| 2021 | An open label, randomised controlled trial of rifapentine versus rifampicin based short course regimens for the treatment of latent tuberculosis in England: the HALT LTBI pilot study. | BMC Infect Dis | 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 ). |
| 2021 | Toward patient-centered tuberculosis preventive treatment: preferences for regimens and formulations in Lima, Peru. | BMC Public Health | To ensure patient-centered tuberculosis preventive treatment, it is important to consider factors that make it easier for patients to complete treatment. However, there is little published literature about patient preferences for different preventive treatment regimen options, particularly from countries with high tuberculosis burdens.We conducted a qualitative research study using a framework analysis approach to understand tuberculosis preventive treatment preferences among household contacts. We conducted three focus group discussions with 16 members of families affected by tuberculosis in Lima, Peru. Participants were asked to vote for preferred preventive treatment regimens and discuss the reasons behind their choices. Coding followed a deductive approach based on prior research, with data-driven codes added.In total, 7 (44%) participants voted for 3 months isoniazid and rifapentine, 4 (25%) chose 3 months isoniazid and Rifampicin, 3 (19%) chose 4 months Rifampicin, and 2 (13%) chose 6 months isoniazid. Preferences for shorter regimens over 6 months of isoniazid were driven by concerns over "getting tired" or "getting bored" of taking medications, the difficulty of remembering to take medications, side effects, and interference with daily life. For some, weekly dosing was perceived as being easier to remember and less disruptive, leading to a preference for 3 months isoniazid and rifapentine, which is dosed weekly. However, among caregivers, having a child-friendly formulation was more important than regimen duration. Caregivers reported difficulty in administering pills to children, and preferred treatments available as syrup or dispersible formulations.There is demand for shorter regimens and child-friendly formulations for tuberculosis preventive treatment in high-burden settings. Individual preferences differ, suggesting that patient-centered care would best be supported by having multiple shorter regimens available. |
| 2020 | Potential inhibitors of SARS-cov-2 RNA dependent RNA polymerase protein: molecular docking, molecular dynamics simulations and MM-PBSA analyses. | J Biomol Struct Dyn | The SARS-cov-2 RNA dependent RNA polymerase (nsp12) is a crucial viral enzyme that catalyzes the replication of RNA from RNA templates. The fixation of some ligands in the active site may alter the viral life cycle. The aim of the present study is to identify the conservation level of nsp12 motifs (A-G), using consurf server, and discover their interactions with rifabutin, Rifampicin, rifapentin, sorangicin A, streptolydigin, myxopyronin B, VXR and VRX using AutoDockTools-1.5.6, Gromacs 2018.2 and g-mmpbsa. Thus, the most of amino acids residues located in nsp12 protein Motifs (A-G) were predicted as highly conserved. The binding energies of streptolydigin, VXR, rifabutin, rifapentine, VRX, sorangicin A, myxopyronin B and Rifampicin with nsp12 protein are -8.11, -8.23, -7.14, -6.94, -6.55, -5.46, -5.33 and -5.26 kcal/mol, respectively. In the other hand, the binding energies of ligand in the same order with nsp7-nsp8-nsp12 complex are -7.23, -7.08, -7.21, -7, -6.59, -8.73, -5.52, -5.87 kcal/mol, respectively. All ligands interact with at least two nsp12 motifs. The molecular dynamics simulation of nsp12-streptolydigin and nsp12-VXR complexes shows that these two complexes are stable and the number of hydrogen bonds as a function of time, after 30 ns of simulation, varies between 0 and 6 for nsp12-streptolydigin complex and between 0 and 4 for nsp12-VXR complex. The average of free binding energies obtained using g_mmpbsa, after 30 ns of simulation, is -191.982 Kj/mol for nsp12-streptolydigin complex and -153.583 Kj/mol for nsp12-VXR complex. Our results suggest that these ligands may be used as inhibitors of SARS-cov-2 nsp12 protein.Communicated by Ramaswamy H. Sarma. |
| 2020 | Design, synthesis and antimycobacterial activity of new benzothiazinones inspired by rifampicin/rifapentine. | Bioorg Chem | 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. |
| 2020 | Rapid and simultaneous determination of ten anti-tuberculosis drugs in human plasma by UPLC-MS/MS with applications in therapeutic drug monitoring. | J Chromatogr B Analyt Technol Biomed Life Sci | Tuberculosis remains a global challenge, particularly with a growing number of resistant cases, which may become an obstacle to eliminating this disease. Standardized short-course therapy composed of first-line anti-tuberculosis drugs isoniazid (INH), Rifampicin (RIF), ethambutol (EMB), and pyrazinamide (PZA) is playing vital roles for curbing the rapid spread of tuberculosis. However, some patients have poor responses to standardized short-course therapy. As the number of drug-resistant tuberculosis increase, some other anti-tuberculous drugs are needed to achieve better treatment outcomes. In this study, we established a UPLC-MS/MS method for simultaneous detection of ten anti-tuberculosis drugs in human plasma including INH, EMB, PZA, RIF, rifampin, rifapentine as well as four second-line antituberculosis drugs, i.e. ethionamide, protionamide, thiosemicarbazone and clofazimine. This study contains almost all the commonly used anti-tuberculosis drugs. The plasma samples were treated with acetonitrile to precipitate proteins, and doped with the isotope internal standard. A Shiseido CAPCELL RAK-ADME (2.1 mm × 50 mm, 3 μm) column was used for chromatographic separation, and acetonitrile-water (containing 0.1% formic acid) was the mobile phase. The separation used gradient elution with a flow rate of 0.4 mL/min. The column temperature was 40 °C, and the sample volume was 1 μL. The electrospray ionization source (ESI) and the positive ion multiple reaction monitoring (MRM) mode were used for the detection. The analysis time was as short as 7 min. The results show a good linear relationship under optimized conditions in the range of 5.00-7.50 × 10, 1.00-1.50 × 10, 5.00-5.00 × 10, 5.00-7.50 × 10, 1.00-3.00 × 10, 1.00 × 10-1.00 × 10, 1.00-3.00 × 10, 1.00-3.00 × 10, 2.00-4.00 × 10, and 1.00 × 10-2.00 × 10 ng/mL for INH, EMB PZA, RIF, rifabutin, rifapentine, ethionamide, protionamide, thiosemicarbazone, and clofazimine, respectively, with a linear correlation coefficient of R > 0.99. Finally, 34 patients with pulmonary TB were tested for therapeutic drug monitoring. The results showed that the presented method have significant advances in sensitivity, separation efficiency and simplicity. |
| 2020 | Risk-benefit analysis of tuberculosis infection testing for household contact management in high-burden countries: a mathematical modelling study. | Lancet Glob Health | Preventive therapy for tuberculosis reduces the risk of disease in people who have been infected but who are not sick. Countries with a high burden of tuberculosis that are expanding preventive therapy use must decide how tuberculosis infection testing should be used for risk stratification among household contacts of patients with tuberculosis.We modelled the risks of tuberculosis disease and severe adverse events, comparing the following two preventive therapy strategies: preventive therapy for all household contacts, or preventive therapy for only household contacts with a positive tuberculin skin test (TST) result. We used data from clinical trials and literature on tuberculosis natural history to model outcomes, assuming different preventive therapy regimens, ages, and TST positivity prevalence.Assuming 25% prevalence of TST positivity among 1000 household contacts aged 0-17 years, a treat-all approach with isoniazid and rifapentine compared with a treat-TST-only approach led to 13 fewer incident tuberculosis cases (IQR -5 to -18) and four additional severe adverse events (2 to 6). With Rifampicin, the difference was 11 fewer incident tuberculosis cases (-3 to -17) and two additional severe adverse events (1 to 3). For adults, a treat-all approach led to fewer incident tuberculosis cases, and additional adverse events increased with age. Assuming 25% prevalence of TST positivity among adult contacts, a treat-all approach would lead to around two fewer tuberculosis cases per 1000 contacts for all regimens; the number of additional severe adverse events ranged from seven (IQR 5 to 8) for 18 to 34-year-olds treated with Rifampicin to 63 (50 to 74) for people older than 64 years treated with isoniazid and rifapentine. A Rifampicin-only regimen was associated with the fewest additional severe adverse events (seven [IQR 5 to 8] per 1000 adults aged 18-34 years and 35-64 years, and 17 [9 to 23] per 1000 adults older than 64 years).Based on the available data, giving preventive therapy to all household contacts would probably reduce the incidence of tuberculosis cases in high-burden settings. Adverse events could be minimised by using non-isoniazid regimens and, in adults older than 18 years, focusing treatment on individuals with a positive infection test.Bill & Melinda Gates Foundation, UK Medical Research Council, and UK Department for International Development. |
| 2020 | Antibiofilm and intraosteoblastic activities of rifamycins against Staphylococcus aureus: promising in vitro profile of rifabutin. | J Antimicrob Chemother | Targeting biofilm-embedded and intraosteoblastic Staphylococcus aureus, Rifampicin gained a pivotal role in bone and joint infection (BJI) treatment. Two other rifamycins, rifabutin and rifapentine, may represent better-tolerated alternatives, but their activity against bacterial reservoirs associated with BJI chronicity has never been evaluated.To evaluate the activities of Rifampicin, rifabutin and rifapentine in osteoblast infection models.Using three S. aureus isolates, rifamycins were compared regarding: (i) their intracellular activity in 'acute' (24 h) and 'chronic' (7 days) osteoblast infection models at 0.1× MIC, 1× MIC, 10× MIC and 100× MIC, while impacting infection-induced cytotoxicity (MTT assay), intracellular phenol-soluble modulin (PSM) secretion (RT-PCR), resistance selection and small colony variant (SCV) emergence; and (ii) their minimal biofilm eradication concentration (MBEC) and their MIC to prevent biofilm formation (bMIC).At 0.1× MIC, only rifabutin significantly reduced intracellular inoculum and PSM secretion. All rifamycins allowed a 50% reduction of intraosteoblastic inoculum at higher concentrations, with no difference between acute and chronic infection models, while reducing infection-induced cytotoxicity and PSM secretion. Dose-dependent emergence of intracellular SCVs was observed for all molecules. No intracellular emergence of resistance was detected. bMICs were equivalent for all molecules, but MBEC90s of rifapentine and rifabutin were 10- to 100-fold lower than those of Rifampicin, respectively.All rifamycins are efficient in reducing the S. aureus intraosteoblastic reservoir while limiting infection-induced cytotoxicity, with a higher activity of rifabutin at low concentrations. All molecules prevent biofilm formation, but only rifapentine and rifabutin consistently reduce formed biofilm-embedded bacteria for all isolates. The activity of rifabutin at lower doses highlights its therapeutic potential. |
| 2020 | Frequency, Risk Factors, and Outcome of Active Tuberculosis following Allogeneic Hematopoietic Stem Cell Transplantation. | Biol Blood Marrow Transplant | We aimed to investigate the frequency, risk factors, and outcome of active tuberculosis (TB) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This retrospective, nested, case-control study reviewed data from 6236 patients who received allo-HSCT from January 2008 to December 2018 at a single center; thirty-three patients (0.5%) with active TB and 99 controls without active TB after allo-HSCT were identified. We performed propensity score matching by randomly selecting 3 controls for each identified active TB patient according to the time of transplantation and follow-up period. History of pretransplant active TB previously treated and inactive at time of transplantation (P< .001) was an independent risk factor. No significant differences in overall survival (P= .342), nonrelapse mortality (P= .497), or incidence of relapse (P= .807) were found. Thirty (90.9%) patients were treated with 4-drug (isoniazid, Rifampicin/three rifapentine, pyrazinamide, and ethambutol) or 3-drug combination first-line therapy, with a response rate of 76.7%. Twenty-six (78.8%) patients were treated with first-line and second-line combined therapy, and the response rate was 76.9%. Five (15.2%) patients developed hepatotoxicity. In conclusion, history of pretransplant active TB previously treated and inactive at time of transplantation was an independent risk factor of active TB after allo-HSCT. No significant differences in prognosis between the TB and control groups were found. More studies are needed to help develop standardized therapeutic strategies for patients with post-transplant TB. |
