9H, particularly if the cost of rifapentine decreases, the effectiveness of 3HP can be maintained without DOT, and 3HP treatment is limited to those with a high risk of progression to TB disease.

Topics: Antitubercular Agents; Computer Simulation; Cost-Benefit Analysis; Directly Observed Therapy; Drug Administration Schedule; Drug Costs; Drug Therapy, Combination; Hospital Costs; Humans; Isoniazid; Latent Tuberculosis; Models, Economic; Quality-Adjusted Life Years; Rifampin; Time Factors; Treatment Outcome; United States

Substitution of rifapentine (RFP) for rifampin (RIF) in the standard antituberculous regimen reduces the time required to cure chronic tuberculosis (TB) infection in mice, but not in guinea pigs. In order to gain insight into these discrepant findings, we conducted a steady-state pharmacokinetic (PK) study in healthy guinea pigs to study the metabolism and autoinduction of RIF and RFP. Both RFP and RIF 25-desacetyl metabolites (desRFP and desRIF, respectively), were detected at low concentrations in the serum of guinea pigs. The metabolite concentrations in guinea pigs are much lower than those seen in humans at steady state.

Topics: Animals; Antitubercular Agents; Area Under Curve; Chromatography, High Pressure Liquid; Chromatography, Liquid; Drug Administration Schedule; Female; Guinea Pigs; Host Specificity; Humans; Mice; Rifampin

Novel oral regimens composed of new drugs with potent activity against Mycobacterium tuberculosis and no cross-resistance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tuberculosis. As part of a continuing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, several 3- and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sutezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3- and 4-drug combinations composed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapentine plus clofazimine ≥ clofazimine ≥ rifapentine > PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against susceptible isolates may shorten the duration of treatment further.

Topics: Animals; Antitubercular Agents; Drug Therapy, Combination; Female; Isoniazid; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nitroimidazoles; Oxazolidinones; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

Rifamycins are key sterilizing drugs in the current treatment of active tuberculosis (TB). Daily dosing of rifapentine (P), a potent rifamycin with high intracellular accumulation, in place of rifampin (R) in the standard antitubercular regimen significantly shortens the duration of treatment needed to prevent relapse in a murine model of active TB. We undertook the current study to compare directly the activities of human-equivalent doses of P and R in a guinea pig model of chronic TB, in which bacilli are predominantly extracellular within human-like necrotic granulomas. Hartley strain guinea pigs were aerosol infected with ~200 bacilli of Mycobacterium tuberculosis H37Rv, and treatment given 5 days/week was initiated 6 weeks later. R at 100 mg/kg of body weight and P at 100 mg/kg were given orally alone or in combination with isoniazid (H) at 60 mg/kg and pyrazinamide (Z) at 300 mg/kg. Culture-positive relapse was assessed in subgroups of guinea pigs after completion of 1 and 2 months of treatment. Human-equivalent doses of R and P showed equivalent bactericidal activity when used alone and in combination therapy. In guinea pigs treated with rifampin, isoniazid, and pyrazinamide (RHZ) or PHZ, microbiological relapse occurred in the lungs of 8/10 animals treated for 1 month and in 0/10 animals treated for 2 months. Substitution of P for R in the standard antitubercular regimen did not shorten the time to cure in this guinea pig model of chronic TB. Data from ongoing clinical trials comparing the activity of these two drugs are awaited to determine the relevance of the guinea pig TB model in preclinical drug screening.

Topics: Animals; Antitubercular Agents; Female; Guinea Pigs; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis

In previous experiments, replacing the 10-mg/kg of body weight daily dose of rifampin with 7.5 to 10 mg/kg of rifapentine in combinations containing isoniazid and pyrazinamide reduced the duration of treatment needed to cure tuberculosis in BALB/c mice by approximately 50% due to rifapentine's more potent activity and greater drug exposures obtained. In the present study, we performed dose-ranging comparisons of the bactericidal and sterilizing activities of rifampin and rifapentine, alone and in combination with isoniazid and pyrazinamide with or without ethambutol, in BALB/c mice and in C3HeB/FeJ mice, which develop necrotic lung granulomas after infection with Mycobacterium tuberculosis. Each rifamycin demonstrated a significant increase in sterilizing activity with increasing dose. Rifapentine was roughly 4 times more potent in both mouse strains. These results reinforce the rationale for ongoing clinical trials to ascertain the highest well-tolerated doses of rifampin and rifapentine. This study also provides an important benchmark for the efficacy of the first-line regimen in C3HeB/FeJ mice, a strain in which the lung lesions observed after M. tuberculosis infection may better represent the pathology of human tuberculosis.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Isoniazid; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide; Random Allocation; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Mycobacterium tuberculosis 18b, a streptomycin (STR)-dependent mutant that enters a viable but nonreplicating state in the absence of STR, has been developed as a simple model for drug testing against dormant bacilli. Here, we further evaluated the STR-starved 18b (SS18b) model both in vitro and in vivo by comparing the behavior of 22 approved and experimental tuberculosis drugs. Using the resazurin reduction microplate assay (REMA), rifampin (RIF), rifapentine (RPT), TMC207, clofazimine (CFM), and linezolid (LIN) were found to be active against SS18b in vitro, and their bactericidal activity was confirmed by determining the number of CFU. A latent 18b infection was established in mice, and some of the above-mentioned drugs were used for treatment, either alone or in combination with RIF. RIF, RPT, TMC207, CFM, and pyrazinamide (PZA) were all active in vivo, while cell wall inhibitors were not. A comparative kinetic study of rifamycin efficacy was then undertaken, and the results indicated that RPT clears latent 18b infection in mice faster than RIF. Intrigued by the opposing responses of live and dormant 18b cells to cell wall inhibitors, we conducted a systematic analysis of 14 such inhibitors using REMA. This uncovered an SS18b signature (CWPRED) that accurately predicted the activities of cell wall inhibitors and performed well in a blind study. CWPRED will be useful for establishing the mode of action of compounds with unknown targets, while the SS18b system should facilitate the discovery of drugs for treating latent tuberculosis.

Topics: Acetamides; Amino Acid Sequence; Animals; Antitubercular Agents; Clofazimine; Diarylquinolines; Disease Models, Animal; Drug Discovery; Drugs, Investigational; Female; Genetic Engineering; Latent Tuberculosis; Linezolid; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Molecular Sequence Data; Mycobacterium tuberculosis; Oxazines; Oxazolidinones; Quinolines; Rifampin; Streptomycin; Structure-Activity Relationship; Xanthenes

treatment of Mycobacterium ulcerans disease, or Buruli ulcer (BU), has shifted from surgery to treatment with streptomycin(STR)+rifampin(RIF) since 2004 based on studies in a mouse model and clinical trials. We tested two entirely oral regimens for BU treatment, rifampin(RIF)+clarithromycin(CLR) and rifapentine(RPT)+clarithromycin(CLR) in the mouse model.. BALB/c mice were infected in the right hind footpad with M. ulcerans strain 1059 and treated daily (5 days/week) for 4 weeks, beginning 11 days after infection. Treatment groups included an untreated control, STR+RIF as a positive control, and test regimens of RIF, RPT, STR and CLR given alone and the RIF+CLR and RPT+CLR combinations. The relative efficacy of the drug treatments was compared on the basis of footpad CFU counts and median time to footpad swelling. Except for CLR, which was bacteriostatic, treatment with all other drugs reduced CFU counts by approximately 2 or 3 log(10). Median time to footpad swelling after infection was 5.5, 16, 17, 23.5 and 36.5 weeks in mice receiving no treatment, CLR alone, RIF+CLR, RIF alone, and STR alone, respectively. At the end of follow-up, 39 weeks after infection, only 48%, 26.4% and 16.3% of mice treated with RPT+CLR, RPT alone and STR+RIF had developed swollen footpads. An in vitro checkerboard assay showed the interaction of CLR and RIF to be indifferent. However, in mice, co-administration with CLR resulted in a roughly 25% decrease in the maximal serum concentration (Cmax) and area under the serum concentration-time curve (AUC) of each rifamycin. Delaying the administration of CLR by one hour restored Cmax and AUC values of RIF to levels obtained with RIF alone.. these results suggest that an entirely oral daily regimen of RPT+CLR may be at least as effective as the currently recommended combination of injected STR+oral RIF.

Topics: Animals; Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Disease Models, Animal; Drug Therapy, Combination; Female; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Rifampin; Treatment Outcome

Daily rifapentine plus isoniazid-pyrazinamide in mice infected with Mycobacterium tuberculosis produces cure in 3 months. Whether cure corresponds to latent infection contained by host immunity or true tissue sterilization is unknown.. To determine the length of treatment with rifapentine-isoniazid-pyrazinamide or rifampin-isoniazid-pyrazinamide needed to prevent relapse in immune-deficient mice.. Aerosol-infected BALB/c and nude mice were treated 5 days per week with either 2 months of the rifapentine-based regimen followed by rifapentine-isoniazid up to 12 months or the same regimen with rifampin instead of rifapentine. Cultures of lung homogenates were performed during the first 3 months and then every 3 months. Relapse rates were assessed after 3, 6, 9, and 12 months of treatment in BALB/c (± 1 mo of cortisone) and nude mice.. All rifapentine-treated mice were lung culture-negative at 3 months but 13% of BALB/c that received cortisone and 73% of nude mice relapsed. After 6, 9, and 12 months of treatment no mouse relapsed. Rifampin-treated BALB/c mice remained culture positive at 3 months. All were culture negative at 6, 9, and 12 months. None, including those receiving cortisone, relapsed. Rifampin-treated nude mice harbored more than 4 log(10) lung cfu at Month 2 and approximately 6 log(10) cfu with isoniazid resistance at Month 3. A supplementary experiment demonstrated that 7 days a week treatment did not prevent isoniazid resistance, whereas addition of ethambutol did.. In nude mice, sterilization of tuberculosis is obtained with rifapentine-containing treatment, whereas failure with development of isoniazid resistance is obtained with rifampin-containing treatment.

Topics: Animals; Anti-Inflammatory Agents; Antibiotics, Antitubercular; Antitubercular Agents; Cortisone; Disease Models, Animal; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Isoniazid; Lung; Mice; Mice, Inbred BALB C; Mice, Nude; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Secondary Prevention; Time Factors; Tuberculosis, Pulmonary

Multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) is an emerging global health threat. Proper management of close contacts of infectious patients is increasingly important. However, no evidence-based recommendations for treating latent TB infection (LTBI) after MDR/XDR-TB exposure (DR-LTBI) exist. An ultrashort regimen for LTBI caused by drug-susceptible strains (DS-LTBI) is also desirable. TMC207 has bactericidal and sterilizing activity in animal models of TB and improves the activity of current MDR-TB therapy in patients.. The objective of this study was to determine whether TMC207 might enable short-course treatment of DR-LTBI and ultrashort treatment of DS-LTBI.. Using an established experimental model of LTBI chemotherapy in which mice are aerosol-immunized with a recombinant bacillus Calmette-Guérin vaccine before low-dose aerosol infection with Mycobacterium tuberculosis, the efficacy of TMC207 alone and in combination with rifapentine was compared with currently recommended control regimens as well as once-weekly rifapentine + isoniazid and daily rifapentine ± isoniazid.. Outcomes included monthly lung colony-forming unit counts and relapse rates.. Lung colony-forming unit counts were stable at about 3.75 log(10) for up to 7.5 months postinfection in untreated mice. Rifamycin-containing regimens were superior to isoniazid monotherapy. TMC207 exhibited sterilizing activity at least as strong as that of rifampin alone and similar to that of rifampin + isoniazid, but daily rifapentine +/- isoniazid was superior to TMC207. Addition of TMC207 to rifapentine did not improve the sterilizing activity of rifapentine in this model.. TMC207 has substantial sterilizing activity and may enable treatment of DR-LTBI in 3-4 months.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Female; Latent Tuberculosis; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Quinolines; Rifampin; Stem Cells; Treatment Outcome

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Infant; Infant, Newborn; Isoniazid; Rifampin; Tuberculosis

Rifapentine-based regimens for treating latent tuberculosis infection (LTBI) are being considered for future clinical trials, but even if they prove effective, high drug costs may limit their economic viability.. To inform clinical trial design by estimating the potential costs and effectiveness of rifapentine-based regimens for treatment of latent tuberculosis infection (LTBI).. We used a Markov model to estimate cost and societal benefits for three regimens for treating LTBI: Isoniazid/rifapentine daily for one month, isoniazid/rifapentine weekly for three months (self-administered and directly-observed), and isoniazid daily for nine months; a strategy of "no treatment" used for comparison. Costs, quality-adjusted life-years gained, and instances of active tuberculosis averted were calculated for all arms.. Both daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months were less expensive and more effective than other strategies under a wide variety of clinically plausibly parameter estimates. Daily isoniazid/rifapentine for one month was the least expensive and most effective regimen.. Daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months should be studied in a large-scale clinical trial for efficacy. Because both regimens performed well even if their efficacy is somewhat reduced, study designers should consider relaxing non-inferiority boundaries.

Topics: Antitubercular Agents; Cost-Benefit Analysis; Drug Administration Schedule; Humans; Isoniazid; Latent Tuberculosis; Models, Biological; Patient Compliance; Rifampin; Self Administration; United States

Rifamycins such as rifampicin, rifabutin, and rifapentine are used for the treatment of tuberculosis and induce various drug-metabolizing enzymes. Rifamycins have been reported to be mainly deacetylated by esterase(s) expressed in human liver microsomes (HLM) to 25-deacetylrifamycins, but the responsible enzyme remained to be determined. In this study, we found that recombinant human arylacetamide deacetylase (AADAC) could efficiently deacetylate rifamycins, whereas human carboxylesterases, which are enzymes responsible for the hydrolysis of many prodrugs, showed no activity. The involvement of AADAC in the deacetylation of rifamycins in HLM was verified by the similarities of the K(m) and K(i) values and the inhibitory characteristics between recombinant AADAC and HLM. Rifamycins exhibited potent cytotoxicity to HepG2 cells, but their 25-deacetylated metabolites did not. Luciferase assay using a reporter plasmid containing CYP3A4 direct repeat 3 and everted repeat 6 motifs revealed that 25-deacetylrifamycins have lesser potency to transactivate CYP3A4 compared with the parent drugs. Supporting these results, HepG2 cells infected with a recombinant adenovirus expressing human AADAC showed low cytotoxicity and induction potency of CYP3A4 by rifamycins. In addition, CYP3A4 induction in human hepatocytes by rifamycins was increased by transfecting siRNA for human AADAC. Thus, we found that human AADAC was the enzyme responsible for the deacetylation of rifamycins and would affect the induction rate of drug-metabolizing enzymes by rifamycins and their induced hepatotoxicity.

