| 2021 | Comparison of Rifamycins for Efficacy Against Complex and Resistance Emergence in the Hollow Fiber Model System. | Front Pharmacol | Rifamycins are integral part of the combination regimen for treatment of pulmonary [MAC] infection, but different practitioners prefer different rifamycins. The objective of the study was to compare microbial kill and resistance emergence of rifamycins using principles of pharmacokinetics/pharmacodynamics. First, we identified rifamycin MICs in 20 MAC isolates from patients followed by concentration-response studies in test-tubes. Next, we examined efficacy and resistance suppression of three doses of each rifamycin in the hollow fiber system model of pulmonary MAC [HFS-MAC], mimicking human like concentration-time profile of the drugs. HFS-MAC units were repetitively sampled for total and drug-resistant MAC burden and for drug concentration measurements. Inhibitory sigmoid E model, linear regression, and analysis of variance was used for data analysis. For Rifabutin 90% of isolates had MIC ≤ 0.125 mg/L while for both rifampin and rifapentine this was ≤2.0 mg/L. There was no statistically significant difference ( > 0.05) in maximal kill and effective concentration mediating 50% of the bacterial kill among three rifamycins in the static concentration experiment. In the HFS-MAC, the bactericidal kill (day 0-4) for rifampin was 0.89 (95% Confidence Interval (CI): 0.43-1.35), for rifapentine was 1.05 (95% CI: 0.08-1.23), and for Rifabutin was 0.92 (95% CI: 0.61-1.24) log CFU/ml, respectively. Rifamycins monotherapy failed after just 4-days of treatment and entire MAC population was drug resistant on day 26 of the study. There was no dose dependent difference in MAC kill or resistance suppression among the three rifamycins tested in the HFS-MAC. Therefore, replacing one rifamycin, due to emergence of drug-resistance, with other may not be beneficial in clinical setting. |
| 2021 | The Enzymes of the Rifamycin Antibiotic Resistome. | Acc Chem Res | Rifamycin antibiotics include the WHO essential medicines rifampin, Rifabutin, and rifapentine. These are semisynthetic derivatives of the natural product rifamycins, originally isolated from the soil bacterium . These antibiotics are primarily used to treat mycobacterial infections, including tuberculosis. Rifamycins act by binding to the β-subunit of bacterial RNA polymerase, inhibiting transcription, which results in cell death. These antibiotics consist of a naphthalene core spanned by a polyketide bridge. This structure presents a unique 3D configuration that engages RNA polymerase through a series of hydrogen bonds between hydroxyl groups linked to the naphthalene core and C21 and C23 of the bridge. This binding occurs not in the enzyme active site where template-directed RNA synthesis occurs but instead in the RNA exit tunnel, thereby blocking productive formation of full-length RNA. In their clinical use to treat tuberculosis, resistance to rifamycin antibiotics arises principally from point mutations in RNA polymerase that decrease the antibiotic's affinity for the binding site in the RNA exit tunnel. In contrast, the rifamycin resistome of environmental mycobacteria and actinomycetes is much richer and diverse. In these organisms, rifamycin resistance includes many different enzymatic mechanisms that modify and alter the antibiotic directly, thereby inactivating it. These enzymes include ADP ribosyltransferases, glycosyltransferases, phosphotransferases, and monooxygenases.ADP ribosyltransferases catalyze group transfer of ADP ribose from the cofactor NAD, which is more commonly deployed for metabolic redox reactions. ADP ribose is transferred to the hydroxyl linked to C23 of the antibiotic, thereby sterically blocking productive interaction with RNA polymerase. Like ADP ribosyltransferases, rifamycin glycosyl transferases also modify the hydroxyl of position C23 of rifamycins, transferring a glucose moiety from the donor molecule UDP-glucose. Unlike other antibiotic resistance kinases that transfer the γ-phosphate of ATP to inactivate antibiotics such as aminoglycosides or macrolides, rifamycin phosphotransferases are ATP-dependent dikinases. These enzymes transfer the β-phosphate of ATP to the C21 hydroxyl of the rifamycin bridge. The result is modification of a critical RNA polymerase binding group that blocks productive complex formation. On the other hand, rifamycin monooxygenases are FAD-dependent enzymes that hydroxylate the naphthoquinone core. The result of this modification is untethering of the chain from the naphthyl moiety, disrupting the essential 3D shape necessary for productive RNA polymerase binding and inhibition that leads to cell death.All of these enzymes have homologues in bacterial metabolism that either are their direct precursors or share common ancestors to the resistance enzyme. The diversity of these resistance mechanisms, often redundant in individual bacterial isolates, speaks to the importance of protecting RNA polymerase from these compounds and validates this enzyme as a critical antibiotic target. |
| 2021 | Activity of Rifamycin Derivatives against Nontuberculous Mycobacteria, including Macrolide-/Amikacin-Resistant Clinical Isolates. | Antimicrob Agents Chemother | We evaluated the activity of rifamycin derivatives, including rifampin, rifapentine, rifaximin, and Rifabutin, against clinical nontuberculous mycobacteria (NTM) isolates. Of the rifamycin derivatives, Rifabutin showed the lowest MICs against all NTM species, including complex, , and Rifabutin also had effective activity against macrolide- and aminoglycoside-resistant NTM isolates. Rifabutin could be worth considering as a therapeutic option for NTM disease, particularly drug-resistant disease. |