| 2019 | Shortened treatment regimens versus the standard regimen for drug-sensitive pulmonary tuberculosis. | Cochrane Database Syst Rev | Tuberculosis causes more deaths than any other infectious disease worldwide, with pulmonary tuberculosis being the most common form. Standard first-line treatment for drug-sensitive pulmonary tuberculosis for six months comprises isoniazid, Rifampicin, pyrazinamide, and ethambutol (HRZE) for two months, followed by HRE (in areas of high TB drug resistance) or HR, given over a four-month continuation phase. Many people do not complete this full course. Shortened treatment regimens that are equally effective and safe could improve treatment success.To evaluate the efficacy and safety of shortened treatment regimens versus the standard six-month treatment regimen for individuals with drug-sensitive pulmonary tuberculosis.We searched the following databases up to 10 July 2019: the Cochrane Infectious Diseases Group Specialized Register; the Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; MEDLINE (PubMed); Embase; the Latin American Caribbean Health Sciences Literature (LILACS); Science Citation Index-Expanded; Indian Medlars Center; and the South Asian Database of Controlled Clinical Trials. We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform, ClinicalTrials.gov, the Clinical Trials Unit of the International Union Against Tuberculosis and Lung Disease, the UK Medical Research Council Clinical Trials Unit, and the Clinical Trials Registry India for ongoing trials. We checked the reference lists of identified articles to find additional relevant studies.We searched for randomized controlled trials (RCTs) or quasi-RCTs that compared shorter-duration regimens (less than six months) versus the standard six-month regimen for people of all ages, irrespective of HIV status, who were newly diagnosed with pulmonary tuberculosis by positive sputum culture or GeneXpert, and with presumed or proven drug-sensitive tuberculosis. The primary outcome of interest was relapse within two years of completion of anti-tuberculosis treatment (ATT).Two review authors independently selected trials, extracted data, and assessed risk of bias for the included trials. For dichotomous outcomes, we used risk ratios (RRs) with 95% confidence intervals (CIs). When appropriate, we pooled data from the included trials in meta-analyses. We assessed the certainty of evidence using the GRADE approach.We included five randomized trials that compared fluoroquinolone-containing four-month ATT regimens versus standard six-month ATT regimens and recruited 5825 adults with newly diagnosed drug-sensitive pulmonary tuberculosis from 14 countries with high tuberculosis transmission in Asia, Africa, and Latin Ameria. Three were multi-country trials that included a total of 572 HIV-positive people. These trials excluded children, pregnant or lactating women, people with serious comorbid conditions, and those with diabetes mellitus. Four trials had multiple treatment arms. Moxifloxacin replaced ethambutol in standard four-month, daily or thrice-weekly ATT regimens in two trials; moxifloxacin replaced isoniazid in four-month ATT regimens in two trials, was given daily in one trial, and was given with rifapentine instead of Rifampicin daily for two months and twice weekly for two months in one trial. Moxifloxacin was added to standard ATT drugs for three to four months in one ongoing trial that reported interim results. Gatifloxacin replaced ethambutol in standard ATT regimens given daily or thrice weekly for four months in two trials. Follow-up ranged from 12 months to 24 months after treatment completion for the majority of participants. Moxifloxacin-containing four-month ATT regimens Moxifloxacin-containing four-month ATT regimens that replaced ethambutol or isoniazid probably increased the proportions who experienced relapse after successful treatment compared to standard ATT regimens (RR 3.56, 95% CI 2.37 to 5.37; 2265 participants, 3 trials; moderate-certainty evidence). For death from any cause, there was probably little or no difference between the two regimens (2760 participants, 3 trials; moderate-certainty evidence). Treatment failure was rare, and there was probably little or no difference in proportions with treatment failure between ATT regimens (2282 participants, 3 trials; moderate-certainty evidence). None of the participants given moxifloxacin-containing regimens developed resistance to Rifampicin, and these regimens may not increase the risk of acquired resistance (2282 participants, 3 trials; low-certainty evidence). Severe adverse events were probably little or no different with moxifloxacin-containing four-month regimens that replaced ethambutol or isoniazid, and with three- to four-month regimens that augmented standard ATT with moxifloxacin, when compared to standard six-month ATT regimens (3548 participants, 4 trials; moderate-certainty evidence). Gatifloxacin-containing four-month ATT regimens Gatifloxacin-containing four-month ATT regimens that replaced ethambutol probably increased relapse compared to standard six-month ATT regimens in adults with drug-sensitive pulmonary tuberculosis (RR 2.11, 95% CI 1.56 to 2.84; 1633 participants, 2 trials; moderate-certainty evidence). The four-month regimen probably made little or no difference in death compared to the six-month regimen (1886 participants, 2 trials; moderate-certainty evidence). Treatment failure was uncommon and was probably little or no different between the four-month and six-month regimens (1657 participants, 2 trials; moderate-certainty evidence). Acquired resistance to isoniazid or Rifampicin was not detected in those given the gatifloxacin-containing shortened ATT regimen, but we are uncertain whether acquired drug resistance is any different in the four- and six-month regimens (429 participants, 1 trial; very low-certainty evidence). Serious adverse events were probably no different with either regimen (1993 participants, 2 trials; moderate-certainty evidence).Evidence to date does not support the use of shortened ATT regimens in adults with newly diagnosed drug-sensitive pulmonary tuberculosis. Four-month ATT regimens that replace ethambutol with moxifloxacin or gatifloxacin, or isoniazid with moxifloxacin, increase relapse substantially compared to standard six-month ATT regimens, although treatment success and serious adverse events are little or no different. The results of six large ongoing trials will help inform decisions on whether shortened ATT regimens can replace standard six-month ATT regimens. 9 December 2019 Up to date All studies incorporated from most recent search All eligible published studies found in the last search (10 Jul, 2019) were included. |
| 2019 | Specific Interactions between Rifamycin Antibiotics and Water Influencing Ability To Overcome Natural Cell Barriers and the Range of Antibacterial Potency. | ACS Infect Dis | Rifamycins are a group of macrocyclic antibiotics mainly used for the treatment of various bacterial infections including tuberculosis. Spectroscopic studies of rifamycins evidence the formation of temperature- and solvent-dependent equilibria between A-, B-, and C-type conformers in solutions. The B- and C-type conformers of rifamycin antibiotics are exclusively formed in the presence of water molecules. A- and B-type conformers exhibit a hydrophilic and "open" -bridge nature whereas the C-type conformer is more lipophilic due to the presence of a "closed" -bridge structure. The involvement of the lactam moiety of the -bridge in intramolecular H-bonds within rifapentine and Rifampicin implicates the formation of a more hydrophilic A-type conformer. In contrast to Rifampicin and rifapentine, for rifabutin and rifaximin, the "free" lactam group enhances conformational flexibility of the -bridge, thereby enabling interconversion between A- and C-type conformers. In turn, an equilibrium between A- and C-type conformers for rifamycins improves their adaptation to the changing nature of bacteria cell membranes, especially those of Gram-negative strains and/or to efflux pump systems. |
| 2019 | Tuberculosis. | Lancet | Tuberculosis remains the leading cause of death from an infectious disease among adults worldwide, with more than 10 million people becoming newly sick from tuberculosis each year. Advances in diagnosis, including the use of rapid molecular testing and whole-genome sequencing in both sputum and non-sputum samples, could change this situation. Although little has changed in the treatment of drug-susceptible tuberculosis, data on increased efficacy with new and repurposed drugs have led WHO to recommend all-oral therapy for drug-resistant tuberculosis for the first time ever in 2018. Studies have shown that shorter latent tuberculosis prevention regimens containing Rifampicin or rifapentine are as effective as longer, isoniazid-based regimens, and there is a promising vaccine candidate to prevent the progression of infection to the disease. But new tools alone are not sufficient. Advances must be made in providing high-quality, people-centred care for tuberculosis. Renewed political will, coupled with improved access to quality care, could relegate the morbidity, mortality, and stigma long associated with tuberculosis, to the past. |
| 2019 | Facile in situ generation of bismuth tungstate nanosheet-multiwalled carbon nanotube composite as unconventional affinity material for quartz crystal microbalance detection of antibiotics. | J Hazard Mater | Overuse and thus a constant presence of antibiotics leads to various environmental hazards and health risks. Thus, accurate sensors are required to determine their presence. In this work, we present a mass-sensitive sensor for the detection of Rifampicin. We chose this molecule as it is an important antibiotic for tuberculosis, one of the leading causes of deaths worldwide. Herein, we have prepared a carbon nanotube reinforced with bismuth tungstate nanocomposite material in a well-defined nanosheet morphology using a facile in situ synthesis mechanism. Morphological characterization revealed the presence of bismuth tungstate in the form of square nanosheets embedded in the intricate network of carbon nanotubes, resulting in higher surface roughness of the nanocomposite. The synergy of the composite, so formed, manifested a high affinity for Rifampicin as compared to the individual components of the composite. The developed sensor possessed a high sensitivity toward Rifampicin with a detection limit of 0.16 μM and excellent specificity, as compared to rifabutin and rifapentine. Furthermore, the sensor yielded statistically good recoveries for the monitoring of Rifampicin in human urine samples. This work opens up a new horizon for the exploration of unconventional nanomaterials bearing different morphologies for the detection of pharmaceuticals. |
| 2018 | Treatment completion for latent tuberculosis infection in Norway: a prospective cohort study. | BMC Infect Dis | 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. |
| 2019 | Cost-effectiveness of 3 months of weekly rifapentine and isoniazid compared with other standard treatment regimens for latent tuberculosis infection: a decision analysis study. | J Antimicrob Chemother | 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. |
| 2018 | Effect of the alkyl group in the piperazine N-substitution on the therapeutic action of rifamycins: A drug-membrane interaction study. | Chem Biol Interact | 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. |
| 2017 | Assessment of vocation of rifabutin and rifapentine in replace of rifampcin in drug resistance leprosy patients: a molecular simulation study. | Mol Biol Res Commun | The emergence of drug resistance in leprosy is a major hurdle in leprosy elimination programme. Although the problem of drug resistance is presently not acute, it is important that we collect data more systematically and monitor the trend carefully so that effective measures to combat this problem can be developed. The present study aimed at the explication of cross resistance of rifabutin and rifapentine to Rifampicin which would be helpful to programme managers for implementing rifabutin or rifapentine in replace of Rifampicin. In this study we built 3D model of the rpoB using Swiss Model and the modelled structure was docked with Rifampicin, rifabutin and rifapentine. We established that these 3 antibiotics interact with the same binding region in the modelled rpoB of Thus we conclude that vocation of rifabutin and rifapentine could not be suitable in replace of Rifampicin to combat with drug resistance leprosy. |
| 2017 | Clinical and pharmacological hallmarks of rifapentine's use in diabetes patients with active and latent tuberculosis: do we know enough? | Drug Des Devel Ther | 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. |
| 2017 | Efficacy and completion rates of rifapentine and isoniazid (3HP) compared to other treatment regimens for latent tuberculosis infection: a systematic review with network meta-analyses. | BMC Infect Dis | 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. |