Topics: Acetylation; Antitubercular Agents; Carboxylic Ester Hydrolases; Cell Survival; Cytochrome P-450 CYP3A; Cytotoxins; Enzyme Induction; HEK293 Cells; Hep G2 Cells; Humans; In Vitro Techniques; Kinetics; Microsomes, Liver; Promoter Regions, Genetic; Recombinant Proteins; Rifabutin; Rifampin

Topics: Antitubercular Agents; Humans; Isoniazid; Male; Rifampin; Tuberculosis

Preventing tuberculosis (TB) by treating latent Mycobacterium tuberculosis infection (LTBI) is a cornerstone of the U.S. strategy for TB elimination. Three randomized controlled trials have shown that a new combination regimen of isoniazid (INH) and rifapentine (RPT) administered weekly for 12 weeks as directly observed therapy (DOT) is as effective for preventing TB as other regimens and is more likely to be completed than the U.S. standard regimen of 9 months of INH daily without DOT. This report provides CDC recommendations for using the INH-RPT regimen. The new regimen is recommended as an equal alternative to the 9-month INH regimen for otherwise healthy patients aged≥12 years who have LTBI and factors that are predictive of TB developing (e.g., recent exposure to contagious TB). The new regimen also can be considered for other categories of patients when it offers practical advantages. Although the INH-RPT regimen was well tolerated in treatment trials, monitoring for adverse effects is recommended. Severe adverse effects should be reported to the Food and Drug Administration (FDA) and CDC.

Topics: Adult; Antitubercular Agents; Child; Child, Preschool; Contraindications; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Isoniazid; Latent Tuberculosis; Randomized Controlled Trials as Topic; Rifampin

We report a case of rifampicin (RMP) dependent/enhanced multidrug-resistant (MDR-TB) from a patient who had been treated with the World Health Organization optional thrice-weekly treatment and document the clinical and bacteriological features. RMP-enhanced tubercle bacilli that grew poorly without RMP but grew better in its presence were isolated from the patient with treatment failure. The bacteria grown without RMP consisted of mixed morphologies of short rod-shaped acid-fast bacteria and poorly stained coccoid bacteria, but stained normally as acid-fast rods when grown in the presence of RMP. The isolated RMP-enhanced bacteria harbored the common S531L mutation and a novel mutation F584S in the rpoB gene. Treatment containing RMP or replacement of RMP with more powerful rifapentine paradoxically aggravated the disease, but its removal led to successful cure of the patient. This study highlights the potential dangers of continued treatment of MDR-TB with rifamycins that can occur due to delayed or absent drug susceptibility results and calls for timely detection of RMP-dependent/-enhanced bacteria in treatment failure patients by including RMP in culture media and removal of RMP from treatment regimen upon detection.

Topics: Adult; Antibiotics, Antitubercular; Bacterial Proteins; DNA-Directed RNA Polymerases; Humans; Male; Mutation; Mycobacterium tuberculosis; Rifampin; Treatment Failure; Tuberculosis, Multidrug-Resistant

TMC207, rifapentine, and moxifloxacin are in clinical testing for the treatment of tuberculosis. Five experimental regimens with various combinations of TMC207, rifapentine, moxifloxacin, and pyrazinamide were tested for their bactericidal and sterilizing potencies in Swiss mice intravenously inoculated with Mycobacterium tuberculosis bacilli. TMC207 had the strongest bactericidal efficacy, while rifapentine was the strongest contributor to sterilizing efficacy. The rank order of sterilizing potencies was different from the rank order of bactericidal potencies, underlining the importance of prioritizing new regimens designed to shorten the treatment duration by their sterilizing potencies rather than by their bactericidal potencies. Both 3 months of treatment with a regimen combining TMC207, pyrazinamide, and rifapentine and 5 months of treatment with a regimen combining TMC207, pyrazinamide, and moxifloxacin resulted in relapse rates similar to the rate obtained by 6 months of treatment with rifampin-isoniazid-pyrazinamide.

Topics: Animals; Antibiotics, Antitubercular; Aza Compounds; Diarylquinolines; Disease Models, Animal; Female; Fluoroquinolones; Mice; Moxifloxacin; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Tuberculosis

R207910 (TMC207 or J) is a member of the diarylquinolines, a new family of antituberculous drugs with high bactericidal activity when given daily in the murine model of tuberculosis. R207910 exhibits a long half-life and thus is a good candidate for once-weekly therapy of tuberculosis.. To study the activity of once-weekly R207910 monotherapy and combinations of R207910 with other antituberculous agents (isoniazid, rifapentine, moxifloxacin, and pyrazinamide).. The established infection model of murine tuberculosis was used. Colony counts were determined in the lungs.. Eight weeks of monotherapy reduced the bacillary load by 3 to 4 log(10) for rifapentine and by 5 to 6 log(10) for R207910 (P < 0.05). The addition of rifapentine and isoniazid or moxifloxacin did not improve the bactericidal activity of R207910 monotherapy. In contrast, the triple combination of R207910 plus rifapentine plus pyrazinamide given once weekly for 2 months (i.e., a total of only eight administrations), was significantly (P < 0.05) more active than R207910 monotherapy or other R207910 combinations, and led to lung culture negativity in 9 of 10 mice, whereas all lungs were culture positive in the groups treated with other drug combinations. Moreover, R207910 plus rifapentine plus pyrazinamide given once weekly was more active than the current standard regimen of rifampin plus isoniazid plus pyrazinamide given five times per week.. The unprecedented activity of the triple combination of R207910 plus rifapentine plus pyrazinamide suggests that it may be feasible to develop a fully intermittent once-weekly regimen.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Lung; Mice; Pyrazinamide; Quinolines; Rifampin; Tuberculosis

Topics: Antitubercular Agents; Diarylquinolines; Half-Life; Humans; Quinolines; Rifampin; Tuberculosis, Pulmonary

Isoniazid given daily for 9 months is the standard treatment for latent tuberculosis infection (LTBI), but its effectiveness is limited by poor completion rates. Shorter course regimens and regimens using directly observed therapy result in improved adherence but have higher upfront costs.. To evaluate the costs and cost-effectiveness of regimens for the treatment of LTBI.. We used a computerized Markov model to estimate total societal costs and benefits associated with four regimens for the treatment of LTBI: self-administered isoniazid daily for 9 months, directly observed isoniazid twice-weekly for 9 months, directly observed isoniazid plus rifapentine once weekly for 3 months, and self-administered rifampin daily for 4 months. In the base-case analysis, subjects were assumed to have newly positive tuberculin skin tests after recent exposure to infectious tuberculosis.. We determined the costs of treatment, quality-adjusted life-years gained, and cases of active tuberculosis prevented. In the base-case analysis, rifampin dominated (less costly with increased benefits) all other regimens except isoniazid plus rifapentine, which was more effective at a cost $48,997 per quality-adjusted life year gained. Isoniazid plus rifapentine dominated all regimens at a relative risk of disease 5.2 times the baseline estimate, or with completion rates less than 34% for isoniazid or 37% for rifampin. Rifampin could be 17% less efficacious than self-administered isoniazid and still be cost-saving compared with this regimen.. In our model, rifampin is cost-saving compared with the standard therapy of self-administered isoniazid. Isoniazid plus rifapentine is cost-saving for extremely high-risk patients and is cost-effective for lower-risk patients.

Topics: Antitubercular Agents; Cost-Benefit Analysis; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Markov Chains; Rifampin; Tuberculosis

The role of microbial factors in outcomes of tuberculosis treatment has not been well studied. We performed a case-control study to evaluate the association between a Beijing strain and tuberculosis treatment outcomes. Isolates from patients with culture-positive treatment failure (n = 8) or relapse (n = 54) were compared with isolates from randomly selected controls (n = 296) by using spoligotyping. Patients with Beijing strains had a higher risk for relapse (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.0-4.0, p = 0.04) but not for treatment failure. Adjustment for factors previously associated with relapse had little effect on the association between Beijing strains and relapse. Beijing strains were strongly associated with relapse among Asian-Pacific Islanders (OR 11, 95% CI 1.1-108, p = 0.04). Active disease caused by a Beijing strain was associated with increased risk for relapse, particularly among Asian-Pacific Islanders.

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Asian People; Case-Control Studies; China; HIV Infections; Humans; Mycobacterium tuberculosis; Recurrence; Rifampin; Risk Factors; Treatment Failure; Treatment Outcome; Tuberculosis; Tuberculosis, Pulmonary

Regimens recommended to treat latent tuberculosis infection (LTBI) are 3 to 9 months long. A 2-month rifampin+pyrazinamide regimen is no longer recommended. Shorter regimens are highly desirable. Because substituting rifapentine for rifampin in the standard regimen for active tuberculosis halves the treatment duration needed to prevent relapse in mice, we hypothesized daily rifapentine-based regimens could shorten LTBI treatment to 2 months or less.. To improve an existing model of LTBI chemotherapy and evaluate the efficacy of daily rifapentine-based regimens.. Mice were immunized with a more immunogenic recombinant Bacille Calmette-Guérin strain (rBCG30) and received very low-dose aerosol infection with Mycobacterium tuberculosis to establish a stable lung bacterial burden below 10(4) CFU without drug treatment. Mice received a control (isoniazid alone, rifampin alone, rifampin+isoniazid, rifampin+pyrazinamide) or test (rifapentine alone, rifapentine+isoniazid, rifapentine+pyrazinamide, rifapentine+isoniazid+pyrazinamide) regimen for 8 weeks. Rifamycin doses were 10 mg/kg/d, analogous to the same human doses. Outcomes were biweekly lung CFU counts and relapse after 4 to 8 weeks of treatment.. M. tuberculosis CFU counts remained stable around 3.65 log(10) in immunized, untreated mice. Isoniazid or rifampin left all or most mice culture-positive at week 8. Rifampin+isoniazid cured 0 and 53% of mice and rifampin+pyrazinamide cured 47 and 100% of mice in 4 and 8 weeks, respectively. Rifapentine-based regimens were more active than rifampin+isoniazid and indistinguishable from rifampin+pyrazinamide.. In this improved murine model of LTBI chemotherapy with very low lung burden, existing regimens were well represented. Daily rifapentine-based regimens were at least as active as rifampin+pyrazinamide, suggesting they could effectively treat LTBI in 6 to 8 weeks.

Topics: Animals; Antibiotics, Antitubercular; Disease Models, Animal; Drug Administration Schedule; Female; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis

RUTI is a therapeutic vaccine that is generated from detoxified and liposomed Mycobacterium tuberculosis cell fragments that has demonstrated its efficacy in the control of bacillus reactivation after short-term chemotherapy. The aim of this study was to characterize the cellular immune response generated after the therapeutic administration of RUTI and to corroborate the lack of toxicity of the vaccine. Mouse and guinea pig experimental models were infected with a low-dose M. tuberculosis aerosol. RUTI-treated animals showed the lowest bacillary load in both experimental models. RUTI also decreased the percentage of pulmonary granulomatous infiltration in the mouse and guinea pig models. This was not the case after Mycobacterium bovis BCG treatment. Cellular immunity was studied through the characterization of the intracellular gamma interferon (IFN-gamma)-producing cells after the splenocytes' stimulation with M. tuberculosis-specific structural and growth-related antigens. Our data show that the difference between the therapeutic administration of BCG and RUTI resides mainly in the stronger activation of IFN-gamma(+) CD4(+) cells and CD8(+) cells against tuberculin purified protein derivative, ESAT-6, and Ag85B that RUTI generates. Both vaccines also triggered a specific immune response against the M. tuberculosis structural antigens Ag16kDa and Ag38kDa and a marked mRNA expression of IFN-gamma, tumor necrosis factor, interleukin-12, inducible nitric oxide synthase, and RANTES in the lung. The results show that RUTI's therapeutic effect is linked not only to the induction of a Th1 response but also to the stimulation of a quicker and stronger specific immunity against structural and growth-related antigens that reduces both the bacillary load and the pulmonary pathology.

Topics: Animals; Antigens, Bacterial; Antitubercular Agents; BCG Vaccine; Female; Guinea Pigs; Humans; Interferon-gamma; Isoniazid; Liposomes; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Rifampin; Specific Pathogen-Free Organisms; T-Lymphocytes; Time Factors; Treatment Outcome; Tuberculosis Vaccines; Tuberculosis, Pulmonary

Patients with cavitary pulmonary tuberculosis (TB) on baseline chest radiograph (CXR) who remain culture-positive after 8 weeks of treatment are at high risk of relapse. The role of end-of-treatment (EOT) CXR in predicting relapse is unclear.. To determine whether EOT CXR independently predicts TB relapse.. We conducted a secondary analysis of a randomized trial of intermittent treatment using rifapentine in the continuation phase of TB treatment among 1004 human immunodeficiency virus seronegative adults with culture-proven pulmonary TB.. Relapse occurred in 17.3% of subjects with persistent cavity on EOT CXR, in 7.6% of subjects with a cavity that resolved by EOT, and 2.5% (P=0.002 for trend) of subjects who never had a cavity. In multivariable analysis, patients with persistent cavity on EOT CXR were significantly more likely to relapse than patients with no cavity on baseline or 2-month CXR (hazard ratio [HR] 4.22, 95%CI 2.00-8.91), and were more likely to relapse than subjects whose early cavity had resolved by EOT CXR (HR 1.92, 95%CI 1.09-3.39).. A persistent cavity after 6 months of TB treatment was independently associated with disease relapse after controlling for other variables. EOT CXR may help predict those likely to relapse.

Topics: Adult; Antibiotics, Antitubercular; Female; HIV Seronegativity; Humans; Male; Mass Chest X-Ray; Predictive Value of Tests; Randomized Controlled Trials as Topic; Recurrence; Rifampin; Risk Factors; Sensitivity and Specificity; Treatment Outcome; Tuberculosis, Pulmonary

Recent studies have demonstrated that combined substitutions of rifapentine for rifampin and moxifloxacin for isoniazid in the standard, daily, short-course regimen of rifampin, isoniazid, and pyrazinamide produces stable cure in 12 weeks or less. This study was designed to more precisely evaluate the contribution of moxifloxacin and isoniazid to rifapentine-based regimens.. We compared bactericidal activity and treatment-shortening potential between regimens consisting of isoniazid or moxifloxacin plus rifapentine and pyrazinamide administered either thrice-weekly or daily.. Using a mouse model of tuberculosis, we assessed bactericidal activity by performing quantitative cultures of lung homogenates over the first 12 weeks of treatment. Relapse rates were assessed after completing 8, 10, and 12 weeks of treatment to determine the duration of treatment necessary for stable cure.. After 4 weeks of treatment, daily and thrice-weekly therapy with rifapentine, moxifloxacin, and pyrazinamide was significantly more active than treatment with rifapentine, isoniazid, and pyrazinamide. By 8 weeks of treatment, all mice receiving the moxifloxacin-containing regimens were lung culture negative, whereas those mice receiving the isoniazid-containing regimens continued to be lung culture positive. However, the duration of treatment necessary to achieve stable cure was 10 weeks for daily regimens and 12 weeks for thrice-weekly regimens, regardless of whether isoniazid or moxifloxacin was used. All mice receiving standard daily therapy with rifampin, isoniazid, and pyrazinamide relapsed after 12 weeks of treatment.. These results suggest that regimens consisting of isoniazid or moxifloxacin plus rifapentine and pyrazinamide may dramatically shorten the duration of treatment needed to cure human tuberculosis.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Aza Compounds; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluoroquinolones; Isoniazid; Lung; Mice; Mice, Inbred BALB C; Moxifloxacin; Pyrazinamide; Quinolines; Recurrence; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

Topics: Animals; Antibiotics, Antitubercular; Disease Models, Animal; Drug Approval; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Mice; Rifampin; Tuberculosis; United States; United States Food and Drug Administration

Topics: Antitubercular Agents; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis; Virus Latency

Availability of an ultra-short-course drug regimen capable of curing patients with tuberculosis in 2 to 3 mo would significantly improve global control efforts. Because immediate prospects for novel treatment-shortening drugs remain uncertain, we examined whether better use of existing drugs could shorten the duration of treatment. Rifapentine is a long-lived rifamycin derivative currently recommended only in once-weekly continuation-phase regimens. Moxifloxacin is an 8-methoxyfluoroquinolone currently used in second-line regimens.. Using a well-established mouse model with a high bacterial burden and human-equivalent drug dosing, we compared the efficacy of rifapentine- and moxifloxacin-containing regimens with that of the standard daily short-course regimen based on rifampin, isoniazid, and pyrazinamide. Bactericidal activity was assessed by lung colony-forming unit counts, and sterilizing activity was assessed by the proportion of mice with culture-positive relapse after 2, 3, 4, and 6 mo of treatment. Here, we demonstrate that replacing rifampin with rifapentine and isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen. After just 2 mo of treatment, mice receiving rifapentine- and moxifloxacin-containing regimens were found to have negative lung cultures, while those given the standard regimen still harbored 3.17 log10 colony-forming units in the lungs (p < 0.01). No relapse was observed after just 3 mo of treatment with daily and thrice-weekly administered rifapentine- and moxifloxacin-containing regimens, whereas the standard daily regimen required 6 mo to prevent relapse in all mice.. Rifapentine should no longer be viewed solely as a rifamycin for once-weekly administration. Our results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and moxifloxacin may permit shortening the current 6 mo duration of treatment to 3 mo or less. Such regimens warrant urgent clinical investigation.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Aza Compounds; Colony Count, Microbial; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Fluoroquinolones; Isoniazid; Lung; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Secondary Prevention; Time Factors; Tuberculosis

Topics: Animals; Antitubercular Agents; Aza Compounds; Clinical Trials as Topic; Drug Combinations; Fluoroquinolones; Humans; Mice; Moxifloxacin; Quinolines; Rifampin; Treatment Outcome; Tuberculosis

This investigation retrospectively assessed inexpensive non-invasive qualitative methods to monitor the ingestion of anti-tuberculosis drugs isoniazid, rifampicin and rifapentine. Results showed that commercial test strips detected the isoniazid metabolites isonicotinic acid and isonicotinylglycine as efficiently as the isonicotinic acid method in 150 urine samples. The presence of rifamycins in urine samples (n=1085) was detected by microbiological assay techniques and the sensitivity compared to the n-butanol extraction colour test in 91 of these specimens. The proportions detected by the two methods were significantly different and the sensitivity of the n-butanol procedure was only 63.8% (95% CL 51.2-76.4%) as compared to that of the superior microbiological method. Final validation (n=691) showed that qualitative assays measure isoniazid and rifamycin ingestion with an efficiency similar to high-performance liquid chromatography. The qualitative procedures may therefore be valuable in clinical trials and in tuberculosis clinics to confirm drug ingestion.

Topics: Antitubercular Agents; Drug Monitoring; Humans; Isoniazid; Isonicotinic Acids; Microbial Sensitivity Tests; Patient Compliance; Reproducibility of Results; Retrospective Studies; Rifampin; Self Administration; Staphylococcus aureus

Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of tuberculosis relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substituting rifapentine for rifampin.. To test this hypothesis, we compared the activities of standard daily and twice-weekly rifampin plus isoniazid-based regimens to those of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing regimens in the murine model of tuberculosis. Relapse rates were assessed after 4, 5, and 6 mo of treatment to assess stable cure. Single- and multiple-dose pharmacokinetics of rifampin and rifapentine were also determined.. After 2 mo of treatment, twice-weekly therapy with rifapentine (15 or 20 mg/kg), moxifloxacin, and pyrazinamide was significantly more active than standard daily or twice-weekly therapy with rifampin, isoniazid, and pyrazinamide. Stable cure was achieved after 4 mo of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing therapy, but only after 6 mo of standard daily therapy. Twice-weekly rifapentine (15 mg/kg) displayed more favorable pharmacodynamics than did daily rifampin (10 mg/kg).. By virtue of the enhanced rifamycin exposure, twice-weekly regimens containing rifapentine (15 or 20 mg/kg) may permit shortening the current treatment duration by 2 mo. Such regimens warrant clinical investigation.

Topics: Animals; Antitubercular Agents; Aza Compounds; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluoroquinolones; Isoniazid; Mice; Mice, Inbred BALB C; Moxifloxacin; Pyrazinamide; Quinolines; Rifampin; Tuberculosis, Pulmonary

A well-known problem of anti-tuberculosis fixed-dose combination (FDC) products containing rifampicin (R) and isoniazid (H) is the fall in bioavailability, in particular of R, when two or more drugs are present together. The same has been ascribed to hydrolysis of R to 3-formylrifamycin (3-RIF) under stomach acid conditions and reaction of the latter with H to form isonicotinyl hydrazone (HYD). The objective of present study was to explore whether the same reaction occurred when H was present along with rifapentine (Rp), a newer long acting rifamycin, which is structurally similar to R. Clinical trials are currently undergoing for co-administration of Rp with H in patients who had completed 2 months of standard chemotherapy. For the purpose, first a validated HPLC method was developed for the separation of Rp and H, and the same was used for the study of interaction between the two drugs. Like R, Rp was also found to convert to 3-RIF in acid conditions, which reacted further with H to form HYD. The pH-rate profile was also similar in shape to that established with the combination of R and H; maximum decomposition occurred at pH 2, where Rp loss was to an extent of approximately 30%, while corresponding decomposition of H was approximately 9%. These values were similar to those reported for the combination of R (approximately 33%) and H (approximately 10%). Hence, the study suggests that co-administration of Rp and H should be avoided, like in case of R and H, and the two drugs should not be formulated directly into a single dosage form.

Topics: Antitubercular Agents; Chromatography, High Pressure Liquid; Drug Interactions; Hydrogen-Ion Concentration; Isoniazid; Rifampin

Rifapentine is a rifamycin antibiotic approved for the treatment of pulmonary infections caused by Mycobacterium tuberculosis. Although the pharmacokinetics of rifapentine has been investigated in adolescents and adults, no studies have assessed the pharmacokinetics of this drug in children or infants.. Twenty-four children (7.1 +/- 3.3 years; mean +/- 1 SD, 27.9 +/- 11.9 kg) were enrolled in this open label study. Children received a single oral dose (10 to <30 kg body weight received 150 mg; 30 to <60 kg body weight received 300 mg), followed by repeated blood sampling (n = 11) for 32 hours. Rifapentine and 25-desacetyl rifapentine were quantitated by a validated high-pressure liquid chromatography method. Pharmacokinetic parameters were determined using a model-independent approach.. A significant difference in dose-normalized area under the curves (AUC0-n and AUC0-infinity) was observed between children receiving the 150 and 300 mg doses, which was accounted for by differences in age between the dosing arms. In separate analyses, including data from adults, further age-dependence in total body exposure (reflected by AUC) and elimination was observed. Adverse events associated with rifapentine were mild and included gastric distress (n = 1) and vomiting (n = 2).. Given a comparable weight-normalized dose, rifapentine exposure estimates are lower in children than those reported in adults, suggesting that a larger weight-normalized (ie, mg/kg) dose of rifapentine is needed in children.

Topics: Administration, Oral; Antibiotics, Antitubercular; Area Under Curve; Child; Child, Preschool; Chromatography, High Pressure Liquid; Female; Humans; Male; Rifampin

To prepare rifapentine (RIF) liposomes modified by surfactants for studying their the water-solubility, drug loading effeciency, release rate and pulmonary drug delivery.. The film method was used to prepare RIF liposomes. Of verious RIF liposomes morphology by lauric diethanolamide (LDEA), Tween 80 and azone, the properties were studied, envolving morphology, entrapment drug release rate and dissected lung-membrance penetration rate of swine. Pulmonary delivery study was carried out through bronchoscope.. The particle size of RIF-LDEA liposomes was between 15 - 50 nm. The top entrapment efficiency reached 83.0%. The apparent coefficient of membrane penetration (Kp) was 44.29. LD50 was 675 mg x kg(-1) by iv.. LDEA increased the water-solubility, loading effeciency and release rate of RIF liposomes. The prepared RIF-LDEA liposomes were suitable for the treatment of pulmonary tubrculosis through bronchoscope.

Topics: Animals; Antibiotics, Antitubercular; Drug Carriers; Drug Delivery Systems; Ethanolamines; Lauric Acids; Liposomes; Lung; Particle Size; Permeability; Rifampin; Solubility; Swine

To study the bactericidal effect of rifapentine and its cross-resistance with rifampin for Mycobacterium tuberculosis and to determine the critical concentration of rifapentine for laboratory drug susceptibility test and therefore to provide the laboratory data for using rifapentine in the treatment of tuberculosis, particularly rifampin resistant tuberculosis.. We detected the minimal inhibitory concentrations (MICs) of rifampin and rifapentine to H(37) Rv and isolated strains of rifampin susceptible and resistant Mycobacterium tuberculosis by using Middlebrook 7H9, Sauton and Lowenstein-Jensen media.. The MICs of rifampin were > or = 0.32 microg/ml for 80% of the 19 rifampin susceptible strains on Middlebrook 7H9 and the MICs of rifapentine ranged from 0.02 microg/ml to 0.32 microg/ml for most of the strains (84%). The MICs of rifapentine were 2 - 4 times lower than those of rifampin to H(37) Rv and most clinical isolates. The rifapentine susceptible isolates were mostly separated from resistant strains at MICs 5-10 microg/ml.. Our results demonstrate the cross resistance of rifampin and rifapentine and the stronger bactericidal potency of rifapentine than rifampin. Some rifampin resistant strains still show susceptibility to rifapentine, which suggests rifapentine may be effective in the treatment of rifampin resistant tuberculosis. Our results also determined a critical resistant concentration of rifapentine for routine drug susceptibility test.

Topics: Antibiotics, Antitubercular; Culture Media; Drug Resistance, Bacterial; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity

Topics: Antibiotics, Antitubercular; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Rifamycins; Secondary Prevention; Time Factors; Tuberculosis, Pulmonary

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.. 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 high-risk 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.. 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 once-weekly isoniazid plus rifapentine (15 mg/kg) and the Denver regimen.. These results suggest that the efficacy of the once-weekly 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.

Topics: Animals; Antibiotics, Antitubercular; Aza Compounds; Colony Count, Microbial; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluoroquinolones; Follow-Up Studies; Lung; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium tuberculosis; Quinolines; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Priorities for developing improved regimens for treatment of latent tuberculosis (TB) infection include (1) developing shorter and/or more intermittently administered regimens that are easier to supervise and (2) developing and evaluating regimens that are active against multidrug-resistant organisms.. By using a previously validated murine model that involves immunizing mice with Mycobacterium bovis bacillus Calmette-Guérin to augment host immunity before infection with virulent Mycobacterium tuberculosis, we evaluated new treatment regimens including rifapentine and moxifloxacin, and assessed the potential of the Mycobacterium leprae heat shock protein-65 DNA vaccine to augment the activity of moxifloxacin.. Quantitative spleen colony-forming unit counts, and the proportion of mice with culture-positive relapse after treatment, were determined.. Three-month, once-weekly regimens of rifapentine combined with either isoniazid or moxifloxacin were as active as daily isoniazid for 6-9 mo. Six-month daily combinations of moxifloxacin with pyrazinamide, ethionamide, or ethambutol were more active than pyrazinamide plus ethambutol, a regimen recommended for latent TB infection after exposure to multidrug-resistant TB. The combination of moxifloxacin with the experimental nitroimidazopyran PA-824 was especially active. Finally, the heat shock protein-65 DNA vaccine had no effect on colony-forming unit counts when given alone, but augmented the bactericidal activity of moxifloxacin.. Together, these findings suggest that rifapentine, moxifloxacin, and, perhaps, therapeutic DNA vaccination have the potential to improve on the current treatment of latent TB infection.

Topics: Animals; Antibiotics, Antitubercular; Aza Compounds; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Female; Fluoroquinolones; Follow-Up Studies; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium tuberculosis; Quinolines; Rifampin; Spleen; Treatment Outcome; Tuberculosis; Vaccines, DNA

Long-half-life drugs raise the hope of once-a-week administration of antituberculous treatment. In a previous study with the murine model of tuberculosis, the most active intermittent regimen which contained rifapentine (RFP), isoniazid (INH), and moxifloxacin (MXF) given once a week during 5.5 months, preceded by 2 weeks of daily treatment with INH, rifampin (RIF), pyrazinamide (PZA), and MXF, was less active than the standard 6-month daily RIF-INH-PZA regimen. We evaluated with the same model similar regimens in which we increased the dosing of rifapentine from 10 to 15 mg/kg of body weight and of moxifloxacin from 100 to 400 mg/kg. Mice infected intravenously by 6.2 x10(6) CFU of Mycobacterium tuberculosis H37Rv were treated 2 weeks later when infection was established. After 6 months of treatment, all mice had negative lung culture. After 3 months of follow-up, no relapse occurred in the two groups that received moxifloxacin at 400 mg/kg, whatever the dosage of RFP, and in the group receiving the standard RIF-INH-PZA control regimen. In contrast, in the two groups receiving moxifloxacin at a lower dosage, the relapse rate was significantly higher (13% in mice receiving RFP at 15 mg/kg and 27% in those receiving RFP at 10 mg/kg). Finally, the fully intermittent once-a-week regimen (26 drug ingestions) of INH, RFP (15 mg/kg), and MXF (400 mg/kg) led to a relapse rate of 11%. In conclusion, when used at high dosage, rifapentine and moxifloxacin are very efficient when combined with isoniazid in a once-a-week treatment in mouse tuberculosis.