| The Possible Innovative Use of Bifidobacterium longum W11 in Association With Rifaximin: A New Horizon for Combined Approach? | J Clin Gastroenterol | The aim of the study was to unequivocally demonstrate the nontransmissibility of the genes mediating the resistance of the strain Bifidobacterium longum W11 (LMG P-21586) to rifaximin.Most antibiotic treatments can induce unfavorable side effects such as antibiotic-associated diarrhea, which is largely attributable to the disruption of the intestinal microbiota. The parallel intake of probiotic bacteria might reduce these events, even if with generally very poor results. In this regard, the use of antibiotic-resistant beneficial bacteria could represent a worthy strategy.Rifaximin was tested in parallel with Rifampicin, rifapentine, and rifabutin, all rifamycin derivates, using 5 different concentrations. Susceptibility tests were performed by the disc diffusion method of Kirby-Bauer, and inhibition zones were measured after incubation at 37°C. B. longum BL03 was used as comparison. The B. longum W11 genome was sequenced on Illumina MiSeq with a 250 PE reads module. After mapping the reads with the reference bacterial genome, the alignment data were processed using FreeBayes software.B. longum BL03 was inhibited by all antibiotics even at the lowest concentration. In contrast, the W11 strain was inhibited by Rifampicin, rifabutin, and rifaximin only at the highest concentration (512 μg/mL). The genomic analysis showed a mutation into the chromosomal DNA. No transposable elements were found, and the genetic locus was not flanked by close mobile genetic elements.B. longum W11 could be used in combined therapy with rifaximin, thus opening new focused frontiers in the probiotic era while preserving the necessary safety of use for consumers. |
| 2016 | Repurposing clinically approved cephalosporins for tuberculosis therapy. | Sci Rep | While modern cephalosporins developed for broad spectrum antibacterial activities have never been pursued for tuberculosis (TB) therapy, we identified first generation cephalosporins having clinically relevant inhibitory concentrations, both alone and in synergistic drug combinations. Common chemical patterns required for activity against Mycobacterium tuberculosis were identified using structure-activity relationships (SAR) studies. Numerous cephalosporins were synergistic with Rifampicin, the cornerstone drug for TB therapy, and ethambutol, a first-line anti-TB drug. Synergy was observed even under intracellular growth conditions where beta-lactams typically have limited activities. Cephalosporins and Rifampicin were 4- to 64-fold more active in combination than either drug alone; however, limited synergy was observed with rifapentine or rifabutin. Clavulanate was a key synergistic partner in triple combinations. Cephalosporins (and other beta-lactams) together with clavulanate rescued the activity of Rifampicin against a Rifampicin resistant strain. Synergy was not due exclusively to increased Rifampicin accumulation within the mycobacterial cells. Cephalosporins were also synergistic with new anti-TB drugs such as bedaquiline and delamanid. Studies will be needed to validate their in vivo activities. However, the fact that cephalosporins are orally bioavailable with good safety profiles, together with their anti-mycobacterial activities reported here, suggest that they could be repurposed within new combinatorial TB therapies. |
| 2017 | Absolute Quantification of Rifampicin by MALDI Imaging Mass Spectrometry Using Multiple TOF/TOF Events in a Single Laser Shot. | J Am Soc Mass Spectrom | Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) allows for the visualization of molecular distributions within tissue sections. While providing excellent molecular specificity and spatial information, absolute quantification by MALDI IMS remains challenging. Especially in the low molecular weight region of the spectrum, analysis is complicated by matrix interferences and ionization suppression. Though tandem mass spectrometry (MS/MS) can be used to ensure chemical specificity and improve sensitivity by eliminating chemical noise, typical MALDI MS/MS modalities only scan for a single MS/MS event per laser shot. Herein, we describe TOF/TOF instrumentation that enables multiple fragmentation events to be performed in a single laser shot, allowing the intensity of the analyte to be referenced to the intensity of the internal standard in each laser shot while maintaining the benefits of MS/MS. This approach is illustrated by the quantitative analyses of Rifampicin (RIF), an antibiotic used to treat tuberculosis, in pooled human plasma using rifapentine (RPT) as an internal standard. The results show greater than 4-fold improvements in relative standard deviation as well as improved coefficients of determination (R) and accuracy (>93% quality controls, <9% relative errors). This technology is used as an imaging modality to measure absolute RIF concentrations in liver tissue from an animal dosed in vivo. Each microspot in the quantitative image measures the local RIF concentration in the tissue section, providing absolute pixel-to-pixel quantification from different tissue microenvironments. The average concentration determined by IMS is in agreement with the concentration determined by HPLC-MS/MS, showing a percent difference of 10.6%. Graphical Abstract ᅟ. |
| Evaluation of New Antibacterial Drugs and their Combinations in a Murine Model to Identify Short Duration Alternative Chemotherapy for Leprosy. | Indian J Lepr | The objective of the research is to test the efficacy of new drugs and drug combinations in mice infected with Mycobacterium leprae (M. leprae) as alternative to current WHO MDT. Individual drugs tested were Rifampicin (RMP), Rifapentine (RPT) and Moxifloxacin (MOXI). Drug combinations were RMP, Clarithromycin (CLARI), Minocycline (MINO) and RMP, MINO and Ofloxacin (OFLO). RPT drug combinations were RPT, CLARI,MINO and RPT, OFLO, MINO. Both the drugs and drug combinations were used as daily regimen and intermittent regimen. WHO MB MDT served as a positive control. Mice pre-inoculated with M. leprae were allotted to daily and intermittent groups and administered selected drugs and drug combinations. At the end of 12 months post sub-inoculation, mice were sacrificed and the proportion % of viable bacilli were counted using Spearman and Karber method. It was noted that RMP, RPT and Moxifloxacin indicated a range of 89.99% to 99.99% bactericidal effect when used in daily or intermittent doses in both normal and TR mice. Drug combinations showed bactericidal effect comparable to that of WHO MDT. From the study it was concluded that if the present duration of MDT has to be shortened then daily dose regimen with RMP/MINO/OFLO or RPT/CLARI/MINO are recommended for a clinical trial. |
| Evaluation of anti-bacterial activity of Rifapentine, Clarithromycin, Minocycline, Moxifloxacin, Ofloxacin and their combinations in Murine Model of Rifampicin Resistant Leprosy. | Indian J Lepr | Leprosy, a debilitating disease of the skin and peripheral nerves is caused by Mycobacterium leprae (M. leprae) and is treated by multidrug therapy (MDT) comprising of Dapsone, Rifampicin and Clofazimine. Resistance to any of these drugs poses a threat to the current disease control strategies. With the emergence of Rifampicin resistance in leprosy, it is important that alternative drugs need to be tested to develop a treatment strategy to combat drug resistant leprosy. In the current study, we have investigated WHO MDT, Rifapentine, Clarithromycin, Minocycline, Moxifloxacin, Ofloxacin and their combinations in intermittent and daily dose regimens in Rifampicin resistant strains of M. leprae through mouse foot pad experiments in order to determine the loss in viability of M. leprae in response to these drugs and their combinations. Our findings suggest that WHO MDT is still the best combination in Rifampicin resistance cases. Combination of Moxifloxacin with Minocycline and Clarithromycin may also be taken up for clinical trials in cases with Rifampicin resistant leprosy. Rifapentine and Moxifloxacin can be effective alternative drugs to replace Rifampicin where required either in daily dose shorter duration regimens or intermittent dose longer regimen to treat resistant strains. |
| 2016 | Rifamycins, Alone and in Combination. | Cold Spring Harb Perspect Med | 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. |
| 2016 | Validation of a simple HPLC-UV method for rifampicin determination in plasma: Application to the study of rifampicin arteriovenous concentration gradient. | J Pharm Biomed Anal | 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. |
| 2015 | [Role of Human Orphan Esterases in Drug-induced Toxicity]. | Yakugaku Zasshi | Esterases hydrolyze compounds containing ester, amide, and thioester bonds, causing prodrug activation or detoxification. Among esterases, carboxylesterases have been studied in depth due to their ability to hydrolyze a variety of drugs. However, there are several drugs for which the involved esterase(s) is unknown. We found that flutamide, phenacetin, rifamycins (Rifampicin, rifabutin, and rifapentine), and indiplon are hydrolyzed by arylacetamide deacetylase (AADAC), which is highly expressed in human liver and gastrointestinal tissues. Flutamide hydrolysis is considered associated with hepatotoxicity. Phenacetin, a prodrug of acetaminophen, was withdrawn due to side effects such as methemoglobinemia and renal failure. It was demonstrated in vitro and in vivo using mice that AADAC is responsible for phenacetin hydrolysis, which leads to methemoglobinemia. In addition, it was shown that AADAC-mediated hydrolysis attenuates the cytotoxicity of rifamycins. Thus AADAC plays critical roles in drug-induced toxicity. Another orphan esterase, α/β hydrolase domain containing 10 (ABHD10), was found responsible for deglucuronidation of acyl-glucuronides including mycophenolic acid acyl-glucuronide and probenecid acyl-glucuronide. Because acyl-glucuronides appear associated with toxicity, ABHD10 would function as a detoxification enzyme. The roles of orphan esterases are becoming increasingly understood. Further studies will facilitate our knowledge of the pharmacologic and toxicological significance of orphan esterases in drug therapy. |
| 2015 | Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries. | Eur Respir J | 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. |
| 2015 | Uniform and amorphous rifampicin microspheres obtained by freezing induced LLPS during lyophilization. | Int J Pharm | 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. |
| 2015 | Inhibitory Potential of Twenty Five Anti-tuberculosis Drugs on CYP Activities in Human Liver Microsomes. | Biol Pharm Bull | The direct inhibitory potential of twenty five anti-tuberculosis drugs on eight CYP-specific reactions in human liver microsomes was investigated to predict in vivo drug-drug interactions (DDIs) from in vitro data. Rifampicin, rifabutin, and thioacetazone inhibited one CYP reaction. Isoniazid and clofazimine had inhibitory effects on four CYP reactions, and rifapentine, ethionamide, and prothionamide widely inhibited CYP reactions. Based on the inhibition constant (Ki) and the therapeutic total inhibitor concentrations [I]max of eight drugs in human plasma, [I]max/Ki values were calculated to evaluate clinical DDIs. The [I]max/Ki values were 0.20 or less for Rifampicin, rifabutin, and thioacetazone; 0.15-2.0 for isoniazid; 0.14-1.5 for rifapentine; 0.29-1.4 for ethionamide; 0.41-2.2 for prothionamide; and 0.12-6.3 for clofazimine. The highest [I]max/Ki values were 2.0 for isoniazid on CYP3A4 [testosterone (T)]; 1.5 for rifapentine on CYP3A4 [midazolam (M)]; 1.4 for ethionamide on CYP2C8; 2.2, 1.8, and 1.3 for prothionamide on CYP2B6, CYP2C19, and CYP2C8, respectively; and 6.3 and 5.7 for clofazimine on CYP3A4 (M) and CYP3A4 (T), respectively. These drugs with high [I]max/Ki values lead to clinical DDIs. Considering the drug regimens for tuberculosis (TB) and co-infection with TB and human immunodeficiency virus, the inhibitory potential for CYP3A4 and CYP2B6 is particularly important. These results suggest that clofazimine and prothionamide are likely to cause clinically relevant DDIs when co-administered with products metabolized by CYP3A4 and CYP2B6, respectively. Isoniazid and rifapentine may cause DDIs with drugs metabolized by CYP3A4. |
| 2015 | Two-stage activity-safety study of daily rifapentine during intensive phase treatment of pulmonary tuberculosis. | Int J Tuberc Lung Dis | 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. |
| 2015 | Rifampicin and rifapentine significantly reduce concentrations of bedaquiline, a new anti-TB drug. | J Antimicrob Chemother | 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. |
| 2015 | Determination of the rifamycin antibiotics rifabutin, rifampin, rifapentine and their major metabolites in human plasma via simultaneous extraction coupled with LC/MS/MS. | J Pharm Biomed Anal | 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. |
| 2015 | Novel Inhaled Combination Powder Containing Amorphous Colistin and Crystalline Rifapentine with Enhanced Antimicrobial Activities against Planktonic Cells and Biofilm of Pseudomonas aeruginosa for Respiratory Infections. | Mol Pharm | 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. |
| 2014 | Rifamycins (rifampicin, rifabutin and rifapentine) compared to isoniazid for preventing tuberculosis in HIV-negative people at risk of active TB. | Evid Based Child Health | 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 among close contacts of TB in the USA, Canada, Brazil and Spain found directly observed weekly treatment to be non-inferior to nine months self-administered INH for the incidence of active TB (0.2% vs 0.4%, RR 0.44, 95% CI 0.18 to 1.07, one trial, 7731 participants; moderate quality evidence). The directly-observed, shorter regimen had higher treatment completion (82% vs 69%, RR 1.19, 95% CI 1.16 to 1.22, moderate quality evidence), and less hepatotoxicity (0.4% versus 2.4%; RR 0.16, 95% CI 0.10 to 0.27; high quality evidence), though treatment-limiting adverse events were more frequent (4.9% versus 3.7%; RR 1.32, 95% CI 1.07 to 1.64 moderate quality evidence)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. |
| 2014 | High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. | N Engl J Med | 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.). |
| 2014 | Novel on-line column extraction apparatus coupled with binary peak focusing for high-performance liquid chromatography determination of rifampicin in human plasma: a strategy for therapeutic drug monitoring. | J Sep Sci | In order to develop a method that is completely suitable for the routine therapeutic drug monitoring, a sensitive and fully automated on-line column extraction apparatus in combination with high-performance liquid chromatography allowing binary peak focusing was developed and validated for the determination of Rifampicin in human plasma. Rifapentine was used as an internal standard. The analytical cycle started with the injection of 100 μL of the sample pretreated by protein precipitation in a Venusil SCX extraction column. After the elution, the analytes were transferred and concentrated in an Xtimate C18 trap column. Finally, the trapped analytes were separated by an Xtimate C18 analytical column and were analyzed by an ultraviolet detector at 336 nm. With this new strategy, continuous on-line analysis of the compounds was successfully performed. The method showed excellent performance for the analysis of Rifampicin in plasma samples, including calibration curve linearity (All r were larger than 0.9996), sensitivity (lowest limit of quantification was 0.12 μg/mL), method accuracy (within 6.6% in terms of relative error), and precision (relative standard deviations of intra- and interday precision were less than 7.8%). These results demonstrated that the simple, reliable, and automatic method based on on-line column extraction and binary peak focusing is a promising approach for therapeutic drug monitoring in complex biomatrix samples. |
| 2014 | Resistance to rifampicin: a review. | J Antibiot (Tokyo) | 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. |
| 2014 | Bedaquiline: a review of human pharmacokinetics and drug-drug interactions. | J Antimicrob Chemother | Bedaquiline has recently been approved for the treatment of pulmonary multidrug-resistant tuberculosis (TB) as part of combination therapy in adults. It is metabolized primarily by the cytochrome P450 isoenzyme 3A4 (CYP3A4) to a less-active N-monodesmethyl metabolite. Phase I and Phase II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant TB have assessed the pharmacokinetics and drug-drug interaction profile of bedaquiline. Potential interactions have been assessed between bedaquiline and first- and second-line anti-TB drugs (Rifampicin, rifapentine, isoniazid, pyrazinamide, ethambutol, kanamycin, ofloxacin and cycloserine), commonly used antiretroviral agents (lopinavir/ritonavir, nevirapine and efavirenz) and a potent CYP3A inhibitor (ketoconazole). This review summarizes the pharmacokinetic profile of bedaquiline as well as the results of the drug-drug interaction studies. |
| 2014 | Treatment optimization in patients co-infected with HIV and Mycobacterium tuberculosis infections: focus on drug-drug interactions with rifamycins. | Clin Pharmacokinet | Tuberculosis (TB) and HIV continue to be two of the major causes of morbidity and mortality in the world, and together are responsible for the death of millions of people every year. There is overwhelming evidence to recommend that patients with TB and HIV co-infection should receive concomitant therapy of both conditions regardless of the CD4 cell count level. The principles for treatment of active TB disease in HIV-infected patients are the same as in HIV-uninfected patients. However, concomitant treatment of both conditions is complex, mainly due to significant drug-drug interactions between TB and HIV drugs. Rifamycins are potent inducers of the cytochrome P450 (CYP) pathway, leading to reduced (frequently sub-therapeutic) plasma concentrations of some classes of antiretrovirals. Rifampicin is also an inducer of the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes and interferes with drugs, such as integrase inhibitors, that are metabolized by this metabolic pathway. Rifampicin is also an inducer of the adenosine triphosphate (ATP) binding cassette transporter P-glycoprotein, which may also lead to decreased bioavailability of concomitantly administered antiretrovirals. On the other side, rifabutin concentrations are affected by the antiretrovirals that induce or inhibit CYP enzymes. In this review, the pharmacokinetic interactions, and the relevant clinical consequences, of the rifamycins-Rifampicin, rifabutin, and rifapentine-with antiretroviral drugs are reviewed and discussed. A Rifampicin-based antitubercular regimen and an efavirenz-based antiretroviral regimen is the first choice for treatment of TB/HIV co-infected patients. Rifabutin is the preferred rifamycin to use in HIV-infected patients on a protease inhibitor-based regimen; however, the dose of rifabutin needs to be reduced to 150 mg daily. More information is required to select optimal treatment regimens for TB/HIV co-infected patients whenever efavirenz cannot be used and rifabutin is not available. Despite significant pharmacokinetic interactions between antiretrovirals and antitubercular drugs, adequate clinical response of both infections can be achieved with an acceptable safety profile when the pharmacological characteristics of drugs are known, and appropriate combination regimens, dosing, and timing of initiation are used. However, more clinical research is needed for newer drugs, such as rifapentine and the recently introduced integrase inhibitor antiretrovirals, and for specific population groups, such as children, pregnant women, and patients affected by multidrug-resistant TB. |
| 2014 | Ability of preventive therapy to cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-burden settings. | Proc Natl Acad Sci U S A | Trials of isoniazid preventive therapy (IPT) for people living with HIV in southern Africa have shown high rates of tuberculosis disease immediately after cessation of therapy. This could be due to the lack of cure following preventive therapy or reinfection with rapid progression to disease. Using a model fitted to trial data, we estimate the degree to which preventive therapies cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-tuberculosis-burden settings. We identified randomized controlled trials that compared IPT to placebo or alternative regimen in HIV-positive, tuberculin skin test positive individuals. A mathematical model describing tuberculosis transmission in a closed cohort of HIV-positive, M. tuberculosis infected, antiretroviral therapy naive individuals following completion of preventive therapy (or placebo) was fitted to posttherapy tuberculosis rates to estimate the annual risk of M. tuberculosis reinfection and the proportion of individuals whose latent infection was cured after therapy. Three trials met our inclusion criteria. Estimated annual risks of reinfection ranged between 3.7 and 4.9%. Our results suggest 6 mo of isoniazid cured in a small proportion [estimated proportion cured = 0% (interquartile range 0-30.9%)]. The proportion cured for 3-mo regimens containing Rifampicin or rifapentine was 19-100%. IPT alone does not cure existing infections in the majority of HIV-infected individuals. In high-incidence settings, continuous IPT should be integrated with HIV care. Where the risk of reinfection is lower, preventive therapy with more curative drugs should be preferred for HIV-positive individuals to achieve durable patient benefit. |
| 2014 | A novel inhalable form of rifapentine. | J Pharm Sci | 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. |
| 2013 | Rifamycins (rifampicin, rifabutin and rifapentine) compared to isoniazid for preventing tuberculosis in HIV-negative people at risk of active TB. | Cochrane Database Syst Rev | 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 among close contacts of TB in the USA, Canada, Brazil and Spain found directly observed weekly treatment to be non-inferior to nine months self-administered INH for the incidence of active TB (0.2% vs 0.4%, RR 0.44, 95% CI 0.18 to 1.07, one trial, 7731 participants; moderate quality evidence). The directly-observed, shorter regimen had higher treatment completion (82% vs 69%, RR 1.19, 95% CI 1.16 to 1.22, moderate quality evidence), and less hepatotoxicity (0.4% versus 2.4%; RR 0.16, 95% CI 0.10 to 0.27; high quality evidence), though treatment-limiting adverse events were more frequent (4.9% versus 3.7%; RR 1.32, 95% CI 1.07 to 1.64 moderate quality evidence)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. |
| 2013 | Improving existing tools for Mycobacterium xenopi treatment: assessment of drug combinations and characterization of mouse models of infection and chemotherapy. | J Antimicrob Chemother | Mycobacterium xenopi is a common agent of non-tuberculous mycobacterial lung diseases in Europe. However, an optimal treatment regimen for M. xenopi infection has not yet been established. Appropriate in vitro and in vivo model systems are needed for characterization of the activity of potential drugs and drug combinations against M. xenopi.We utilized three experimental platforms to analyse the anti-M. xenopi activity of single and combination drug regimens. First, we determined the bacteriostatic and bactericidal activities of drugs alone and in combination in vitro. Second, we used serum from treated mice to evaluate drug activities ex vivo. Third, we analysed M. xenopi growth in four strains of mice (BALB/c, C57BL/6, beige and athymic nude) and developed a mouse model of chemotherapy for this infection.Two-drug combinations of ethambutol with Rifampicin, rifapentine or moxifloxacin, and of clarithromycin with moxifloxacin were bactericidal in vitro, and the combination of ethambutol and Rifampicin with either clarithromycin or moxifloxacin showed significant bactericidal activity ex vivo. Nude mice were the most susceptible strain to M. xenopi infection, and in this model amikacin-containing regimens were the most effective against M. xenopi. No difference in activity was found between regimens containing clarithromycin and moxifloxacin in vivo.The ethambutol/Rifampicin combination with clarithromycin or moxifloxacin had significant bactericidal activity against M. xenopi. The nude mouse, being highly susceptible to M. xenopi, can be utilized for in vivo chemotherapy studies for this infection. |
| 2013 | Rilpivirine: a new non-nucleoside reverse transcriptase inhibitor. | J Antimicrob Chemother | Rilpivirine is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) that is approved for HIV-1 treatment-naive adult patients in combination with other antiretroviral agents. The recommended dose is a 25 mg tablet once daily taken orally with a meal. Due to cytochrome P450 3A4 enzyme induction or gastric pH increase, rilpivirine cannot be coadministered with a number of other drugs (anticonvulsants, rifabutin, Rifampicin, rifapentine, proton pump inhibitors, systemic dexamethasone and St John's wort). Rilpivirine should be used with caution when coadministered with a drug with a known risk for torsade de pointes. Rilpivirine has a better tolerability than a comparative NNRTI, efavirenz, in clinical trials, with fewer central nervous system adverse effects, rashes, lipid abnormalities and discontinuation rates. Virological failure occurs more commonly with higher baseline viral loads (>100,000 copies/mL) and lower baseline CD4 counts (<50 cells/mm(3)). Seventeen NNRTI mutations have been associated with decreased susceptibility to rilpivirine: K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C, M230I/L, Y188L and the combination L100I + K103N. Resistance to rilpivirine largely excludes future use of the NNRTI class. |
| 2012 | Pharmacokinetic/pharmacodynamic parameters and the choice of high-dosage rifamycins. | Int J Tuberc Lung Dis | Clinical trials and the behaviour of bacterial persisters.To explain why the efficacies of isoniazid (INH) and rifamycins during the treatment of tuberculosis (TB) are related not to the area under the curve (AUC)/minimum inhibitory concentration (MIC), but to peak drug concentrations.We examined the response in clinical trials with patients treated with INH alone and divided into slow and rapid acetylators of INH.The efficacy of INH is best related to peak concentrations, as repeated peaks can kill low-degree resistant mutants. A similar process might result in repeated peak concentrations of rifamycins killing low-tolerance persisters.If the efficacy of rifamycins is best related to peak concentrations, we can explain the discrepancy between mouse studies on daily rifapentine (RPT) and the failure to accelerate elimination of TB from sputum in the TBTC Study 29A, as daily RPT greatly increases the AUC but not the peak concentrations. High dosage Rifampicin may be better able than RPT to cause high peaks. |