Topics: Animals; Animals, Outbred Strains; Antibiotics, Antitubercular; Antitubercular Agents; Aza Compounds; Drug Therapy, Combination; Female; Fluoroquinolones; Mice; Moxifloxacin; Mycobacterium tuberculosis; Quinolines; Random Allocation; Rifampin; Survival Rate; Time Factors; Tuberculosis

This study was designed to describe the population pharmacokinetics of rifapentine (RFP) and 25-desacetyl RFP in a South African pulmonary tuberculosis patient population. Special reference was made to studying the influence of previous exposure to rifampin (RIF) and the variability in pharmacokinetic parameters between patients and between occasions and the influence of different covariates. Patients were included in the study if they had been receiving first-line antimycobacterial therapy (rifampin, isoniazid, pyrazinamide, and ethambutol) for not less than 4 weeks and not more than 6 weeks and were divided into three RFP dosage groups based on weight: 600 mg, <45 kg; 750 mg, 46 to 55 kg; and 900 mg, >55 kg. Participants received a single oral dose of RFP together with concomitant antimycobacterial agents, excluding RIF, on study days 1 and 5 after they ingested a soup-based meal. The RFP and 25-desacetyl RFP concentration-time data were analyzed by nonlinear mixed-effect modeling using NONMEM. The pharmacokinetics of the parent drug were modeled separately, and the individual pharmacokinetic parameters were used as inputs for the 25-desacetyl RFP pharmacokinetic model. A one-compartment disposition model was found to best describe the data for both the parent and the metabolite, and the metabolite was assumed to be formed only from the central compartment of the parent drug. Prior treatment with RIF did not alter the pharmacokinetics of RFP but appeared to increase the excretion of 25-desacetyl RFP in a nonlinear fashion. The RFP oral clearance and volume of distribution were found to increase by 0.049 liter/h and 0.691 liter, respectively, with a 1-kg increase from the median weight of 50 kg. The oral clearance of 25-desacetyl RFP was found to be 35% lower in female patients. The model developed here describes the population pharmacokinetics of RFP and its primary metabolite in tuberculosis patients and includes the effects of prior administration with RIF and covariate factors.

Topics: Adult; Antibiotics, Antitubercular; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Rifampin; Tuberculosis, Pulmonary

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.

Topics: Anti-Infective Agents; Antitubercular Agents; Aza Compounds; Drug Combinations; Fluoroquinolones; Isoniazid; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium tuberculosis; Quinolines; Rifampin

Topics: Antibiotics, Antitubercular; Dose-Response Relationship, Drug; Drug Combinations; Half-Life; Humans; Isoniazid; Rifampin; Tuberculosis, Pulmonary

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Hong Kong; Humans; Isoniazid; Prognosis; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Thioacetazone; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; World Health Organization

Mycobacterium kansasii was administered intravenously to congenitally athymic (nude) mice. Beginning 1 week later, rifapentine, azithromycin, ethambutol or combined therapy was initiated orally. All three drugs were highly active individually. Although there was no evidence of antagonism, combined therapy was not more effective than either component used alone.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Drug Interactions; Drug Therapy, Combination; Ethambutol; Mice; Mice, Inbred BALB C; Mycobacterium Infections, Nontuberculous; Mycobacterium kansasii; Rifampin; Survival Analysis

Mice infected with 1.6 x 10(7) CFU of Mycobacterium tuberculosis were treated 14 days later for 6 months with a regimen of once-weekly 10 mg of rifapentine and 75 mg of isoniazid per kg of body weight supplemented with either 150 mg of streptomycin per kg or 100 mg of moxifloxacin per kg during either both the 2-week daily initial and once-weekly continuation phases or only in the daily 2-week initial phase. On completion of treatment, all lung cultures were negative, except for three mice, each with a single colony: two whose rifapentine-isoniazid regimen was supplemented with streptomycin during the whole course of therapy and one whose rifapentine-isoniazid regimen had no initial daily phase, but was supplemented with streptomycin and moxifloxacin during the whole course of therapy. After 3 months of follow-up, positive lung cultures were obtained from 61 and 56% of mice supplemented with streptomycin during either the full course of therapy or only the daily 2-week initial phase, respectively, and 15 and 50% of mice supplemented with moxifloxacin during either the full course of therapy or only the daily 2-week initial phase, respectively. These results suggest that moxifloxacin has sterilizing activity against M. tuberculosis.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antitubercular; Antitubercular Agents; Aza Compounds; Colony Count, Microbial; Drug Resistance, Microbial; Female; Fluoroquinolones; Isoniazid; Lung; Mice; Moxifloxacin; Mycobacterium tuberculosis; Organ Size; Quinolines; Rifampin; Spleen; Streptomycin; Survival Rate; Tuberculosis

The effectiveness of various once-weekly 10 mg/kg rifapentine (P)- containing regimens for treatment of tuberculosis was assessed in mice infected intravenously with 4.3 x 10(6) colony-forming units (cfu) of Mycobacterium tuberculosis H37Rv, and treated 14 d later with various combinations of rifampin (R), P, isoniazid (H), pyrazinamide (Z), ethambutol (E), or streptomycin (S). Control mice treated daily with either 2-mo HRZ + 4-mo HR or 2-mo HRZ + 6-mo HE were rendered spleen and lung culture-negative at 6 mo and 8 mo, respectively. Treatment failure with emergence of R-resistant bacilli occurred in all mice given once-weekly monotherapy with P for 6 mo. Once-weekly PH treatment was successful at 6 mo when it was preceded by a 2-mo daily phase with HRZ. When the initial daily phase was reduced to 2 wk, once-weekly PH-containing treatment was successful, at 6 mo, only if it was supplemented with S during the initial daily and the once-weekly phases, and at 8 mo if it was supplemented with daily H during the once-weekly phase. Without these supplements, once-weekly treatment failed in some mice with selection of R-resistant or H-resistant mutants.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Female; Isoniazid; Lung; Mice; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Spleen; Streptomycin; Tuberculosis

Bactericidal activities of HMR 3647 (HMR), moxifloxacin (MXFX), and rifapentine (RPT) against Mycobacterium leprae, measured by the proportional bactericidal technique in the mouse footpad system, were compared with those of the established antileprosy drugs clarithromycin (CLARI), ofloxacin (OFLO), and rifampin (RMP). Administered in five daily doses of 100 mg/kg of body weight, HMR appeared slightly more bactericidal than CLARI. In a single dose, MXFX at 150 mg/kg was more active than the same dose of OFLO and displayed exactly the same level of activity as RMP at 10 mg/kg; the combination MXFX-minocycline (MINO) (MM) was more bactericidal than the combination OFLO-MINO (OM); RPT at 10 mg/kg was more bactericidal than the same dose of RMP and even more active than the combination RMP-OFLO-MINO (ROM); the combination RPT-MXFX-MINO (PMM) killed 99.9% of viable M. leprae and was slightly more bactericidal than RPT alone, indicating that the combination PMM showed an additive effect against M. leprae.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Aza Compounds; Female; Fluoroquinolones; Foot; Ketolides; Leprostatic Agents; Leprosy; Macrolides; Mice; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium leprae; Quinolines; Rifampin; Skin

The in vitro activity of rifapentine and its metabolite, 25-O:-desacetylrifapentine, as compared with that of rifampicin and rifabutin, was determined against Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis and M. bovis BCG. MICs were determined radiometrically and by the 1% proportional method using Middlebrook 7H11 agar. The bactericidal effect of the drugs was determined in parallel at selected concentrations. For drugsusceptible isolates of M. tuberculosis, the Bactec MICs of rifapentine and 25-O:-desacetylrifapentine were 0.03-0.06 mg/L and 0. 125-0.25 mg/L, respectively. Similar MICs were obtained for M. africanum (0.03-0.125 and 0.125-0.50 mg/L, respectively), and M. bovis (0.063-0.25 and 0.125-1.0 mg/L, respectively), but MICs were considerably lower for M. bovis BCG (0.008-0.063 mg/L for rifapentine and 0.016-0.125 mg/L for its metabolite). In general, MICs determined using 7H11 agar medium were usually one or two dilutions higher than those obtained using Bactec broth. When compared with rifampicin and rifabutin, the inhibitory activity of rifapentine for drug-susceptible isolates was roughly equal to that of rifabutin, and the inhibitory activity of 25-O:-desacetylrifapentine was comparable to that of rifampicin; however, rifapentine was somewhat more bactericidal than rifabutin at equal concentrations. Clinical isolates of M. tuberculosis with a high degree of resistance to rifampicin (MIC >/= 32 mg/L) were also highly resistant to rifabutin, rifapentine and 25-O:-desacetylrifapentine, although the MICs of rifabutin in this case were somewhat lower than the MICs of rifapentine.

Topics: Animals; Antibiotics, Antitubercular; Cattle; Microbial Sensitivity Tests; Mycobacterium bovis; Mycobacterium tuberculosis; Rifabutin; Rifampin

The in vitro activity of rifapentine for 44 clinical isolates of Mycobacterium tuberculosis complex was compared with that of rifampicin using the Bactec radiometric method and the absolute concentration method for susceptibility testing. Twenty-nine M. tuberculosis, 11 Mycobacterium bovis and four Mycobacterium africanum strains were studied. Control tests showed that rifapentine was stable for 14 days in 7H9 broth and for 3 weeks in 7H10 agar medium. The 44 M. tuberculosis complex strains were more susceptible to rifapentine than to rifampicin, irrespective of the testing method. In the radiometric system, the MIC50 and MIC90 of rifapentine for M. tuberculosis complex strains were one or two two-fold dilutions lower than those of rifampicin (0.06-0.125 mg/L versus 0.25 mg/L, respectively). By the absolute concentration method, the MIC50 and MIC90 of rifapentine for M. tuberculosis complex strains were two two-fold dilutions lower than those of rifampicin (0.125-0.25 mg/L versus 0.5-1 mg/L, respectively). The MIC90 of rifapentine for the 44 M. tuberculosis complex strains was always 0.25 mg/L, irrespective of the method used, but the radiometric method was more reliable and more reproducible than the agar 7H10 method.

Topics: Agar; Animals; Antibiotics, Antitubercular; Cattle; Culture Media; Microbial Sensitivity Tests; Mycobacterium bovis; Mycobacterium tuberculosis; Radiometry; Reproducibility of Results; Rifampin

To further the development of a multidrug regimen for treatment of leprosy that is suitable for monthly administration and fully supervisable, the bactericidal activities against Mycobacterium leprae of HMR 3647 (HMR), moxifloxacin (MXFX) and rifapentine (RPT) were measured by the proportional bactericide technique in the mouse footpad system, and compared with those of the established antileprosy drugs clarithromycin (CLARI), ofloxacin (OFLO) and rifampicin (RMP). Administered in five daily doses of 100 mg per kg body weight, HMR appeared slightly more bactericidal than CLARI, but the difference did not attain statistical significance. Administered as single doses, MXFX in a dosage of 150 mg per kg was more active than OFLO in the same dosage, and displayed the same level of activity as RMP in a dosage of 10 mg per kg; the combination MXFX-minocycline (MINO) (MM) was more bactericidal than the combination OFLO-MINO (OM); RPT in a dosage of 10 mg per kg was more bactericidal than RMP administered in the same dosage, and even more active than the combination RMP-OFLO-MINO (ROM); the combination RPT-MXFX-MINO (PMM) killed 99.9% of viable M. leprae, and was slightly more bactericidal than was RPT alone, indicating that the combination PMM showed an additive effect against M. leprae. These promising results justify a clinical trial among lepromatous patients, in which MM is being compared with OM, and PMM with ROM, in terms of efficacy and tolerance.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Aza Compounds; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fluoroquinolones; Leprostatic Agents; Leprosy; Mice; Mice, Inbred Strains; Minocycline; Moxifloxacin; Probability; Quinolines; Rifampin; Treatment Outcome

Two methods for testing the susceptibility of Mycobacterium tuberculosis to rifapentine have been developed: the agar proportion method and the radiometric BACTEC technique. A critical concentration of 0.5 microg of rifapentine per ml is proposed for both methods since it provides a reliable means of distinguishing between susceptible and resistant M. tuberculosis isolates. It is recommended that two quality control M. tuberculosis strains be used at the introduction of these tests in a clinical laboratory: one that is pansusceptible (H37Rv) and one that is resistant to rifapentine. The resistant strain can be obtained from the American Type Culture Collection, where it is deposited under the number ATCC 700457.

Topics: Antitubercular Agents; Colony Count, Microbial; Culture Media; Drug Resistance, Microbial; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Quality Control; Rifampin

Topics: Antitubercular Agents; Clinical Trials as Topic; Dosage Forms; Drug Administration Schedule; HIV Seronegativity; Humans; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis

Topics: Acetates; Anti-Asthmatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Antitubercular Agents; Antiviral Agents; Capecitabine; Cyclopropanes; Deoxycytidine; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Etanercept; Fluorouracil; Humans; Immunoglobulin G; Isoxazoles; Leflunomide; Phosphodiesterase Inhibitors; Piperazines; Purines; Quinolines; Receptors, Tumor Necrosis Factor; Rifampin; Sildenafil Citrate; Sulfides; Sulfones; Thionucleotides

Topics: Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antiviral Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Monitoring; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Etidronic Acid; Humans; Infliximab; Leprostatic Agents; Osteitis Deformans; Oxazines; Rifampin; Risedronic Acid; Thalidomide; Thionucleotides; Trastuzumab

Rifapentine is a long-acting rifamycin which may be useful for intermittent drug therapy against tuberculosis. In this study we measured the efficacies of rifapentine-containing intermittent drug regimens for preventive therapy using the Cornell mouse model of latent tuberculosis. We infected groups of mice intravenously with Mycobacterium tuberculosis and then treated them with isoniazid and pyrazinamide for 12 weeks according to the Cornell latency development protocol. After a 4-week interval of no treatment, experimental preventive therapy was administered by esophageal gavage for 12 or 18 weeks. After equilibration and dexamethasone amplification treatment, mouse organs were analyzed by quantitative colony counts to measure the effectiveness of therapy. Our results showed that once-weekly isoniazid plus rifapentine combination therapy for 18 weeks was an effective preventive regimen with sterilizing potency and bacillary load reduction comparable to those of daily isoniazid therapy for 18 weeks. Monotherapy with rifapentine weekly or fortnightly or with rifampin twice weekly for up to 18 weeks did not offer advantages in reducing bacillary load or in sterilizing organs compared to the effects of a placebo. These results with the Cornell mouse model indicate that once-weekly, short-course preventive therapy with isoniazid plus rifapentine is effective and may warrant investigation in humans with latent tuberculosis infection.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Female; Isoniazid; Mice; Mycobacterium tuberculosis; Rifampin; Stem Cells; Tuberculosis

Besides direct bactericidal activity, long-term effectiveness is one of the most important features to consider when developing new drugs for chemotherapy. In this study, we evaluated the ability of rifapentine (RFP), in monotherapy and combination therapy, to completely eradicate a Mycobacterium tuberculosis infection and to prevent relapse posttreatment in a Swiss mouse model. The combination of RFP, isoniazid (INH), and pyrazinamide (PZA) administered daily resulted in an apparent clearance of M. tuberculosis organisms in the lungs and spleens of infected mice after 10 weeks of treatment. However, 3 months after the cessation of therapy, bacterial regrowth occurred in mice treated for a 12-week period, indicating a relapse of infection. In intermittent treatment regimens of RFP in combination with INH and PZA, sterilization was achieved when mice were treated two to five times per week for 9 weeks. Bacterial growth was still observed in the once-weekly treatment group. Our results show that mouse models can predict important parameters for new drugs. We stress the necessity for long-term posttreatment observation in animal models for the routine evaluation of new drugs for antituberculosis chemotherapy.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Disease Models, Animal; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Isoniazid; Mice; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Rifamycins; Tuberculosis

Topics: Antibiotics, Antitubercular; Drug Approval; Humans; Rifampin; Tuberculosis; United States; United States Food and Drug Administration

When tested by agar dilution on Mueller-Hinton agar supplemented with 5% horse blood, the ketolides HMR 3004 and HMR 3647 were slightly more active (MIC at which 90% of the isolates were inhibited [MIC90], 0.03 microg/ml) against Bordetella pertussis than azithromycin, clarithromycin, erythromycin A, and roxithromycin. Azithromycin (MIC90, 0.06 microg/ml) was the most active compound against B. parapertussis. Rifampin and rifapentine were considerably less active.

Topics: Anti-Bacterial Agents; Azithromycin; Bordetella; Bordetella pertussis; Clarithromycin; Erythromycin; Ketolides; Macrolides; Microbial Sensitivity Tests; Rifabutin; Rifampin; Roxithromycin

The bactericidal activities of several once-weekly rifapentine (P)-containing combination regimens against Mycobacterium tuberculosis, and their ability to prevent the selection of rifampin (R)-resistant mutants, were compared with those of the standard six-times-weekly regimen consisting of R, isoniazid (H), and pyrazinamide (Z) in a mouse experiment. Mice were infected intravenously with 1.3 x 10(7) cfu of M. tuberculosis strain H37Rv, and 8 wk of treatment began on Day 14 after infection, when mice were randomly allocated to an untreated control group and nine treatment groups of 30 mice each. At the end of 8 wk of treatment, all the tested regimens showed promising bactericidal activities. Once-weekly P alone was less bactericidal than six-times-weekly R alone; likewise, the once-weekly P-containing combined regimens were less bactericidal than the six-times-weekly standard regimen. However, the difference in killing was about 1 log10, which represented only a fraction of the overall 4 log10 to 5 log10 magnitude of killing effects. The addition of streptomycin (S) improved the bactericidal effect of once-weekly PHZ, and the effect of once-weekly PHZS was further enhanced when it was preceded by 2 wk of daily HZS. The latter regimen achieved the same level of activity as the standard six-times-weekly regimen. All of the once-weekly P-containing combined regimens were able to prevent the selection of R-resistant mutants, whereas monotherapy with R or P selected resistant mutants in approximately 50% of animals.

Topics: Animals; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Lung; Mice; Mutation; Mycobacterium tuberculosis; Organ Size; R Factors; Rifampin; Spleen; Streptomycin; Tuberculosis

Topics: AIDS-Related Opportunistic Infections; Anti-Infective Agents; Antitubercular Agents; Clinical Trials as Topic; Drug Approval; Drug Industry; Fluoroquinolones; Humans; Mycobacterium avium-intracellulare Infection; Rifampin; Technology, Pharmaceutical; Tuberculosis, Multidrug-Resistant; United States

The in vitro activities of 13 antimicrobial agents against 30 strains of Legionella spp. were determined. Rifapentine, rifampin, and clarithromycin were the most potent agents (MICs at which 90% of isolates are inhibited [MIC90s], < or = 0.008 microgram/ml). The ketolide HMR 3647 and the fluoroquinolones levofloxacin and BAY 12-8039 (MIC90s, 0.03 to 0.06 microgram/ml) were more active than erythromycin A or roxithromycin. The MIC90s of dalfopristin-quinupristin and linezolid were 0.5 and 8 micrograms/ml, respectively. Based on class characteristics and in vitro activities, several of these agents may have potential roles in the treatment of Legionella infections.

Topics: Anti-Bacterial Agents; Aza Compounds; Fluoroquinolones; Humans; Ketolides; Legionella; Macrolides; Microbial Sensitivity Tests; Moxifloxacin; Quinolines; Quinolones; Rifampin

Rifapentine is a cyclopentyl derivative of rifampin under development for the treatment of Mycobacterium tuberculosis and Mycobacterium avium complex infections. These studies were designed to investigate the disposition and biotransformation of single iv and oral doses of 14C-rifapentine in mice, bile duct-cannulated and uncannulated rats, and monkeys. Mass balance studies included 14C analyses of urine, feces, bile, cage wash, carcasses, and cage air collected for up to 120 hr postdose. Separation of radioactive compounds extracted from urine, bile, and feces was conducted using high-performance liquid chromatography and radioisotope detection. The mass spectra of selected chromatographic peaks were obtained. Disposition results were similar for all three species. Less than 5% of the radioactive dose of 14C-rifapentine was recovered in urine, indicating that renal excretion is a minor route of elimination in these species. The major route of elimination of radioactivity was into the feces, where more than 75% of the radioactivity was recovered. Biliary excretion was the major route of elimination of radioactivity in bile duct-cannulated rats dosed either po or IV. Radiochromatograms were similar for fecal samples from animals dosed by IV or orally. Ten regions of radioactivity were observed in mouse and rat fecal sample radiochromatograms, and seven regions of radioactivity were observed in monkey fecal sample radiochromatograms. The most abundant compound identified in feces was usually intact rifapentine (27%-41% of dose in mouse, 3%-35% of dose in rat, and 17%-29% of dose in monkey). Other peaks identified or characterized in feces based on liquid chromatography/ultraviolet/14C and/or liquid chromatography/mass spectrometry methods included 25-desacetyl-rifapentine, 3-formyl-25-desacetyl-rifapentine, and 3-formyl-rifapentine. The compounds rifapentine, 25-desacetyl-rifapentine, and 3-formyl-rifapentine were present in rat bile samples. These studies show that the metabolism and disposition of rifapentine in mice, rats, and monkeys were similar.

Topics: Animals; Antitubercular Agents; Bile; Biotransformation; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Feces; Macaca fascicularis; Male; Mass Spectrometry; Mice; Rats; Rats, Wistar; Rifampin; Species Specificity; Tissue Distribution

Rifapentine is a long-acting cyclopentyl-derivative of rifampin. This study was designed to investigate the mass balance and biotransformation of 14C-rifapentine in humans. Four healthy male volunteers received a single 600-mg oral dose of 14C-rifapentine in a hydroalcoholic solution. Whole blood, urine, and fecal samples were collected before and at frequent intervals after drug administration. Amount of radioactivity recovered in urine and feces was assessed for up to 18 days postdose. Metabolite characterization in urine and feces was conducted using high-performance liquid chromatography with radiometric detection and liquid chromatography/mass spectroscopy. The total recovery of radioactive dose was 86.8%, with the majority of the radioactive dose recovered in feces (70.2%). Urine was a minor pathway for excretion (16.6% of the dose recovered). More than 90% of the excreted radioactivity was profiled as 14C chromatographic peaks and 50% was structurally characterized. These characterized compounds found in feces and urine were rifapentine, 25-desacetyl-rifapentine, 3-formyl-rifapentine, and 3-formyl-25-desacetyl-rifapentine. The 25-desacetyl metabolite, formed by esterase enzymes found in blood, liver, and other tissues, was the most abundant compound in feces and urine, contributing 22% to the profiled radioactivity in feces and 54% in urine. The 3-formyl derivatives of rifapentine and 25-desacetyl-rifapentine, formed by nonenzymatic hydrolysis, were also prominent in feces and, to a lesser extent, in urine. In contrast to the feces and urine, rifapentine and 25-desacetyl-rifapentine accounted for essentially all of the plasma radioactivity (99% of the 14C area under the concentration-time curve), indicating that 25-desacetyl-rifapentine is the primary metabolite in plasma. It appears, therefore, that the nonenzymatic hydrolysis of rifapentine to 3-formyl byproducts occurs primarily in the gut and the acidic environment of the urine.

Topics: Administration, Oral; Adolescent; Adult; Antitubercular Agents; Blood Proteins; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Erythrocytes; Feces; Humans; Kidney; Male; Middle Aged; Protein Binding; Rifampin

Topics: Antitubercular Agents; Humans; Legislation, Drug; Rifampin; United States; United States Food and Drug Administration

Topics: Antitubercular Agents; Drug Interactions; HIV Protease Inhibitors; Humans; Indinavir; Rifampin; United States; United States Food and Drug Administration

Topics: Antitubercular Agents; Biological Availability; China; Clinical Trials as Topic; Drug Industry; Hong Kong; Humans; Recurrence; Rifampin; Tuberculosis

Gender can be an important variable in the absorption and disposition of some drugs. In this open-label study, 15 healthy, nonsmoking women received a single 600-mg oral dose of rifapentine. Plasma samples were obtained at frequent intervals for up to 72 hr after the dose to determine the pharmacokinetic (PK) parameters of rifapentine and its active metabolite, 25-desacetyl-rifapentine. Peak plasma rifapentine concentrations (Cmax) were observed 5.9 hr after ingestion of the single dose. The mean area under the rifapentine plasma concentration-time curve [AUC(0-->infinity)] was 325 micrograms.hr ml and the mean elimination half-life (t1/2) was 16.3 hr. Plasma concentrations for the 25-desacetyl metabolite peaked at 15.4 hr after the rifapentine dose and declined with a terminal half-life of 17.3 hr. These rifapentine and 25-desacetyl-rifapentine PK data in women were compared to data generated previously in healthy men. Striking similarities in the PK profiles of parent drug and metabolite were found in the two populations. Mean differences in rifapentine CL/F (12%) and t1/2 (2%) were small. The only adverse event reported in the female subjects was discoloration of the urine. Based on these PK and safety data, no dosage adjustments for rifapentine based on gender are recommended.

Topics: Adult; Antibiotics, Antitubercular; Area Under Curve; Dealkylation; Female; Half-Life; Humans; Middle Aged; Rifampin

Topics: Antitubercular Agents; Humans; India; Rifampin; Typhoid-Paratyphoid Vaccines; United States; United States Food and Drug Administration

The purpose of this study was to establish the correlation between biological and chemical assays for the quantification of rifapentine in human plasma. The bioassay was found to overestimate antibiotic plasma concentration when compared to the high-performance liquid chromatography (HPLC) assay for rifapentine (r = 0.9538, n = 220). This was because of the presence of varying amounts of the biologically active 25-O-desacetyl metabolite in the test samples. A better correlation (r = 0.9804, n = 220) was observed when the bioassay data were compared to combined parent-metabolite HPLC values. Such correlative data are necessary adjuncts in the establishment of antibiotic susceptibility test breakpoints.

Topics: Bacteriological Techniques; Chromatography, High Pressure Liquid; Humans; Microbial Sensitivity Tests; Regression Analysis; Reproducibility of Results; Rifampin

In our laboratory, primary human hepatocytes are being investigated as an in vitro experimental system for the evaluation of pharmacokinetic drug-drug interactions. Our study here represents the first reported study that directly compares the cytochrome P450 isozyme 3A (CYP3A) induction potential of three antimicrobials derived from rifamycin B, namely, rifampin, rifapentine and rifabutin. Two endpoints of CYP3A activity, testosterone 6 beta-hydroxylation and midazolam 1-hydroxylation have been used. Results obtained with hepatocytes from four different human donors show consistently that rifampin and rifapentine are potent inducers of CYP3A, while a significantly lower induction potential is observed for rifabutin. The relative induction potency of the three antimicrobials (rifampin > rifapentine >> rifabutin) is consistent with the available human in vivo data. For CYP1A measured as ethoxyresorufin O-deethylase activity, CYP2C8/9 measured as tolbutamide 4-hydroxylation activity, CYP2D6 measured as dextromethorphan O-demethylation, and AZT glucuronidation, there is either no effect or, where induction is found to be statistically significant in these other endpoints, the maximum induction values are consistently < 100% of the control. Our results suggest that CYP3A is the major CYP induced by these rifamycin B derivatives. These studies illustrate the application of human hepatocytes in the evaluation of the structure-activity relationships in CYP induction for this class of chemicals and as an in vitro screen for drug-drug interaction potential via CYP induction.

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Cytochrome P-450 Enzyme System; Drug Evaluation, Preclinical; Enzyme Induction; Glucuronates; Humans; Hydroxylation; Isoenzymes; Liver; Rifabutin; Rifampin; Structure-Activity Relationship; Testosterone; Time Factors; Zidovudine

Topics: Antitubercular Agents; Clinical Trials as Topic; Drug Industry; Ethics, Medical; Humans; Rifampin; Tuberculosis

Rifapentine, a derivative of rifamycin, was examined for its in vitro and in vivo activities against the protozoan parasite Toxoplasma gondii. The drug inhibited the intracellular replication of parasites and was not cytotoxic for the host cells at inhibitory concentrations. Mice infected either intraperitoneally with tachyzoites of the RH strain or orally with tissue cysts of the C56 strain were protected against death by treatment with rifapentine. The degree of protection was similar to that induced by atovaquone and apparently higher than that induced by rifabutin. Rifapentine may be a useful drug for the treatment of toxoplasmosis in immunocompromised individuals.

Topics: Animals; Anti-Bacterial Agents; Female; Mice; Rifabutin; Rifampin; Toxoplasma; Toxoplasmosis, Animal

A high-performance liquid chromatographic method for the determination of rifapentine in human serum was developed. The method utilized a Spherisorb C18 column, ultraviolet detection (336 nm), rifampin as internal standard and a calibration curve (C = 7.010 As/Ain +/- 0.156, r = 0.999) with reproducibility studies which yield a coefficient of variation (C.V.) of intra-day and inter-day assays lower than 10%. The average recovery of rifapentine from serum in the concentration range of 0.5 to 30 micrograms/ml was 92.93 +/- 9.704%.

Topics: Antitubercular Agents; Chromatography, High Pressure Liquid; Half-Life; Humans; Reproducibility of Results; Rifampin

We sought to study the nature of rifampicin resistance in Pseudomonas aeruginosa. We hypothesized that the rifamycin regions of RNA polymerase are conserved in P. aeruginosa and that rifampicin resistance is mediated by a mutation in the rpoB gene encoding the beta subunit of RNA polymerase. Transcription assays showed that 50 nM of rifampicin inhibited transcription > 99% in a clinical isolate (MIC = 32 mg/L) and only < 40% in the rifampicin resistant mutant (MIC = 1000 mg/L). DNA sequencing revealed that the rifampicin regions are conserved in P. aeruginosa and the rifampicin regions of the rifampicin-resistant strain contained a mutation. Sodium hexametaphosphate lowered rifamycin MIC in a rifamycin-resistant mutant four-fold and in the clinical isolate 32-fold, suggesting that P. aeruginosa has a natural membrane barrier to rifamycins.