| 2011 | New regimens for reducing the duration of the treatment of drug-susceptible pulmonary tuberculosis. | Drug Dev Res | Tuberculosis (TB) remains an important health problem worlwide. The structure necessary for delivering TB treatment and implementing the directly observed treatment accounts for more than two-thirds of its final cost. Furthemore, although with efficacy greater than 90%, the effectiveness of present treatment regimens ranges from 55-85%, depending on the setting, mainly due to poor adherence. Duration of treatment with the current first-line anti-TB drugs is a minimum of 6 months. Reducing the duration of the treatment from six to two months or less could result in significant increase of adherence to treatment and cost reduction. The aim of this review is to highlight potential new agents or new drug combinations that could reduce the time of treatment of drug-susceptible TB, currently under study or recently evaluated through clinical trials. We conducted a literature search in the English language for clinical studies as well as an electronic computer-assisted and manual search. The literature search was conducted on November 2010, using MEDLINE (2000-2010), EMBASE (2000-2010) and the National Institute of Health (NIH) Clinical Trials Register database (2000-2010). Most of the new agents identified as anti-TB drug candidates are still in the preclinical phases. Nitroimidazole-PA-824 and fluoroquinolones are evaluated while two first line drugs - Rifampicin and rifapentine -are re-evaluated to optimize their efficacy in new ultra-short anti-TB regimens through phases II/III clinical studies. A summary of the studies are presented, with their potential to change recommendations for TB treatment in the near future. |
| 2012 | In vitro reaction phenotyping studies on rifamycins to explain the auto-induction of rifabutin metabolism. | Int J Tuberc Lung Dis | A study was carried out to establish the relative contribution of human cytochrome P450 (CYP450) enzymes in the metabolism of Rifampicin (RMP), rifapentine (RPT) and rifabutin (RFB). It involved the incubation of the three drugs in five major CYP450 isoforms. Both RMP and RPT showed minimal metabolism by CYP450 enzymes, whereas RFB showed extensive metabolic degradation by CYP3A4. A known inducer of CYP3A4, RFB was shown in this study to be also a substrate for the same enzyme. The latter might be one of the reasons for the auto-induction of RFB metabolism and the consequent lower bioavailability of the drug on repeated administration. |
| 2011 | The activity of several newer antimicrobials against logarithmically multiplying M. leprae in mice. | Lepr Rev | Moxifloxacin, Rifampicin, rifapentine, linezolid, and PA 824, alone and in combination, have been previously administered, as single doses and five times daily doses, to M. leprae infected mice during lag phase multiplication and were each found to have some bactericidal activity.The fluroquinolones, ofloxacin, moxifloxacin and gatifloxacin, (50 mg/kg, 150 mg/kg and 300 mg/kg) and the rifamycins (5 mg/kg, 10 mg/kg, and 20 mg/kg), Rifampicin and rifapentine, were evaluated alone and in combination for bactericidal activity against M. leprae using the mouse footpad model during logarithmic multiplication. Linezolid and PA 824 were similarly evaluated alone and linezolid in combination with Rifampicin, minocycline and ofloxacin.The three fluroquinolones and rifamycins were found alone and in combination to be bactericidal at all dosage schedules. PA 824 had no activity against M. leprae, while linezolid at a dose of 25 mg/kg was bacteriostatic, and progressively more bactericidal at doses of 50 mg/kg and 100 mg/kg. No antagonisms were detected between any of these drugs when used in combinations.Moxifloxacin, gatifloxacin, rifapentine and linezolid were found bactericidal against rapidly multiplying M. leprae. |
| 2011 | Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antifungal, antitubercular and miscellaneous anti-infective agents. | Clin Pharmacokinet | Epithelial lining fluid (ELF) is often considered to be the site of extracellular pulmonary infections. During the past 25 years, a limited number of studies have evaluated the intrapulmonary penetration of antifungal, antitubercular, antiparasitic and antiviral agents. For antifungal agents, differences in drug concentrations in ELF or bronchoalveolar lavage (BAL) fluid were observed among various formulations or routes of administration, and between agents within the same class. Aerosolized doses of deoxycholate amphotericin B, liposomal amphotericin B and amphotericin B lipid complex resulted in higher concentrations in ELF or BAL fluid than after intravenous administration. The mean concentrations in ELF following intravenous administration of both anidulafungin and micafungin ranged between 0.04 and 1.38 μg/mL, and the ELF to plasma concentration ratios (based on the area under the concentration-time curve for total drug concentrations) were between 0.18 and 0.22 during the first 3 days of therapy. Among the azole agents, intravenous administration of voriconazole resulted in the highest mean ELF concentrations (range 10.1-48.3 μg/mL) and ratio of penetration (7.1). The range of mean ELF concentrations of itraconazole and posaconazole following oral administration was 0.2-1.9 μg/mL, and the ELF to plasma concentration ratios were <1. A series of studies have evaluated the intrapulmonary penetration of first- and second-line oral antitubercular agents in healthy adult subjects and patients with AIDS. The ELF to plasma concentration ratio was >1 for isoniazid, ethambutol, pyrazinamide and ethionamide. For Rifampicin (rifampin) and rifapentine, the ELF to plasma concentration ratio ranged between 0.2 and 0.32, but in alveolar macrophages the concentration of Rifampicin was much higher (145-738 μg/mL compared with 3.3-7.5 μg/mL in ELF). No intrapulmonary studies have been conducted for rifabutin. Sex, AIDS status or smoking history had no significant effects on the magnitude of ELF concentrations of antitubercular agents. Subjects who were slow acetylators had higher plasma and ELF concentrations of isoniazid than those who were fast acetylators. Penetration of dapsone into ELF was very good, with the range of mean ELF to plasma concentration ratios being 0.65-2.91 at individual sampling times over 48 hours. Once-daily dosing of aerosolized pentamidine resulted in higher concentrations in BAL fluid than after intravenous administration. The mean BAL concentrations at 15-32 days after once- or twice-monthly administration of aerosolized pentamidine 300 and 600 mg ranged from 6.5 to 28.4 ng/mL. No differences in pentamidine BAL concentrations were observed in symptomatic patients who developed Pneumocystis jirovecii pneumonia compared with patients who did not. Zanamivir concentrations in ELF were similar in magnitude (range 141-326 ng/mL) following administration by continuous intravenous infusion (3 mg/hour), oral inhalation (10 mg every 12 hours) and intravenous bolus (200 mg every 12 hours). Data from case reports have suggested that concentrations of nelfinavir and saquinavir in ELF are undetectable, whereas tipranavir and lopinavir had measureable ELF concentrations (2.20 μmol/L and 14.4 μg/mL, respectively) when these protease inhibitors were co-administrated with ritonavir. While the clinical significance of ELF or BAL concentrations remains unknown for this group of anti-infective agents, the knowledge of drug penetration into the extracellular space of the lung should assist in re-evaluating and designing specific dosing regimens for use against potential pathogens. |
| 2011 | Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: rifampicin, rifabutin, and rifapentine. | Biochem Pharmacol | 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. |
| 2011 | Pharmacokinetic interactions between etravirine and non-antiretroviral drugs. | Clin Pharmacokinet | Etravirine (formerly TMC125) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant strains of HIV-1. Etravirine has been approved in several countries for use as part of highly active antiretroviral therapy in treatment-experienced patients. In vivo, etravirine is a substrate for, and weak inducer of, the hepatic cytochrome P450 (CYP) isoenzyme 3A4 and a substrate and weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein. An extensive drug-drug interaction programme in HIV-negative subjects has been carried out to assess the potential for pharmacokinetic interactions between etravirine and a variety of non-antiretroviral drugs. Effects of atorvastatin, clarithromycin, methadone, omeprazole, oral contraceptives, paroxetine, ranitidine and sildenafil on the pharmacokinetic disposition of etravirine were of no clinical relevance. Likewise, etravirine had no clinically significant effect on the pharmacokinetics of fluconazole, methadone, oral contraceptives, paroxetine or voriconazole. No clinically relevant interactions are expected between etravirine and azithromycin or ribavirin, therefore, etravirine can be combined with these agents without dose adjustment. Fluconazole and voriconazole increased etravirine exposure 1.9- and 1.4-fold, respectively, in healthy subjects, however, no increase in the incidence of adverse effects was observed in patients receiving etravirine and fluconazole during clinical trials, therefore, etravirine can be combined with these antifungals although caution is advised. Digoxin plasma exposure was slightly increased when co-administered with etravirine. No dose adjustments of digoxin are needed when used in combination with etravirine, however, it is recommended that digoxin levels should be monitored. Caution should be exercised in combining rifabutin with etravirine in the presence of certain boosted HIV protease inhibitors due to the risk of decreased exposure to etravirine. Although adjustments to the dose of clarithromycin are unnecessary for the treatment of most infections, the use of an alternative macrolide (e.g. azithromycin) is recommended for the treatment of Mycobacterium avium complex infection since the overall activity of clarithromycin against this pathogen may be altered when co-administered with etravirine. Dosage adjustments based on clinical response are recommended for clopidogrel, HMG-CoA reductase inhibitors (e.g. atorvastatin) and for phosphodiesterase type-5 inhibitors (e.g. sildenafil) because changes in the exposure of these medications in the presence of co-administered etravirine may occur. When co-administered with etravirine, a dose reduction or alternative to diazepam is recommended. When combining etravirine with warfarin, the international normalized ratio (INR) should be monitored. Systemic dexamethasone should be co-administered with caution, or an alternative to dexamethasone be found as dexamethasone induces CYP3A4. Caution is also warranted when co-administering etravirine with some antiarrhythmics, calcineurin inhibitors (e.g. ciclosporin) and antidepressants (e.g. citalopram). Co-administration of etravirine with some antiepileptics (e.g. carbamazepine and phenytoin), Rifampicin (rifampin), rifapentine or preparations containing St John's wort (Hypericum perforatum) is currently not recommended as these are potent inducers of CYP3A and/or CYP2C and may potentially decrease etravirine exposure. Antiepileptics that are less likely to interact based on their known pharmacological properties include gabapentin, lamotrigine, levetiracetam and pregabalin. Overall, pharmacokinetic and clinical data show etravirine to be well tolerated and generally safe when given in combination with non-antiretroviral agents, with minimal clinically significant drug interactions and no need for dosage adjustments of etravirine in any of the cases, or of the non-antiretroviral agent in the majority of cases studied. |
| 2010 | New approaches in the diagnosis and treatment of latent tuberculosis infection. | Respir Res | With nearly 9 million new active disease cases and 2 million deaths occurring worldwide every year, tuberculosis continues to remain a major public health problem. Exposure to Mycobacterium tuberculosis leads to active disease in only ~10% people. An effective immune response in remaining individuals stops M. tuberculosis multiplication. However, the pathogen is completely eradicated in ~10% people while others only succeed in containment of infection as some bacilli escape killing and remain in non-replicating (dormant) state (latent tuberculosis infection) in old lesions. The dormant bacilli can resuscitate and cause active disease if a disruption of immune response occurs. Nearly one-third of world population is latently infected with M. tuberculosis and 5%-10% of infected individuals will develop active disease during their life time. However, the risk of developing active disease is greatly increased (5%-15% every year and ~50% over lifetime) by human immunodeficiency virus-coinfection. While active transmission is a significant contributor of active disease cases in high tuberculosis burden countries, most active disease cases in low tuberculosis incidence countries arise from this pool of latently infected individuals. A positive tuberculin skin test or a more recent and specific interferon-gamma release assay in a person without overt signs of active disease indicates latent tuberculosis infection. Two commercial interferon-gamma release assays, QFT-G-IT and T-SPOT.TB have been developed. The standard treatment for latent tuberculosis infection is daily therapy with isoniazid for nine months. Other options include therapy with Rifampicin for 4 months or isoniazid + Rifampicin for 3 months or Rifampicin + pyrazinamide for 2 months or isoniazid + rifapentine for 3 months. Identification of latently infected individuals and their treatment has lowered tuberculosis incidence in rich, advanced countries. Similar approaches also hold great promise for other countries with low-intermediate rates of tuberculosis incidence. |
| 2010 | Drugs in development for tuberculosis. | Drugs | Tuberculosis (TB) drug research and development efforts have resurged in the past 10 years to meet urgent medical needs, but enormous challenges remain. These urgent needs are largely driven by the current long and arduous multidrug regimens, which have significant safety, tolerability and compliance issues; rising and disturbing rates of multidrug- and extensively drug-resistant TB; the existence of approximately 2 billion individuals already latently infected with Mycobacterium tuberculosis, the causative pathogen of TB; and a global TB-HIV co-epidemic. Stakeholders in TB drug development are moving to enable and streamline development and registration of novel, multidrug treatment regimens, comprised of multiple new chemical entities with novel mechanisms of action that do not demonstrate cross-resistance to current first- and second-line TB drugs. Ideally, these new regimens will ultimately provide a short, simple treatment suitable for essentially all TB patients, whether sensitive or resistant to the current anti-TB agents, whether HIV-positive or -negative, and irrespective of patient age. This article reviews the challenges faced by those trying to develop these novel regimens and the key agents currently in clinical testing for TB; the latter are organized for discussion into three categories: (i) novel drugs (TMC207, SQ109, sudoterb [LL3858]); (ii) present first-line TB drugs being re-evaluated to optimize their efficacy (Rifampicin, rifapentine); and (iii) currently licensed drugs for other indications and 'next-generation' compounds of the same chemical class being repurposed for TB (gatifloxacin and moxifloxacin; linezolid, PNU100480 and AZD5847; metronidazole, OPC-67683 and PA-824). |
| 2010 | [Therapeutic efficacy of drug susceptibility test-guided individualized anti-tuberculosis chemotherapy for spinal tuberculosis]. | Zhonghua Wai Ke Za Zhi | To investigate the efficacy of individualized anti-tuberculosis chemotherapy guided by drug susceptibility testing for spinal tuberculosis through analyses on the post-operative follow-up outcomes.The diagnoses of spinal tuberculosis were established by clinical, radiological and histological evaluation in 132 patients who were admitted from August 2005 to January 2010, 62 patients (37 male and 25 female) with follow-up more than 12 months in this study. The average age was 33.6 years (ranging from 4 - 67 years). The infected samples were collected during surgery. After processed in a routine laboratory procedure, the samples were inoculated into vials of the BACT/ALERT 3D system. The drug susceptibility testing was performed using absolute concentration method, which included 11 first-line and second-line drugs. Four or five anti-tuberculosis drug regimen was chosen according to the results of drug susceptibility testing. All the patients were followed up a month later, and then once 3 months in the following 11 months, and subsequently at intervals of half a year. The clinical status, erythrocyte sedimentation rate (ESR), roentgenogram, MRI and 3D-CT were concerned to estimate the progress of tuberculosis.The culture positive rate was 45.2% (28/62). The average detection time was 42 d (ranging from 28 - 58 d). The drug susceptibility testing showed a total drug resistance level of 24.2%:12.9% for isoniazid, 4.8% for Rifampicin, 3.2% for ethambutol, 9.7% for streptomycin, 6.4% for pasiniazid, 14.5% for levofloxacin, 1.6% for rifapentine. The mean follow-up period was 21 months (ranging from 12 - 44 months). According to Bridwell criteria, grade I bony fusion was obtained in all patients in 8 - 12 months.Guided by drug susceptibility testing, individualized anti-tuberculosis chemotherapy for 12 to 18 months is effective for spinal tuberculosis. |
| 2010 | The near future: improving the activity of rifamycins and pyrazinamide. | Tuberculosis (Edinb) | While we wait for improved new anti-tuberculosis drugs, the main aim for improving current treatment should be to optimize the use of the two current drugs, Rifampicin and the pro-drug pyrazinamide, which are responsible to a similar extent for the entire sterilizing activity of current therapy. The rifamycin activity could be improved by increasing the dose size of Rifampicin or by daily dosing with long acting rifapentine. Increasing the dose size of pyrazinamide is limited by toxicity but an alternative approach is to use inhalation with pyrazinoic acid, as an adjunct to standard oral therapy. This would acidify pulmonary lesions, thus increasing the bactericidal activity of the orally administered pyrazinamide. Because pyrazinoic acid is the active moiety, it should also increase overall pyrazinamide activity and, because most resistance arises in the pncA gene that converts pyrazinamide to pyrazinoic acid, it should act on most pyrazinamide resistant strains. Inhalation technology allows delivery of drug to lesions rapidly and without first pass toxicity. The properties of drug containing microparticles and nanoparticles during inhalation and storage are reviewed. Spray-dried larger Trojan particles in which the smaller encapsulated particles can reside should be able to improve localisation within alveoli and avoid some storage problems. |
| 2010 | Resistance to rifampicin: at the crossroads between ecological, genomic and medical concerns. | Int J Antimicrob Agents | The first antibiotic of the ansamycin family, Rifampicin (RIF), was isolated in 1959 and was introduced into therapy in 1962; it is still a first-line agent in the treatment of diseases such as tuberculosis, leprosy and various biofilm-related infections. The antimicrobial activity of RIF is due to its inhibition of bacterial RNA polymerase (RNAP). Most frequently, bacteria become resistant to RIF through mutation of the target; however, this mechanism is not unique. Other mechanisms of resistance have been reported, such as duplication of the target, action of RNAP-binding proteins, modification of RIF and modification of cell permeability. We suggest that several of these alternative resistance strategies could reflect the ecological function of RIF, such as autoregulation and/or signalling to surrounding microorganisms. Very often, resistance mechanisms found in the clinic have an environmental origin. One may ask whether the introduction of the RIF analogues rifaximin, rifalazil, rifapentine and rifabutin in the therapeutic arsenal, together with the diversification of the pathologies treated by these molecules, will diversify the resistance mechanisms of human pathogens against ansamycins. |
| 2010 | An interesting case of rifampicin-dependent/-enhanced multidrug-resistant tuberculosis. | Int J Tuberc Lung Dis | 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. |
| 2010 | Experimental and clinical studies on Rifacinna--the new effective antituberculous drug (review). | Recent Pat Antiinfect Drug Discov | A new rifamycin derivative 3-(4-cinnamyl-piperazinyl iminomethyl) rifamycin SV (T9) and its sodium salt (T11, Rifacinna((R))) were in vitro, in vivo, toxicologically and clinically investigated in comparison with Rifampicin, rifapentine, rifabutin, rifalazil. Our experiments showed that Rifacinna exhibits excellent in vitro activity against Gram(+), Gram (-) aerobic, anaerobic pathogens and mycobacteria. Rifacinna is active against Staphylococcus, Streptococcus spp. including MRSA, with MIC90- 0.06-0.5 mg/L; against Gram(+), Gram (-) anaerobes with MIC90 0.5 - 1 mg/L; against Mycobacterium tuberculosis (MTB) with MIC90 0.062 mg/L; against MDR resistant MTB (25%-30 %) and Mycobacterium avium complex (MAC) strains with MICs 0.6-1.0 mg/L. It shows high intraphagocytic activity against MAC strains (0.06 0.125mg/L). Single daily dose 10 mg/kg provides complete erradication of mycobacteria in experimental generalized tuberculosis. Pharmacological studies established: excellent pharmacokinetic profile following single oral dose 10mg/kg Tmax 5-6 h, C(max) 5-9 mg/L, T1/2 33-34 h; low toxicity; no teratogenic and embryotoxic effects. The clinical study of Rifacinna shows higher therapeutic efficacy than Rifampicin in patients with infiltrative, disseminated and cavitary form of pulmonary tuberculosis, good tolerability and safety profile. Some of the recent patents related to the treatment of tuberculosis are discussed in this review article. |
| 2009 | Rifapentine vs. rifampicin for the treatment of pulmonary tuberculosis: a systematic review. | Int J Tuberc Lung Dis | 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. |
| 2007 | Overview of anti-tuberculosis (TB) drugs and their resistance mechanisms. | Mini Rev Med Chem | One-third of the world's population is infected with Mycobacterium (M.) tuberculosis. Tuberculosis continues to be the most common infectious cause of death and still has a serious impact, medically, socially and financially. Multidrug-resistant tuberculosis (MDR-TB), caused by tubercle bacilli that are resistant to at least isoniazid and rifampin, is among the most worrisome elements of the pandemic of antibiotic resistance because TB patients for whom treatment has failed have a high risk of death. Drugs used to treat tuberculosis are classified into first-line and second-line agents. First-line essential anti-tuberculosis agents are the most effective, and are a necessary component of any short-course therapeutic regimen. The drugs in this category are isoniazid, rifampin, ethambutol, pyrazinamide and streptomycin. Second-line anti-tuberculosis drugs are clinically much less effective than first-line agents and elicit severe reactions much more frequently. These drugs include para-aminosalicylic acid (PAS), ethionamide, cycloserine, amikacin and capreomycin. New drugs, which are yet to be assigned to the above categories, include rifapentine, levofloxacin, gatifloxacin and moxifloxacin. Recently there has been much development in the molecular pharmacology of anti-tuberculosis drugs. This review summarizes information for isoniazid, Rifampicin, ethambutol, pyrazinamide, and fluoroquinolones, and describes their resistance mechanisms. |
| 2006 | [Development of antituberculous drugs: current status and future prospects]. | Kekkaku | Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world's population is infected with Mycobacterium tuberculosis (MTB), the etiologic agent of TB. The World Health Organization estimates that about eight to ten million new TB cases occur annually worldwide and the incidence of TB is currently increasing. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and approximately two million deaths are attributable to TB annually. In particular, pulmonary TB, the most common form of TB, is a highly contagious and life-threatening infection. Moreover, enhanced susceptibility to TB in HIV-infected populations is another serious health problem throughout the world. In addition, multidrug-resistant TB (MDR-TB) has been increasing in incidence in many areas, not only in developing countries but industrialized countries as well, during the past decade. These situations, particularly the global resurgence of TB and the rapid emergence of MDR-TB, underscore the importance of the development of new antituberculous drugs and new protocols for efficacious clinical control of TB patients using ordinary antimycobacterial drugs. Concerning the development of new antituberculous drugs, the following points are of particular importance. (1) Development of drugs which display lasting antimycobacterial activity in vivo is desirable, since they can be administered with long intervals and consequently facilitate directly observed therapy and enhance patient compliance. (2) Development of novel antituberculosis compounds to combat MDR-TB is urgently needed. (3) The eradication of slowly metabolizing and, if possible, dormant populations of MTB organisms that cause relapse, using new classes of anti-TB drugs is very promising for prevention of TB incidence, because it will markedly reduce the incidence of active TB from persons who are latently infected with MTB. Unfortunately, no new drugs except rifabutin and rifapentine has been marketed for TB in the US and other countries during the 40 years after release of Rifampicin. There are a number of constraints that have deterred companies from investing in new anti-TB drugs. The research is expensive, slow and difficult, and requires specialized facilities for handling MTB. There are few animal models that closely mimic the human TB disease. Development time of any anti-TB drug will be long. In fact, clinical trials will require the minimum six-month therapy, with a follow-up period of one year or more. In addition, it is hard to demonstrate obvious benefit of a new anti-TB agents over pre-existing drugs, since clinical trials involve multidrug combination therapy using highly effective ordinary anti-TB drugs. Finaly, there is the perceived lack of commercial return to companies engaged in the development of new anti-TB drugs, because over 95% of TB cases worldwide are in developing countries. In this symposium, we reviewed the following areas. 