Topics: Amino Acid Sequence; Anti-Bacterial Agents; Drug Resistance, Microbial; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Phosphates; Pseudomonas aeruginosa; Rifampin; Rifamycins; Sequence Homology, Amino Acid; Transcription, Genetic

A collection of 24 rifampin-resistant clinical isolates of Mycobacterium tuberculosis with characterized RNA polymerase beta-subunit (rpoB) gene mutations was tested against the antimycobacterial agents rifampin, rifapentine, and KRM-1648 to correlate levels of resistance with specific rpoB genotypes. The results indicate that KRM-1648 is more active in vitro than rifampin and rifapentine, and its ability to overcome rifampin resistance in strains with four different genetic alterations may prove to be useful in understanding structure-function relationships.

Topics: Antibiotics, Antitubercular; Drug Resistance, Microbial; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifampin; Rifamycins

Human monocytes can be derived from the leukocyte-rich by-product of donors' blood available after platelet separation. Large volumes of the monocyte samples obtained from this product provided an opportunity to conduct experiments with relatively high concentrations of the antimicrobial agents sufficient for their detection in bioassays, thus avoiding the necessity of working with the radiolabelled drugs. Washing of the cells after their exposure to the drug may lead to an extraction of the tested agent from the cell, especially if it is a substance of low molecular weight. In our experiments we excluded the washing step, and separated the monocytes from the extracellular medium by velocity gradient centrifugation. In experiments with two rifamycins, the cell pellet as well as the extracellular fluid were subjected to a bioassay using Micrococcus luteus as a target organism. The method showed good reproducibility and consistency in results obtained.

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Biological Assay; Cells, Cultured; Humans; Leprostatic Agents; Micrococcus luteus; Monocytes; Reproducibility of Results; Rifampin

Topics: Antitubercular Agents; DNA-Directed RNA Polymerases; Drug Resistance, Microbial; Genes, Bacterial; Genotype; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Phenotype; Rifabutin; Rifampin; Tuberculosis, Pulmonary

The activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human monocyte-derived macrophages were determined. The MICs and MBCs of rifapentine for intracellular bacteria were two- to fourfold lower than those of rifampin. For extracellular bacteria, this difference was less noticeable. Nevertheless, the more favorable pharmacokinetics of rifapentine over rifampin was addressed in other experimental models. These models showed substantial differences after short pulsed exposures of the infected macrophages to the drugs and when the infected macrophages were exposed to changing drug concentrations that imitated the pharmacokinetic curves observed in blood. Once-a-week exposures to rifapentine concentrations equivalent to those attained in blood after one 600-mg dose resulted during the first week in a dramatic decline in the number of bacteria, and this decline was maintained at a minimal level for a period of four weeks. The results of this study have shown the suitability of rifapentine for intermittent-treatment regimens. The prolonged effect of rifapentine found in this study may be associated with high ratios of intracellular accumulation, which were four- to fivefold higher than those found for rifampin. Further studies on the intracellular distribution of rifamycins and on the sites of actual interaction between the drugs and bacteria residing in macrophages are necessary.

Topics: Antitubercular Agents; Cells, Cultured; Humans; Macrophages; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin

The effectiveness of intermittent administration of rifapentine (RPT), with or without isoniazid (INH), for preventive therapy of tuberculosis was evaluated in immunocompetent (normal) and nude mice. After infection with a small inoculum of Mycobacterium tuberculosis H37Rv, normal mice developed a chronic and nonfatal infection, and the bacterial population became relatively stable after an initial period of limited multiplication. On the other hand, nude mice developed an acute and fatal infection, and all untreated mice died within 5 wk, with very high colony-forming-unit (CFU) counts in their organs. Various degrees of bactericidal activity were shown in normal mice after daily treatment with rifampin (RMP) plus pyrazinamide (PZA) for 13 wk, INH daily for 26 wk, or RPT once weekly for 13 or 26 wk or once fortnightly for 26 wk. The activity of RPT was significantly enhanced when INH was added at the same dosing frequency. In nude mice the response of M. tuberculosis infection to certain regimens was less favorable than that in normal mice, suggesting that preventive therapy may be less effective in severely immunodeficient hosts even during treatment. After chemotherapy was stopped, virtually all nude mice relapsed within 12 wk regardless of the regimen administered, whereas no or very few relapses were observed in normal mice that had been treated with RMP+PZA daily for 13 wk, or RPT alone or RPT+INH once weekly for 26 wk. The latter three regimens and RPT+INH once weekly for 13 wk may be applied for fixed-duration preventive therapy in human immunodeficiency virus (HIV)-negative subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antitubercular Agents; Colony-Forming Units Assay; Drug Therapy, Combination; Female; Immunity; Isoniazid; Mice; Mice, Nude; Pyrazinamide; Rifampin; Tuberculosis

The activity of azithromycin (AZI) was evaluated in the beige mouse model of disseminated Mycobacterium avium infection. Mice were infected intravenously with approximately 10(7) viable avium ATCC 49601. AZI at 50, 100, or 200 mg/kg of body weight or clarithromycin (CLA) at 200 mg/kg was given by gavage 5 days per week for 4 weeks. Groups of treated mice were compared with untreated control animals. A dose-related reduction in cell counts in organs was observed with AZI treatment. AZI at 200 mg/kg was more active than CLA at 200 mg/kg against organisms in spleens. The activities of these two agents at 200 mg/kg were comparable against organisms in lungs. In a second study, AZI at 200 mg/kg was given daily for 5 days; this was followed by intermittent AZI treatment for the next 3 weeks. The activities of AZI given on a three-times- and five-times-per-week basis in the continuation phase were comparable. AZI given on a once-weekly basis was less active. The regimen of AZI given in combination with rifapentine on a once-weekly basis for 8 weeks showed promising activity. Clinical evaluation of AZI and rifapentine will help to define the roles of these agents in the treatment of disseminated M. avium complex infection.

Topics: Animals; Azithromycin; Clarithromycin; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mycobacterium avium; Rifampin; Tuberculosis

The dose-response activity of rifabutin and the comparative activities of rifabutin and rifapentine were evaluated in the beige mouse model of disseminated Mycobacterium avium complex (MAC) infection. In the dose-response study, mice were infected intravenously with approximately 10(7) viable M. avium ATCC 49601. Treatment with rifabutin at 10, 20, or 40 mg/kg of body weight was started 7 days postinfection and was administered daily for 10 days. The mice were sacrificed 3 to 5 days after the last dose. Spleens, livers, and lungs were homogenized, and viable cell counts were determined by serial dilution and plating onto Middlebrook 7H10 agar. A dose-related reduction in MAC cell counts in the organs was noted for this MAC isolate. The comparative activities of rifabutin and rifapentine were determined against a total of five MAC isolates in the beige mouse model. Rifabutin or rifapentine (20 mg/kg each) was administered to infected mice for 10 days. Groups of treated mice were compared with untreated control animals. Despite favorable in vitro susceptibility results, rifabutin and rifapentine had activities in the spleens against only two of the five MAC isolates. For these two MAC isolates, rifabutin was more active than rifapentine. These agents had activities in the lungs against three of five isolates. Further study of rifabutin or rifapentine against a broader range of clinical isolates in a murine infection model may be useful as part of the continuing development of newer rifamycins as anti-MAC agents.

Topics: Animals; Antitubercular Agents; Colony Count, Microbial; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Lung; Mice; Mice, Inbred C57BL; Mycobacterium avium; Mycobacterium avium Complex; Rifabutin; Rifampin; Tuberculosis

To identify alternative regimens for preventive therapy of tuberculosis, the pharmacokinetics and antimicrobial activities of rifampin (RMP), rifabutin (RBT), and rifapentine (RPT) were compared in BCG-vaccinated and M. tuberculosis-infected immunocompetent mice. RPT showed the highest serum peak level (Cmax) and the longest half-life (t1/2), whereas RBT displayed the lowest Cmax and the shortest t1/2. On weight-to-weight basis, both RPT and RBT were more bactericidal than RMP. The activity of RMP was significantly reduced when the frequency of administration was reduced from six to three times weekly, whereas significant bactericidal activity was still observed in mice treated with RPT, 10 mg/kg up to once fortnightly, or RBT, 10 mg/kg twice weekly. Because the bactericidal activity of RBT, 10 mg/kg six times/wk for 6 wk, or RPT, 10 mg/kg two times/wk for 12 wk, was comparable to that of RMP, 10 mg/kg six times/wk for 12 wk in mice, the two regimens are appropriate for clinical trials of preventive therapy of tuberculosis.

Topics: Animals; Antitubercular Agents; BCG Vaccine; Colony Count, Microbial; Female; Mice; Mycobacterium tuberculosis; Rifabutin; Rifampin; Spleen; Tuberculosis

Azithromycin, rifabutin, and rifapentine were used to treat or prevent disseminated Mycobacterium avium complex (MAC) infections produced in rats immunosuppressed with cyclosporine. Animals with bacteremic infections were treated 1 week after intravenous inoculation with 10(7) CFU of MAC with azithromycin, 100 mg/kg of body weight administered subcutaneously for 5 days and then 75 mg/kg on Monday, Wednesday, and Friday, or with rifabutin or rifapentine, 20 mg/kg administered intraperitoneally on Monday through Friday. All three drugs showed efficacy after 1 and 2 months. Rifabutin cleared the organisms from tissues more rapidly than azithromycin or rifapentine. To approximate prophylaxis, treatment was started 2 weeks before intravenous inoculation with 10(4) organisms. MAC infections were undetectable in treated animals after 4 months, while control animals had disseminated infections. These findings support the rationale for clinical trials of treatment and prophylaxis with these agents. The cyclosporine-treated rat appears to be a useful model in which to evaluate compounds for the treatment and prophylaxis of disseminated MAC infections.

Topics: Animals; Antitubercular Agents; Azithromycin; Cyclosporine; Erythromycin; Male; Mycobacterium avium-intracellulare Infection; Rats; Rats, Sprague-Dawley; Rifabutin; Rifampin; Rifamycins; Tissue Distribution

We have tested the in vitro activities of streptomycin, rifampin, tetracyclines, trimethoprim-sulfamethoxazole, erythromycin, four new macrolides (roxithromycin, azithromycin, clarithromycin, and dirithromycin), and rifapentine against 62 strains of Brucella spp. Azithromycin and clarithromycin were, respectively, eight- and twofold more active than erythromycins (MIC for 90% of strains = 2, 8, and 16 micrograms/ml, respectively). The activity of rifapentine was similar to that of rifampin (MIC for 90% of strains = 1 microgram/ml).

Topics: Anti-Bacterial Agents; Antitubercular Agents; Brucella; Drug Resistance, Microbial; Macrolides; Microbial Sensitivity Tests; Rifampin

The activities of the rifamycins, rifabutin, FCE 22807, rifapentine, and rifampin, were studied within unstimulated peritoneal macrophages infected with Mycobacterium microti and in cultures of M. microti and M. tuberculosis in 7H-9 medium without Tween 80. In macrophage cultures, serial rifamycin concentrations were added after a 2.5 h phagocytosis period, and viable counts were done after incubation for 5 to 6 days. To ensure comparability with the daily drug replacements in the macrophage experiments, the period of exposure to serial rifamycin concentrations in 7H-9 medium was kept to only 3 days. The MICs of M. microti and M. tuberculosis were similar. The MICs of rifabutin and FCE 22807 were 2.5 times lower and that of rifapentine 1.7 times lower than the MIC of rifampin. None of the rifamycins were concentrated in macrophages, the MICs being higher in the macrophages than in vitro by a factor of 2-fold for rifabutin, 6.7-fold for rifampin, 20-fold for FCE 22807, and 26-fold for rifapentine.

Topics: Animals; Antitubercular Agents; Macrophages; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium; Mycobacterium tuberculosis; Peritoneal Cavity; Rifabutin; Rifampin; Rifamycins

The activity of TLC G-65 (a liposomal gentamicin preparation), alone and in combination with rifapentine, clarithromycin, clofazimine and ethambutol, was evaluated in the beige mouse (C57BL/6J--bgj/bgj) model of disseminated Mycobacterium avium infection. TLC G-65 was found to be more active than amikacin. The combination of rifapentine and TLC G-65 was more active than either agent alone. The activity of clarithromycin in combination with TLC G-65 was similar to that of either agent alone. Clofazimine improved the activity of TLC G-65 with respect to the spleen, while ethambutol improved the activity with respect to the liver. Clofazimine and ethambutol enhanced the activity of TLC G-65 against bacteria in the lungs. TLC G-65 in combination with rifapentine appears to be an attractive regimen for the treatment of infections caused by bacteria in the M. avium complex.

Topics: Amikacin; Animals; Antitubercular Agents; Clarithromycin; Clofazimine; Culture Media; Drug Therapy, Combination; Erythromycin; Ethambutol; Gentamicins; Liposomes; Mice; Mice, Inbred C57BL; Mycobacterium avium; Rifampin; Tuberculosis

Postantibiotic effect (PAE) has received little attention in the therapy of chronic intracellular infections, such as those caused by mycobacteria. Amikacin is active therapeutically against Mycobacterium avium complex, even though serum levels exceed the MIC for only a few hours. To determine the PAE of amikacin and rifapentine for M. avium, bacteria were exposed to concentrations of 1x, 4x, and 10x the MIC of each drug for up to 120 min. Regrowth of M. avium was compared with similarly diluted untreated cultures. No PAE was observed on an inoculum of 10(4) bacteria when rifapentine was used at 5x MIC, although a slight inhibition of growth was obtained at 10x MIC for 2 h. For amikacin, PAE was observed up to 48 h at concentrations of 4x and 8x MIC and exposure times of 30-120 min. A PAE of 22 h was seen with 10(7) cfu of M. avium during incubation for 30 min with amikacin at 4x MIC. These results show that amikacin, unlike rifapentine, has a long PAE against M. avium.

Topics: Amikacin; Dose-Response Relationship, Drug; Leprostatic Agents; Microbial Sensitivity Tests; Mycobacterium avium Complex; Rifampin; Time Factors

The activity of rifapentine (MDL 473) was evaluated in the beige (C57BL/6J-bgj/bgj) mouse model of disseminated Mycobacterium avium infection. Approximately 10(7) cfu of M. avium, serotype 1, were given iv. Seven days later treatment was started with intraperitoneal rifapentine at 20 mg/kg of body weight. Treatment was given daily for five days followed by twice weekly for three weeks. The mice were killed two days after the last dose. Spleens, livers and lungs were homogenized and cfu/organ determined. Analysis of variance and Tukey honestly significant difference tests indicated that rifapentine reduced cfu in each of the organs compared with untreated controls. A dose-response experiment was performed with a daily rifapentine dose of 10, 20 or 40 mg/kg administered intraperitoneally. Dose-related reductions in cfu counts were observed in each of the organs. The activity of oral rifapentine at 20 mg/kg was demonstrated in a comparative experiment with rifampicin at 20, 40 or 60 mg/kg. Rifapentine significantly reduced cfu counts in organs compared with rifampicin. Rifapentine should be considered for further evaluation in the treatment of M. avium complex infection in humans.

Topics: Administration, Oral; Animals; Antitubercular Agents; Biological Availability; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Mycobacterium avium; Rifampin; Tuberculosis

A high-performance liquid chromatographic method with column switching has been developed for the determination of rifapentine in serum. The serum samples were injected onto a precolumn packed with Corasil RP C18 (37-50 microns) after simple dilution with an internal standard in a 1% ascorbic acid solution. Polar serum components were washed out using 0.05 M phosphate buffer. After valve switching, the concentrated drugs were eluted in the back-flush mode and separated by a mu Bondapak C18 column with acetonitrile-tetrahydrofuran-0.05 M phosphate buffer (pH 7.0) (42:5:53, v/v/v) as the mobile phase. The method showed excellent precision with good sensitivity and speed, and a detection limit of 0.1 microgram/ml. The total analysis time was less than 25 min and the mean coefficients of variation for intra- and inter-assay were less than 4.8%. The method has been successfully applied to serum samples from dogs after the oral administration of rifapentine.

Topics: Animals; Chromatography, High Pressure Liquid; Dogs; Leprostatic Agents; Reproducibility of Results; Rifampin

The efficacy of the long-acting rifamycins, rifapentine (RPE) and FCE 22807 (FCE) in experimental murine tuberculosis was studied by counting viable bacilli in spleens. At 2 weeks after infection with Mycobacterium tuberculosis, strain H37Rv, treatment with isoniazid 25 mg/kg, rifampicin 10 mg/kg and pyrazinamide 150 mg/kg was given daily for 6 weeks. The mice were then divided into groups given RPE or FCE at intervals of 1, 2 or 3 weeks with spleen counts after 18 and 24 weeks of chemotherapy. The first experiment showed the great effect of the size of the dose of RPE, which, in once-weekly regimens, caused rapid sterilization at 16 mg/kg, less rapid sterilization at 10 mg/kg and incomplete activity at 6.25 mg/kg. Regimens of RPE given every 2 or 3 weeks were less effective, though 16 mg/kg fortnightly was as good as 6 mg/kg once-weekly. The second experiment compared RPE and FCE each given at 12 or 8 mg/kg. The results were similar though, at 8 mg/kg every 2 or 3 weeks, FCE was slightly more effective than RPE. Serum assays showed that the levels with 8 and 12 mg/kg FCE were lower than those produced even by 6.25 mg/kg RPE, suggesting that FCE would be a better drug than RPE if its bioavailability could be improved, and that the levels following 16 mg/kg RPE were similar to those found in man after 8 mg/kg RPE taken with a fat-rich meal, suggesting good prospects for effective once-fortnightly human treatment. The potential for long-acting rifamycins in the management of pulmonary tuberculosis is discussed.

Topics: Animals; Antitubercular Agents; Drug Administration Schedule; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Rifampin; Rifamycins; Spleen; Tuberculosis

The activities of sparfloxacin, azithromycin, temafloxacin, and rifapentine against two virulent strains of the Mycobacterium avium complex isolated from patients with AIDS were evaluated in a model of intracellular infection and were compared with that of clarithromycin. Human monocyte-derived macrophages were infected with the M. avium complex at day 6 of culture. The intracellular CFU was counted 60 min after inoculation. The intracellular and supernatant CFU was counted on days 4 and 7 after inoculation. The concentrations used, which were equal to peak levels in serum, were 10 micrograms of rifapentine per ml (MICs for the two strains, 4 and 16 micrograms/ml), 4 micrograms of clarithromycin per ml (MICs, 8 and 4 micrograms/ml), 1 microgram of azithromycin per ml (MICs, 32 and 16 micrograms/ml), 4 micrograms of temafloxacin per ml (MICs, 2 and 16 micrograms/ml), and 1 microgram of sparfloxacin per ml (MICs, 0.5 and 2 micrograms/ml). Compared with controls on day 7 after inoculation, clarithromycin (P less than 0.001), sparfloxacin (P less than 0.001), and azithromycin (P less than 0.001 for the first strain, P less than 0.02 for the second) slowed intracellular replication. Rifapentine (P less than 0.001) and temafloxacin (P less than 0.001) slowed intracellular replication of the first strain but not of the second strain. Azithromycin plus sparfloxacin was as effective as sparfloxacin alone. In this macrophage model, sparfloxacin or clarithromycin (difference not significant) exhibited a better efficacy than rifapentine, azithromycin, or temafloxacin against intracellular M. avium complex infection.

Topics: 4-Quinolones; Acquired Immunodeficiency Syndrome; Anti-Bacterial Agents; Azithromycin; Cell Division; Clarithromycin; Erythromycin; Fluoroquinolones; Humans; In Vitro Techniques; Leprostatic Agents; Macrophages; Microbial Sensitivity Tests; Mycobacterium avium Complex; Quinolones; Rifampin

The comparative activities of newer rifamycin analogs and the activity of rifabutin or rifapentine in combination with other antimycobacterial agents was evaluated in the beige (C57BL/6J; bgj/bgj) mouse model of disseminated Mycobacterium avium infection. Rifabutin and rifapentine at 20 mg/kg of body weight had comparable activities. P/DEA and CGP 7040 at 20 mg/kg were less active. The combination of ethambutol at 125 mg/kg and rifabutin at 20 mg/kg resulted in a slight increase in activity beyond that seen with rifabutin alone against organisms in the spleens. The combination of ethambutol and rifapentine at 20 mg/kg resulted in a modest increase in activity beyond that seen with rifapentine alone against organisms in the lungs. The combination of ethionamide at 125 mg/kg and rifapentine resulted in a decrease in activity compared with that for rifapentine alone. The combination of clofazimine at 20 mg/kg and rifapentine resulted in increased activity in the mouse model. The combination of clofazimine and rifapentine (or rifabutin) appears to be an attractive regimen that should be evaluated for the treatment of human infections due to M. avium complex.

Topics: Animals; Culture Media; Drug Therapy, Combination; Female; Male; Mice; Mice, Inbred C57BL; Mycobacterium avium-intracellulare Infection; Rifabutin; Rifampin; Rifamycins

A simple high-performance liquid chromatographic method for determination of rifapentine, a cyclopentyl semisynthetic analogue of rifamycin belonging to the class of piperazinyl hydrazone derivatives of 3-formylrifamycin SV, and its metabolite, 25-desacetylrifapentine, in human plasma was developed using direct injection of the sample onto a Supelco LC HISEP column. The mean recovery was 100.3% for rifapentine and 99.7% for the metabolite and the precision of the assays was 3% and 7%, respectively. The limit of determination was 0.2 micrograms/ml and the method was validated for concentrations up to 64 micrograms/ml for rifapentine and 32 micrograms/ml for the metabolite. The results correlated well with those of the microbiological assay with Sarcina lutea as test organism.

Topics: Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Humans; Reproducibility of Results; Rifampin; Sarcina; Spectrophotometry, Ultraviolet

Minimal inhibitory and bactericidal concentrations (MICs and MBCs) of rifampin (RMP), rifabutin (RBT), rifapentine (RPT), CGP-7040, and P-DEA, were determined for 50 M. avium strains in 7H12 liquid medium radiometrically under various pH conditions. Half were isolated from patients with AIDS and the other half from patients without AIDS but with pulmonary disease. The MICs and MBCs were also determined in 7H12 broth for M. tuberculosis strains. The MIC results obtained with M. tuberculosis strains, and the serum peak levels in humans, were used as standards for interpretation of the MICs and MBCs of the rifamycins for M. avium. The bactericidal activity of all rifamycins for M. avium was substantially lower than for M. tuberculosis. The majority of M. avium strains was within the "susceptible" category, e.g., comparable to susceptible M. tuberculosis strains, when tested with CGP-7040 and RPT, and all of them were "moderately susceptible" when tested with P-DEA. On the basis of in vitro bacteriostatic and bactericidal activity, it seems that three agents, RPT, P-DEA, and CGP-7040 have more potential than do RMP and RBT against M. avium disease.

Topics: Acquired Immunodeficiency Syndrome; Humans; Microbial Sensitivity Tests; Mycobacterium avium; Mycobacterium tuberculosis; Rifabutin; Rifampin; Rifamycins

Rifapentine (R773, DL473) is a long-acting antituberculous drug used in China. In our experiments we have found some manifestations of induction of hepatic mixed function oxidase system in mice following pretreatment with rifapentine or phenobarbital. Both rifapentine and phenobarbital significantly increased the rate of antipyrine and pentobarbital metabolism in vivo. They also increased liver weight, the content of liver microsomal protein and cytochrome P-450, the activity of NADPH-cytochrome C reductase and NADPH oxidase. SDS-polyacylamide gel electrophoresis showed that the relative proportions of some polypeptide bands in mice microsomal fraction were significantly changed following rifapentine or phenobarbital pretreatment. The results indicate that rifapentine, like phenobarbital, is a potent inducer of hepatic mixed function oxidase system in mice and that it should be used carefully in clinical therapy, when combined with other drugs.

Topics: Animals; Electrophoresis, Polyacrylamide Gel; Enzyme Induction; Leprostatic Agents; Liver; Male; Mice; Mixed Function Oxygenases; Organ Size; Phenobarbital; Rifampin

The activity of clofazimine, amikacin, roxithromycin, rifampicin and rifapentine was tested, alone and in association, against Mycobacterium avium intracellulare. Clofazimine, amikacin and rifapentine were shown to be very active. With all established associations, the MIC observed for each drug alone was appreciably reduced.

Topics: Amikacin; Clofazimine; Drug Interactions; Drug Resistance, Microbial; Drug Therapy, Combination; Mycobacterium avium Complex; Rifampin; Roxithromycin

The purpose of this study was to evaluate the in vitro effect of the naphthalenic ansamycins rifamycin SV, rifampin and cyclopentylrifampicin on neutrophil degranulation and cytokinesis using murine peritoneal exudate cells. It was found that the FMLP-stimulated secretion of myeloperoxidase was significantly inhibited by 80 micrograms rifamycin SV (P less than 0.05) and cyclopentylrifampicin (P less than 0.01) per ml. Nondirected and FMLP-directed migration was significantly (P less than 0.01) inhibited by rifamycin SV and rifampin at assay concentrations above 0.31 and 5.0 micrograms/ml respectively thus confirming the low dose rifamycin effect observed by others using human neutrophils. Finally, cyclopentylrifampicin was shown to have no significant effect on nondirected or FMLP-directed neutrophil migration at assay concentrations of 1.25 to 80 micrograms per ml.

Topics: Animals; Cell Movement; Chemotaxis, Leukocyte; In Vitro Techniques; Male; Mice; Mice, Inbred BALB C; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Peroxidase; Rifampin; Rifamycins

The use of a direct liquid introduction type liquid chromatographic-mass spectrometric interface to study highly thermally labile rifamycin antibiotics is described. Using negative ionization, abundant molecular ions were observed, and the spectra, also contained structurally significant fragments. Variation of the high-performance liquid chromatographic parameters did not change the spectra, thus making it easy to change chromatographic conditions. In quantitative studies, a surprising correlation was found, indicating that the mass spectrometric signal was proportional to the square of the sample concentration.

Topics: Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; Mass Spectrometry; Rifampin; Rifamycins

Rifampin has been noted to exhibit exceptional antimicrobial activity against Staphylococcus epidermidis biofilms as compared to commonly used antibiotics. To further explore this unique effect of rifampin, we evaluated the antimicrobial activity of three commercially available preparations of rifampin, two rifampin analogs (CGP29861 and rifapentine) and the parent compound rifamycin SV. These were tested against standardized S. epidermidis biofilms in various milieus. All six members of the rifamycin group tested demonstrated marked antimicrobial activity but with minor foci of resisters when tested in a peptone water environment. The microscopy of the exposed biofilms showed profound lysis and morphological distortion of the remaining cells. The synergistic elimination of the foci of resistance was achieved in an environment of fresh peritoneal dialysis (PD) solution or by the addition of vancomycin. Neither vancomycin nor fresh PD solution demonstrated significant antimicrobial activity when tested alone with biofilm preparations. Spent PD fluid markedly antagonized the activity of the rifamycins with the exception of the rifampin analogs, an effect primarily of pH. The synergistic effect of vancomycin with the rifamycins was not affected either by protein content or pH, leaving the antagonistic properties of spent PD fluid unexplained. The variable activity of the different members of the rifamycin group underlines the importance of structural differences in determining their interaction with bacterial biofilms. Further precision of the nature of these structural interactions is seen to have considerable potential for therapeutic advancement of catheter-associated sepsis.

Topics: Anti-Bacterial Agents; Humans; Microbial Sensitivity Tests; Peritoneal Dialysis, Continuous Ambulatory; Rifampin; Rifamycins; Staphylococcus epidermidis; Structure-Activity Relationship; Vancomycin

Topics: Adult; Aged; Animals; Female; Humans; Leprostatic Agents; Leprosy; Male; Mice; Middle Aged; Mycobacterium leprae; Rifampin

Topics: Animals; Female; Male; Mice; Rifampin; Rifamycins; Tuberculosis

Comparisons were made of the in vitro activity of rifampicin, and the rifamycin derivatives, rifapentine, rifabutin, CGP 29861, CGP 7040 and CGP 27557, against rifampicin-sensitive and rifampicin-resistant strains of Mycobacterium tuberculosis and against the Mycobacterium avium/intracellulare/scrofulaceum (MAIS) complex. The new rifamycins had MICs four to eight times lower than those of rifampicin against sensitive M. tuberculosis strains. Of the 35 rifampicin-resistant strains of M. tuberculosis, 31% were sensitive to rifabutin but only 3-11% to the other rifamycins. The proportions of the MAIS strains found to be sensitive were 35% for rifampicin, 50-60% for CGP 27557, rifapentine and rifabutin and 85-92% for CGP 29861 and CGP 7040.

Topics: Antitubercular Agents; Drug Resistance, Microbial; Microbial Sensitivity Tests; Mycobacterium avium; Mycobacterium tuberculosis; Rifabutin; Rifampin; Rifamycins

The bactericidal activity of six new rifamycin derivatives--rifabutin (RBU), FCE 22250 (F22), rifapentine (RPE), CGP 29861 (C29), CGP 7040 (C70) and CGP 27557 (C27) and rifampicin (RMP)--have been measured against log phase and, as a better test of sterilising activity, against stationary phase cultures of Mycobacterium tuberculosis, H37Rv. The order of activity of 1.0 and 0.2 mg/l rifamycin against log phase cultures was RMP greater than RPE & C27 greater than RBU & C29 greater than C70. The order of activity of 1.0 and 0.4 mg/l, adjusted for stability of the rifamycin, against stationary phase cultures was F22 & RMP greater than RBU greater than RPE greater than C27 & C29 greater than C70. Viable counts were done during and after pulsed exposures of 6, 24 or 96 h to C29 and RMP. The curves were similar though C29 was less bactericidal and the lag period before recovery was 1-2 days longer. F22, having high bactericidal activity against stationary organisms and a long half-life, was considered likely to be the most effective sterilising drug.

Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifabutin; Rifampin; Rifamycins

Rifapentine uptake by human peritoneal macrophages and polymorphonuclear leukocytes was evaluated and its activity against intracellular Staphylococcus aureus and Staphylococcus epidermidis in both types of phagocytes was compared to that of rifampin, teicoplanin and clindamycin. Uptake of radiolabeled rifapentine by peritoneal macrophages (intracellular/extracellular ratio 61.4 +/- 5.8) and polymorphonuclear leukocytes (intracellular/extracellular ratio 87.6 +/- 3.9) was significantly higher than that of teicoplanin (intracellular/extracellular ratio 40.8 +/- 3.6 and 52.3 +/- 3.2 respectively) and clindamycin (intracellular/extracellular ratio 6.9 +/- 0.4 and 8.3 +/- 0.5 respectively). Rifapentine and rifampin showed the highest activity against intracellular staphylococci in both peritoneal macrophages and polymorphonuclear leukocytes. Clindamycin also showed efficient intracellular activity. In contrast, teicoplanin, which achieved high cellular levels with both types of phagocytes, failed to produce a significant reduction in viable intraphagocytic Staphylococcus epidermidis. On the basis of these findings it is suggested that rifapentine may play a future role in the treatment of certain types of staphylococcal infection.

Topics: Anti-Bacterial Agents; Cells, Cultured; Clindamycin; Glycopeptides; Humans; Macrophages; Neutrophils; Peritoneal Dialysis, Continuous Ambulatory; Rifampin; Staphylococcus aureus; Staphylococcus epidermidis; Teicoplanin

Topics: Animals; Leprosy; Mice; Mycobacterium leprae; Rifabutin; Rifampin; Rifamycins

Topics: Drug Interactions; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Rifampin

In a comparison of in vitro properties of rifapentine (RIF) and rifampicin (RMP), the minimal inhibitory concentration of RIF against Mycobacterium tuberculosis in Tween-albumin liquid medium was usually 0.02 micrograms/ml, 2-3 times lower than for RMP; the bactericidal activity against a log phase culture was slightly less than that of RMP and the recovery after pulsed exposures to 1 microgram/ml of RIF or RMP lasting 6, 24 and 96 h was identical for the two rifamycins. These findings are used to interpret published data from the chronic experimental murine tuberculosis model and support the view that in the mouse, the efficacy of RIF in widely spaced intermittent chemotherapy is the result of its long half-life.

Topics: Animals; Half-Life; In Vitro Techniques; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

Topics: Absorption; Humans; Rifampin; Tuberculosis

The purpose of this study was to determine the effect of rifampin and its cyclopentyl analogue, MDL 473, on delayed type hypersensitivity (DTH) using a murine model. Neither compound has any significant effect on DTH (as measured by ear swelling) to oxazolone when administered i.p. to BALB/c mice at doses of 1, 10, 50 or 100 mg/kg beginning 3 days before oxazolone sensitization and continuing until hapten challenge 5 days later. In contrast, sex and age matched controls receiving 200 mg hydrocortisone/kg i.p. beginning on the day of oxazolone sensitization and continuing to hapten challenge demonstrate a significant (P less than 0.001) abrogation of DTH.

Topics: Animals; Female; Hydrocortisone; Hypersensitivity, Delayed; Mice; Mice, Inbred BALB C; Oxazolone; Rifampin

Topics: Amikacin; Cells, Cultured; Drug Interactions; Humans; Liposomes; Macrophages; Mycobacterium avium; Rifampin

The antimycobacterial activities of two newer ansamycins, isobutylpiperazinylrifamycin SV (R-76-1) and cyclopentylrifamycin SV (DL 473), were compared with those of rifampin (RMP) both in vitro and in vivo. In terms of minimal inhibitory concentrations against a number of cultivable mycobacteria, R-76-1 was about eight times more active in vitro than RMP; whereas DL 473 was only slightly more active than RMP. Therapeutic activities of R-76-1 versus RMP and DL 473 versus RMP were compared, respectively, in the experimental infection of mice with Mycobacterium lepraemurium by different treatment schedules (immediate and delayed) and dosage regimens. R-76-1 appeared to have been three times more effective than RMP; DL 473 was also more effective than RMP in that an equivalent therapeutic effect could be obtained by fewer doses of DL 473 than of RMP, and in that DL 473 exerted a more prolonged activity than RMP. With the kinetic method and a dosage of 0.001% in the diet, R-76-1 demonstrated a bactericidal-type effect against M. leprae whereas RMP did not; with the proportional bactericidal method, R-76-1 possessed about three times the bactericidal activity of RMP against M. leprae. When drugs were administered once in 4 weeks, the RMP dose required to prevent multiplication of M. leprae in the foot pads of half of the mice was in the range of 1.25 to 2.5 mg/kg; whereas that of DL 473 was less than 0.625 mg/kg. With the proportional bactericidal method, even a single dose of 1.25 mg DL 473 per kg was active against M. leprae; whereas the smallest single active dose of RMP was 10 mg/kg. DL 473 in single doses of 5 mg/kg and 10 mg/kg was significantly more effective than RMP in equal doses and, among the intermittent regimens administered four times, once every 4 weeks, no significant differences of bactericidal activity were observed between RMP at 20 mg/kg and DL 473 at 0.625 mg/kg. A preliminary clinical trial of R-76-1 in 20 patients with lepromatous leprosy showed that the compound, administered in a dosage of 150 mg daily, was very effective.

Topics: Animals; Humans; Leprostatic Agents; Leprosy; Mice; Microbial Sensitivity Tests; Mycobacterium Infections; Mycobacterium leprae; Mycobacterium lepraemurium; Rifampin; Rifamycins

Topics: Drug Resistance, Microbial; Mycobacterium; Rifampin

The effects of rifapentine (MDL 473) administration on hepatic mixed function oxidase activity in man have been investigated in six healthy volunteers. Administration of rifapentine (600 mg 48 h-1) for 10 days resulted in a significant reduction in antipyrine half-life (from 13.2 +/- 1.0 h to 7.7 +/- 0.4 h) and a corresponding increase in its total body clearance (from 41.8 +/- 5.5 ml min-1 to 67.4 +/- 5.6 ml min-1). Twelve days after stopping rifapentine administration, these values had largely returned to base-line. 24-Hour excretion of 6 beta-hydroxycortisol was significantly increased, by approximately three-fold, following administration of rifapentine for 10 days. Again, 12 days after stopping drug administration, 6 beta-hydroxycortisol excretion had returned to pretreatment values. Clearance of antipyrine to its three oxidative metabolites was increased by rifapentine administration, although the increase for 3-hydroxymethylantipyrine was not significant. The greatest increase (+140%) was observed for norantipyrine. Twelve days after the last dose of rifapentine, all values had returned to control levels. It is concluded that, like rifampicin, rifapentine is a potent inducer of mixed function oxidase activity in man and that the possibility of clinically significant drug interactions should be anticipated in the therapeutic use of this compound.

Topics: Adult; Antipyrine; Biotransformation; Enzyme Induction; Half-Life; Humans; Hydrocortisone; Male; Mixed Function Oxygenases; Rifampin; Saliva; Time Factors

The antistaphylococcal activity of rifapentine, a new rifamycin SV derivative, was evaluated in vitro and compared with that of rifampin. A total of 313 staphylococcal strains freshly isolated from clinical material and including representatives of all currently recognized Staphylococcus species of human origin were used. The susceptibility to methicillin of all the test strains was determined preliminarily. Despite minor differences with some species, the MICs of rifapentine were found to be substantially similar to those of rifampin. Methicillin-resistant strains of all species were most resistant to rifapentine and rifampin than were their methicillin-susceptible counterparts. For most strains tested, the MBCs of both rifamycins exceeded by twofold the respective MICs. Both the checkerboard dilution and time-kill methods were used to determine the interactions of rifapentine or rifampin with six different antibiotics: cefamandole, vancomycin, teicoplanin, gentamicin, erythromycin, and fusidic acid. No significant differences between the two rifamycins in the combinations were observed against either methicillin-susceptible or methicillin-resistant strains. Minor differences were noted depending on the second antibiotic tested or the staphylococcal species examined. Antagonism was never observed, and indifference was the prevalent response. Cases of synergism were observed occasionally with the checkerboard method and slightly more often with the time-kill method.

Topics: Anti-Bacterial Agents; Drug Combinations; Humans; Methicillin; Microbial Sensitivity Tests; Penicillin Resistance; Rifampin; Staphylococcal Infections; Staphylococcus; Time Factors

The susceptibilities of 20 clinical isolates of Mycobacterium intracellulare to rifampin, MDL 473, and ansamycin were determined by broth and agar dilution methods. Ansamycin was more active than MDL 473, which in turn was usually more active than rifampin by either method. The MICs for 90% of the strains tested by agar dilution were 1, 2, and 4 micrograms of ansamycin, MDL 473, and rifampin per ml, respectively.

Topics: Anti-Bacterial Agents; In Vitro Techniques; Lactams, Macrocyclic; Microbial Sensitivity Tests; Mycobacterium; Rifampin

Rifapentine, a new cyclopentyl rifamycin, was weight for weight less active than rifampicin against Staphylococcus aureus. It was, however, equally effective at reducing the survival of Staph. aureus within human neutrophils even at concentrations below the conventionally determined MIC. The intracellular survival of antibiotic-resistant Staph. aureus was affected by neither agent. The bactericidal activity of neutrophil sonicates after exposure to both antibiotics showed that rifapentine was concentrated three-fold more than rifampicin. Uptake was temperature dependent and rapidly reached a plateau within 10 min. Uptake of rifampicin was unaffected by pH whereas that of rifapentine was reduced when the pH was lowered from 7.3 to 5. Studies with the metabolic inhibitors, sodium cyanide and potassium fluoride, suggested a minor role for both oxidative and glycolytic metabolism in this process. However, neither inhibitor had any demonstrable effect on the intracellular killing of Staph. aureus by either rifapentine or rifampicin.

Topics: Fluorides; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Iodoacetamide; Kinetics; Microbial Sensitivity Tests; Neutrophils; Potassium; Potassium Compounds; Rifampin; Sodium Cyanide; Staphylococcus aureus; Temperature; Time Factors

A study on the pharmacokinetics of rifapentine, a new long-lasting rifamycin, has been carried out in the rat, the mouse and the rabbit. The investigation was made using either radioactive or unlabelled rifapentine and both the total 14C and the unchanged compound were assayed. In the rat, the overall evidence obtained was: the oral absorption of rifapentine into central compartment, due to its poor water solubility, appears to be dose-dependent with a satisfactory oral absorption (84%) after a dose of 3 mg/kg, lower (65%) after 10 mg/kg; the antibiotic undergoes rapid liver uptake while it diffuses into the tissue compartment more slowly, with particular affinity for the adrenals, pancreas and kidneys; concentrations higher than in plasma were also measured in the lungs; elimination of rifapentine from the blood and tissue compartments suggests a non linear capacity-limited kinetics where the terminal elimination phase has monoexponential course. Terminal plasma half-life ranged between 14 and 18 hours; the compound is eliminated mainly via the bile with the feces (92% of dose). In mice rifapentine shows a kinetic profile resembling that obtained in rats, whereas in rabbits is metabolized and/or eliminated much more rapidly with a half-life of only 1.8 hours.

Topics: Animals; Anti-Bacterial Agents; Bile; Blood Proteins; Female; Kinetics; Male; Mice; Mice, Inbred Strains; Protein Binding; Rabbits; Rats; Rats, Inbred Strains; Rifampin; Species Specificity; Tissue Distribution

Rifampicin and rifapentine were used in the treatment of Listeria monocytogenes infections in normal mice and congenitally athymic (nude) mice. Results were compared with untreated controls and with the results obtained from a previous study of ampicillin in which this model was used. Low doses of rifampicin or rifapentine were adequate to cure normal mice. The efficacy of these antibiotic treatment schedules was lost in nude mice. Prolonged antibiotic treatment schedules with increased dosages were also unsuccessful. These studies show that rifampicin and rifapentine , two antimicrobial agents being capable of destroying intracellular bacteria, were not effective in curing the Listeria infection in mice with impaired host defenses.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Female; Half-Life; Listeriosis; Mice; Mice, Nude; Rifampin; T-Lymphocytes

DL 473 is a 3-[(4-cyclopentyl-1-piperazinyl)iminomethyl] rifamycin SV derivative which inhibited staphylococci, streptococci (including Streptococcus faecalis, Listeria species, and Bacteroides species. DL 473 was less active than rifampin against these species. DL 473 did not inhibit Enterobacteriaceae nor most Pseudomonas species. A combination of DL 473 and vancomycin or nafcillin tested against staphylococci was primarily additive and antagonism was not encountered.

Topics: Bacteria; Colony-Forming Units Assay; Drug Synergism; Rifampin

The results of recent experiences with experimental tuberculous chemotherapy in the mouse give information on the activity of rifampicin (RMP) administered intermittently and on the activity of Cyclopentyl-Rifampicin (or DL473). The activity of RMP decreases as one spaces the treatment without increasing the dose. These observations are compatible with the known facts concerning the mechanism of action of RMP on RNA polymerase, and are unfavourable as regards the intermittent administration of RMP. Cyclopentyl-Rifampicin, a new derivative of Rifamycine SV, administered once per week, is as active as RMP administered six days per week, both in the initial as well as the continuation phase of treatment.

Topics: Animals; DNA-Directed RNA Polymerases; Drug Therapy, Combination; Female; Isoniazid; Mice; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

Constant-infusion experiments were performed in 14 dogs to determine the penetration into bone of rifampin and a new C-3 substituted rifamycin, DL 473. The drugs were assayed in cortical bone and medulla from tibia-femur and cortical and cancellous bone from rib. After identical dosage, the concentrations of DL 473 appeared to be higher, except in the medulla, although the serum concentrations of rifampin were almost twice as high as those for DL 473. The concentrations of both drugs in all bone areas were several times higher than their minimum inhibitory concentrations against pathogenic Staphylococcus aureus.

Topics: Animals; Anti-Bacterial Agents; Bone and Bones; Dogs; Male; Rifampin

Topics: Drug Resistance, Microbial; Microbial Sensitivity Tests; Mycobacterium; Rifampin

Topics: Animals; Chromatography, High Pressure Liquid; Haplorhini; Humans; Rats; Rifampin

DL 473, a new semisynthetic rifamycin, was 2-10 times more active in vitro than rifampicin (RAMP) against several clinical isolates of Mycobacterium tuberculosis and only slightly less active than RAMP against Gram-positive and Gram-negative bacteria. It showed excellent therapeutic activity in mice in experimental infections caused by Staphylococcus aureus, Streptococcus pyogenes group A, Streptococcus pneumoniae and Klebsiella pneumoniae. In the experimental TB infection in the mouse DL 473 was clearly more active than isoniazide and RAMP, two of the most effective antitubercular drugs in current use. The LD50 in the mouse was significantly higher than that of RAMP and the half-life was about 5 times longer than that of RAMP.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Dose-Response Relationship, Drug; Isoniazid; Mice; Microbial Sensitivity Tests; Rifampin; Tuberculosis