1. Critical new information on the entire genome of MTB recently obtained and increasing knowledge of various mycobacterial virulence genes are greatly promoting the identification of genes that code for new drug targets. In this context, Dr. Namba reviewed the status of new types of compounds which are being developed as anti-TB drug. He also discussed the development of new antimycobacterial drugs according to new and potential pharmacological targets and the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Using such findings for mycobacterial genomes, bioinformatics/genomics/proteomics-based drug design and drug development using quantitative structure-activity relationships may be possible in the near future. In this context, Dr. Suwa and Dr. Suzuki reviewed the usefulness of chemical genomics in searching novel drug targets for development of new antituberculous drugs. The authors reviewed (1) the history and present status of chemical genomics that is defined as the systemic search for a selective small molecular modulator for each function of all gene products, (2) recent studies of the authors on profiles of the interactions between various kinds of human proteins and small molecule modulators using the new technology devised by Reverse Proteomics Research Institute, and (3) future prospects of the development of new antituberculous drugs based on chemical genomics. 3. It appears also promising to develop new types of drug administration systems using drug vehicles, which enable efficacious drug delivery to their target in vivo. Dr. Izumikawa, Dr. Ohno and Dr. Kohno reviewed the usefulness of liposome- and polymer-based technologies, which enable efficacious delivery of encapsulated drugs at required doses for prolonged periods of time with only a single shot without toxicity, and also enable highly targeted delivery of drugs to their target in vivo. They indicated that the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better clinical outcome. 4. Immunoadjunctive therapy appears to be promising in improving outcome of clinical control of refractory mycobacterial infections, including MDR-TB and M. avium complex infection. Dr. Shimizu, Dr. Sato and Dr. Tomioka reviewed the present status of immunotherapy of mycobacterial infections in combination with antimycobacterial drugs. They indicated that the development of new classes of immunomodulators other than cytokines (IL-2, IFN-gamma, GM-CSF, IL-12, etc.) particularly those with no severe side-effects, are urgently needed. Their review dealed with some promising immunoadjunctive agents, especially ATP and its analogues, which potentiate macrophage antimycobacterial activity via purinergic P2 receptors. The aim of this symposium is to address the future prospects of the development of new drugs and drug regimens for anti-TB chemotherapy. There are a number of difficulties in drug-design for the development of new drug formulations with increased potential for antimycobacterial effects, excellent pharmacokinetics, and tolerability. It should be emphasized that the most urgent goal of chemotherapy of TB and MAC infections, especially that associated with HIV infection, is to develop highly active, low-cost drugs which can be used not only in industrialized countries but also in developing countries, since the incidences of AIDS-associated intractable TB and MAC infections are rapidly increasing in the latter. We strongly wish a great advance of fundametal and practical studies in developing such kinds of new anti-TB drugs in the near future. 1. Prospects for non-clinical or clinical development of new antituberculous drugs in relation to corporate strategy: Kenji NAMBA (New Product Research Laboratories I, Daiichi Pharmaceutical Co., Ltd.) Tuberculosis (TB) remains one of the deadliest threats to public health. No new anti-TB drugs have been brought into the clinic in the past 40 years. Current non-clinical works with progressed technology and Global Alliance for TB Drug Development, a non-profit organization established in 2000, accelerate research and development of faster-acting anti-TB compounds. We reviewed the status of new types of compounds which are being developed as anti-TB drug, such as diarylquinoline (TMC 207), nitroimidazole (PA-824 and OPC-67683), and moxifloxacin (MFLX). We also discussed the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Exploring novel drug targets through the chemical genomics approach and its possible application to the development of anti-tuberculosis drugs: Yorimasa SUWA (Reverse Proteomics Research Institute Co., Ltd.), Yohji SUZUKI (Teijin Ltd.) Recently, chemical genomics approach has been focused as an emerging technology for the drug discovery. In advance to a very large scale national project in US started last year, Reverse Proteomics Research Institute Co., Ltd. (REPRORI) has developed the core technologies for chemical genomics. Here we describe the outline of chemical genomics study, especially that of REPRORI, and discuss about its possible application to the development of anti-tuberculosis drugs. 3. Anti-mycobacterial agents and drug delivery: Koichi IZUMIKAWA, Hideaki OHNO, Shigeru KOHNO (Second Department of Internal Medicine, Nagasaki University School of Medicine) Mycobacterium infection is a major clinical concern in whole world. Since the newly developed anti-mycobacterial agents are few and still unavailable in clinical settings, the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better efficacy. The efficacy of anti-mycobacterial agents modified by liposome or polymer based technology have been investigated and reported using various animal models. Drug delivery system increased and prolonged the drug concentrations at the blood and targeted organs and the duration of sustained drug release, respectively. These effects lead to decrease in the frequency of drug administrations dramatically and better efficacy rates. The studies, however, were performed only in animal models, the further investigations and evaluations in human are required for practical use. 4. Adjunctive immunotherapy of mycobacterial infections: Toshiaki SHIMIZU, Katsumasa SATO, Haruaki TOMIOKA (Department of Microbiology and Immunology, Shimane University School of Medicine) There is an urgent need to develop new antimicrobials and protocols for the administration of drugs that are potently efficacious against intractable mycobacterial infections. Unfortunately, development of the new drugs for solving this problem is not progressing. (ABSTRACT TRUNCATED) |
| 2006 | Antituberculosis drugs and hepatotoxicity. | Respirology | Isoniazid, pyrazinamide and Rifampicin have hepatotoxic potential, and can lead to such reactions during antituberculosis chemotherapy. Most of the hepatotoxic reactions are dose-related; some are, however, caused by drug hypersensitivity. The immunogenetics of antituberculosis drug-induced hepatotoxicity, especially inclusive of acetylaor phenotype polymorphism, have been increasingly unravelled. Other principal clinical risk factors for hepatotoxicity are old age, malnutrition, alcoholism, HIV infection, as well as chronic hepatitis B and C infections. Drug-induced hepatic dysfunction usually occurs within the initial few weeks of the intensive phase of antituberculosis chemotherapy. Vigilant clinical (including patient education on symptoms of hepatitis) and biochemical monitoring are mandatory to improve the outcomes of patients with drug-induced hepatotoxicity during antituberculosis chemotherapy. Some fluoroquinolones like ofloxacin/levofloxacin may have a role in constituting non-hepatotoxic drug regimens for management of tuberculosis (TB) in the presence of hepatic dysfunction. Isoniazid administration is currently the standard therapy for latent TB infection. Rifamycins like Rifampicin or rifapentine, alone or in combination with isoniazid, may also be considered as alternatives, pending accumulation of further clinical data. During treatment of latent TB infection, regular follow up is essential to ensure adherence to therapy and facilitate clinical monitoring for hepatic dysfunction. Monitoring of liver chemistry is also required for those patients at risk of drug-induced hepatotoxicity. |
| 2006 | Study of the interaction between rifapentine and isoniazid under acid conditions. | J Pharm Biomed Anal | 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. |
| 2006 | Monitoring the ingestion of anti-tuberculosis drugs by simple non-invasive methods. | Int J Pharm | 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. |
| 2004 | Consecutive-dose pharmacokinetics of rifapentine in patients diagnosed with pulmonary tuberculosis. | Int J Tuberc Lung Dis | 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. |
| 2002 | Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. | Lancet | 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. |
| 2002 | Rifapentine and isoniazid in the continuation phase of a 6-month regimen. Final report at 5 years: prognostic value of various measures. | Int J Tuberc Lung Dis | 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. |
| 2001 | Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials. | Clin Pharmacokinet | The rifamycin antibacterials, Rifampicin (rifampin), rifabutin and rifapentine, are uniquely potent in the treatment of patients with tuberculosis and chronic staphylococcal infections. Absorption is variably affected by food; the maximal concentration of Rifampicin is decreased by food, whereas rifapentine absorption is increased in the presence of food. The rifamycins are well-known inducers of enzyme systems involved in the metabolism of many drugs, most notably those metabolised by cytochrome P450 (CYP) 3A. The relative potency of the rifamycins as CYP3A inducers is rifampin > rifapentine > rifabutin; rifabutin is also a CYP3A substrate. The antituberculosis activity of Rifampicin is decreased by a modest dose reduction from 600 to 450mg. This somewhat surprising finding may be due to the binding of Rifampicin to serum proteins, limiting free, active concentrations of the drug. However, increasing the administration interval (after the first 2 to 8 weeks of therapy) has little effect on the sterilising activity of Rifampicin, suggesting that relatively brief exposures to a critical concentration of Rifampicin are sufficient to kill intermittently metabolising mycobacterial populations. The high protein binding of rifapentine (97%) may explain the suboptimal efficacy of the currently recommended dose of this drug. The toxicity of Rifampicin is related to dose and administration interval, with increasing rates of presumed hypersensitivity with higher doses combined with administration frequency of once weekly or less. Rifabutin toxicity is related to dose and concomitant use of CYP3A inhibitors. The rifamycins illustrate the complexity of predicting the pharmacodynamics of treatment of an intracellular pathogen with the capacity for dormancy. |
| 2000 | Combination of rifapentine-moxifloxacin-minocycline (PMM) for the treatment of leprosy. | Lepr Rev | 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. |
| 2000 | Comparison of the in vitro activities of rifapentine and rifampicin against Mycobacterium tuberculosis complex. | J Antimicrob Chemother | 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. |
| 2000 | Activity of rifapentine and its metabolite 25-O-desacetylrifapentine compared with rifampicin and rifabutin against Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis and M. bovis BCG. | J Antimicrob Chemother | 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. |
| 2000 | [Evaluation of modern antibiotics efficacy at experimental Northern Asia rickettsiosis]. | Antibiot Khimioter | Comparative investigation of antibiotics therapy efficacy at experimental murine Northern Asia rickettsiosis was performed. The efficacy was evaluated by the determination of protective activity in per cent and by the pathogen erradication. The investigated antibiotics may be ranged in the following order (by the diminishing efficacy): ansamycins (azorif, rifapentine, Rifampicin), tetracyclines (doxycycline), macrolides (azitromycin, sumamed), carbapenems (imipenem/cilastatin), fluoroquinolones (lomefloxacin, pefloxacin). Rifampicin and its derivatives--azorif, rifapentine, along with doxycycline and azitromycm can be recommended for clinical trials at experimental rickettsiosis profilaxy and treatment in natural infection focus. |
| 2000 | Role of individual drugs in the chemotherapy of tuberculosis. | Int J Tuberc Lung Dis | During the course of chemotherapy, certain drugs are predominant in their bactericidal activities. Isoniazid is responsible for an initial kill of about 95% of organisms during the first 2 days of treatment. Its bactericidal role is then replaced by Rifampicin and pyrazinamide during the intensive phase. In the continuation phase with an isoniazid/Rifampicin regimen, Rifampicin is the only effective drug against persisters, as shown by the similarity of response by patients with initially isoniazid-resistant or sensitive strains. If the continuation phase regimen does not contain Rifampicin but does contain isoniazid, the dominant bactericidal drug is isoniazid. In this case, the response of patients with initial isoniazid resistance is appreciably less good than in those with sensitive organisms. The review suggests exploration in randomised control trials of a continuation phase of Rifampicin (or rifapentine) alone. It also suggests the importance of the dose size of Rifampicin and the need for exploring a higher dose. Finally, it emphasises the importance of finding drugs that act on persisting organisms that are phenotypically but not genetically resistant to Rifampicin. |
| 2000 | Rifapentine and isoniazid in the continuation phase of a 6-month regimen. Interim report: no activity of isoniazid in the continuation phase. | Int J Tuberc Lung Dis | 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. |
| Cloning of genes that have environmental and clinical importance from rhodococci and related bacteria. | Antonie Van Leeuwenhoek | Generalised and specialised transduction systems were developed for Rhodococcus by means of bacteriophage Q4. The latter was used in conjunction with DNA from an unstable genetic element of R. rhodochrous to construct resistance plasmids which replicate in strains of R. equi, R. erythropolis and R. rhodochrous. One of the plasmids, pDA21, was joined with Erythropolis coli suicide vector pEcoR251 to obtain shuttle plasmids maintained in both rhodococci and E. coli. Conjugation between these rhodococcal strains demonstrated all were interfertile with each other and that some of the determinants for this were located on the unstable genetic element. Plasmids derived from this element, such as pDA21, carried the conjugative and self-incompatibility capacities; deletion analysis revealed that DNA necessary for self-incompatibility overlapped with that for arsenic resistance. Rifampicin is one of the principal chemotherapeutic agents used to treat infections by rhodococci and related organisms. The genes responsible for two types of inactivation have been cloned. The sequence of the R. equi DNA responsible for decomposition of the antibiotic strongly resembled those of monooxygenases acting upon phenolic compounds, consistent with the presence of a naphthalenyl moiety in the Rifampicin molecule. Antibiotic resistance conferred by the gene was surprisingly specific to the semisynthetic compounds Rifampicin (150-fold increase) and rifapentine (70-fold). Similar specificity was observed with the other inactivation gene cloned, which ribosylates Rifampicin at the 23-hydroxyl position. A 60-bp sequence upstream of the monooxygenase and ribosylation genes is strikingly similar suggesting a shared pattern of regulation. Rhodococcal arsenic resistance and azo dye degradation genes have been cloned and characterised. |
| 1999 | [Current status and perspectives on the development of rifamycin derivative antibiotics]. | Kekkaku | Rifampicin (RFP) was developed as one of the anti-tuberculosis drugs in 1966 and has been used for almost 30 years. Establishment of combination therapy using RFP has been contributing to the treatment/eradication of tuberculosis. A number of rifamycin derivatives, as post RFPs, have been synthesized/developed over the the years. Chemical modification of rifamycins has largely been concentrated on the moiety of naphthalene ring because modification of the ansa chain moiety reduces the activity. In 1992, rifabutin was approved as a preventive drug for MAC infection in AIDS patients in the United States and in European countries. It is noteworthy that rifapentine (RPT) was approved as an anti-tuberculosis drug in 1998 by FDA in the United States. A newly synthesized rifamycin derivative (KRM-1648, rifalazil) possesses a potent activity against both M. Tuberculosis and MAC, and it is now under clinical trial for the treatment of Tuberculosis in the United States. KRM-1648 is metabolized to 30-hydroxy KRM and 25-deacetyl KRM in the body, and its 30-hydroxylation is caused by liver cytochrome P450 3A. It is well known that RFP, RFB and RPT induce liver cytochrome P450 in animals and human, and these accelerate the metabolism of concomitant drugs such as HIV protease inhibitors resulting in lowering their blood levels. While KRM-1648 did not induce liver P450 in animals, but it is not examined yet in human. Clinical study of DOT with intermittent therapy of RPT in combination with INH resulted in the preferable therapeutic effect comparable to the RFP therapy. Since KRM-1648 has a potent activity, a high tissue distribution and a long half-life, it may be also suitable for intermittent therapy. For the future novel anti-tuberculosis drugs and therapy for tuberculosis, it is prerequisite to develop new drugs with a preferable antimicrobial activity, to shorten further the treatment period, and to be effective against multi-drug resistant bacilli. It is expected that more effective novel rifamycin derivatives can be developed with the above view points. |
| 1999 | Determination of rifampicin and its main metabolite in plasma and urine in presence of pyrazinamide and isoniazid by HPLC method. | J Pharm Biomed Anal | A reversed phase HPLC method is described for the simultaneous estimation of Rifampicin and its major metabolite desacetyl Rifampicin, in the presence of isoniazid and pyrazinamide, in human plasma and urine. The assay involves simple liquid extraction of drug, metabolite and internal standard (rifapentine) from biological specimens and their subsequent separation on a C18 reversed phase column and single wavelength UV detection. In plasma as well as in urine samples, all the three compounds of interest eluted within 17 min. Using methanol-sodium phosphate buffer (pH 5.2; 0.01 M) (65:35, v/v) as mobile phase under isocratic conditions, it was established that isoniazid, pyrazinamide and ascorbic acid (added to prevent oxidative degradation of analytes) did not interfere with the analyte peaks. Recoveries (extraction efficiency) for drug were greater than 90% in both plasma and urine, whereas for metabolite the values were found to be 79 and 86% in plasma and urine, respectively. The plasma and urine methods were precise (total coefficient of variation ranged from 5 to 23%) and accurate (-7 to 5% of the nominal values) for both the analytes. Individual variance components, their estimates and their contribution to the total variance were also determined. Using the same method, unknown samples supplied by WHO were assayed and good correlations were obtained between the found and intended values. The method developed proved to be suitable for simultaneous estimation of Rifampicin and desacetyl Rifampicin in plasma and urine samples. |
| 1998 | Rifapentine. | Drugs | 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. |
| 1998 | [Nontuberculous mycobacteriosis; the present status and in the future. 3--(1). The view of development of new drugs against nontuberculous mycobacterial infections]. | Kekkaku | It is obvious that the number of patients with pulmonary nontuberculous mycobacterial infections is increasing gradually in Japan. Of these infections, M. avium complex (MAC) is the most common cause, and is known to be resistant to many antimicrobial drugs. At present, no standard regimen which is able to control MAC infections completely is established. For these reasons, the development of new drugs with strong antimycobacterial activity which are not cross-resistant to conventional antimycobacterial drugs is urgently desired. Thus, we studied in vitro activities of various drugs which are expected to be a new promising drug against nontuberculous mycobacterial infections, and reviewed clinical impact of these drugs. 1) New quinolones New quinolones including ofloxacin, ciprofloxacin, levofloxacin and sparfloxacin (SPFX), are considered to be active against M. tuberculosis, M. kansasii, M. fortuitum, but are inactive against MAC, M. chelonae, M. abscessus, M. scrofulaceum. Both AM-1155 and Du-6859a, newer quinolones, seemed to be comparable to or more active than SPFX which is considered to be most active now. 2) New macrolides Clarithromycin (CAM) has in vitro activities against various nontuberculous mycobacteria including MAC, and also has proven to have clinical potential not only for disseminated MAC infections in AIDS but also for pulmonary MAC infections. Therefore, CAM seems to be a candidate for one of the key drugs in the treatment of MAC infections. 3)Rifamycins Rifabutin (RBT) and rifapentine exhibited more potent in vitro and in vivo antimycobacterial activities than Rifampicin. RBT has already demonstrated clinical effect against intractable tuberculosis and MAC infections. Thus, RBT is recommended for the prophylaxis of M. tuberculosis and MAC infections in AIDS patients in US. KRM-1648 displayed much more potent in vitro and in vivo activities than Rifampicin against both M. tuberculosis and MAC. It is needed an effort to confirm its therapeutic efficacies. Now clinical phase study is going on in US. 4) Phenazines Clofazimine (CFZ), an effective antileprosy drug, is known to be active in vitro against various mycobacteria including MAC, and often used as a component of combination chemotherapy for disseminated MAC infections in AIDS patients in US. Recently, CFZ new analogs have been developed, and it is necessary to evaluate its activities against nontuberculous mycobacteria. |
| 1993 | [A comparative study of rifapentine treatment and three years follow-up on initial pulmonary tuberculous]. | Zhonghua Jie He He Hu Xi Za Zhi | 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. |
| 1992 | Activity of rifapentine against Mycobacterium avium infection in beige mice. | J Antimicrob Chemother | 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. |
| 1992 | Activity of two long-acting rifamycins, rifapentine and FCE 22807, in experimental murine tuberculosis. | Tuber Lung Dis | 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. |
| 1991 | Effect of various antibiotics on Listeria monocytogenes multiplying in L 929 cells. | Infection | Various antibiotics were evaluated as to their effect on Listeria monocytogenes SLCC 4013 multiplying within L 929 mouse fibroblast cells. Antibiotics were employed in concentrations above the MIC value. However, there was no measurable effect of some drugs on intracellular listeriae (azlocillin, mezlocillin, cephalothin, ciprofloxacin, chloramphenicol). With other drugs an inhibition of intracellular growth was observed (penicillin, ampicillin, Rifampicin, rifapentine, erythromycin, doxycycline, co-trimoxazole, coumermycin). Notably, with none of the antibiotics a complete eradication of the listeriae was achieved. There is a good correlation of these results with animal experiments. Therefore, the cell culture system might be useful for the screening of new antibiotics. |
| 1989 | [In vitro activity of clofazimine alone and in combination with amikacin, roxithromycin, rifampicin and rifapentine against Mycobacterium avium-intracellulare]. | Enferm Infecc Microbiol Clin | 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. |
| 1987 | In vitro and ex vivo influence of rifamycins on human phagocytes. | Chemioterapia | We studied the effects of rifamycin SV, Rifampicin and rifapentine on human phagocyte functions. Rifamycins inhibited in vitro neutrophil chemotaxis in the range of their therapeutic levels, and they significantly affected the survival of a rifamycin-sensitive strain of Staphylococcus aureus inside human monocytes. Both effects were related to the intraphagocytic penetration of these antibiotics. For the ex vivo studies, 600 mg of Rifampicin were orally administered to five subjects with defective S. aureus killing. A significant reduction of neutrophil chemotaxis and increased activity against S. aureus were shown 150 and 210 min after administration of the drug. |
| 1987 | In vitro observations on the suitability of new rifamycins for the intermittent chemotherapy of tuberculosis. | Tubercle | 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. |
| 1987 | In vitro activity of new rifamycins against rifampicin-resistant M. tuberculosis and MAIS-complex mycobacteria. | Tubercle | 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. |
| 1987 | In vitro properties of rifapentine (MDL473) relevant to its use in intermittent chemotherapy of tuberculosis. | Tubercle | 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. |
| 1986 | Induction of mixed function oxidase activity in man by rifapentine (MDL 473), a long-acting rifamycin derivative. | Br J Clin Pharmacol | 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. |
| 1984 | Comparative uptake of rifampicin and rifapentine (DL473) by human neutrophils. | J Antimicrob Chemother | 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. |
| 1984 | Rifampicin and rifapentine in treatment of experimental listeriosis in normal mice and athymic (nude) mice. | Chemotherapy | 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. |