| 2021 | Rifampin, Rifapentine, and Rifabutin Are Active against Intracellular Periprosthetic Joint Infection-Associated Staphylococcus epidermidis. | Antimicrob Agents Chemother | is a major cause of periprosthetic joint infection (PJI); its intracellular persistence within osteoblasts may compromise therapy if that therapy is not intracellularly active. The intracellular activity of rifampin, rifapentine, and Rifabutin was assessed against five rifampin-susceptible and two rifampin-resistant isolates. Compared to no treatment, treatment resulted in a ≥2-fold log reduction of intracellular rifampin-susceptible, but not rifampin-resistant, These findings show activity of rifampin, rifapentine, and Rifabutin against intraosteoblast PJI-associated . |
| 2020 | Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach. | Int J Biol Macromol | The pandemic prevalence of COVID-19 has become a very serious global health issue. Scientists all over the world have been seriously attempting in the discovery of a drug to combat SARS-CoV-2. It has been found that RNA-dependent RNA polymerase (RdRp) plays a crucial role in SARS-CoV-2 replication, and thus could be a potential drug target. Here, comprehensive computational approaches including drug repurposing and molecular docking were employed to predict an effective drug candidate targeting RdRp of SARS-CoV-2. This study revealed that Rifabutin, Rifapentine, Fidaxomicin, 7-methyl-guanosine-5'-triphosphate-5'-guanosine and Ivermectin have a potential inhibitory interaction with RdRp of SARS-CoV-2 and could be effective drugs for COVID-19. In addition, virtual screening of the compounds from ZINC database also allowed the prediction of two compounds (ZINC09128258 and ZINC09883305) with pharmacophore features that interact effectively with RdRp of SARS-CoV-2, indicating their potentiality as effective inhibitors of the enzyme. Furthermore, ADME analysis along with analysis of toxicity was also undertaken to check the pharmacokinetics and drug-likeness properties of the two compounds. Comparative structural analysis of protein-inhibitor complexes revealed that the amino acids Y32, K47, Y122, Y129, H133, N138, D140, T141, S709 and N781 are crucial for drug surface hotspot in the RdRp of SARS-CoV-2. |
| 2020 | Novel Use of Rifabutin and Rifapentine to Treat Methicillin-Resistant Staphylococcus aureus in a Rat Model of Foreign Body Osteomyelitis. | J Infect Dis | Owing to patient intolerance or drug interactions, alternative agents to rifampin are needed for management of staphylococcal periprosthetic joint infection. In the current study, we evaluated Rifabutin, rifapentine and rifampin, with and without vancomycin, in a rat model of foreign body osteomyelitis.Proximal tibiae were inoculated with methicillin-resistant Staphylococcus aureus (MRSA) and a Kirschner wire (K-wire) implanted in each. After 4 weeks of infection, rifampin, Rifabutin, or rifapentine were administered, alone or with vancomycin. Tibiae and K-wires were cultured, and medians were reported as log10 colony-forming units (CFUs) per gram of bone or log10 CFUs per K-wire, respectively.Rifampin, Rifabutin or rifapentine administered with vancomycin yielded less MRSA from bones (0.10, 3.02, and 0.10 log10 CFUs/g, respectively) than did no treatment (4.36 log10 CFUs/g) or vancomycin alone (4.64 log10 CFUs/g) (both P ≤ .02). The K-wires of animals receiving no treatment or vancomycin monotherapy recovered medians of 1.76 and 2.91 log10 CFUs/g per K-wire, respectively. In contrast, rifampin, Rifabutin and rifapentine administered with vancomycin yielded medians of 0.1 log10 CFUs per K-wire, respectively. Rifampin resistance was detected in a single animal in the rifampin monotherapy group.Rifabutin or rifapentine with vancomycin were as active as rifampin with vancomycin against MRSA in rat foreign body osteomyelitis, suggesting that Rifabutin and/or rifapentine may be alternatives to rifampin in the clinical management of staphylococcal periprosthetic joint infections. |
| 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 | Hepatocytic transcriptional signatures predict comparative drug interaction potential of rifamycin antibiotics. | Sci Rep | Current strategies to treat tuberculosis (TB) and co-morbidities involve multidrug combination therapies. Rifamycin antibiotics are a key component of TB therapy and a common source of drug-drug interactions (DDIs) due to induction of drug metabolizing enzymes (DMEs). Management of rifamycin DDIs are complex, particularly in patients with co-morbidities, and differences in DDI potential between rifamycin antibiotics are not well established. DME profiles induced in response to tuberculosis antibiotics (rifampin, Rifabutin and rifapentine) were compared in primary human hepatocytes. We identified rifamycin induced DMEs, cytochrome P450 (CYP) 2C8/3A4/3A5, SULT2A, and UGT1A4/1A5 and predicted lower DDIs of rifapentine with 58 clinical drugs used to treat co-morbidities in TB patients. Transcriptional networks and upstream regulator analyses showed FOXA3, HNF4α, NR1I2, NR1I3, NR3C1 and RXRα as key transcriptional regulators of rifamycin induced DMEs. Our study findings are an important resource to design effective medication regimens to treat common co-conditions in TB patients. |
| 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 | 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 | Simple and sensitive method for the analysis of 14 antituberculosis drugs using liquid chromatography/tandem mass spectrometry in human plasma. | Rapid Commun Mass Spectrom | Monitoring plasma concentration and adjusting doses of antituberculosis (TB) drugs are beneficial for improving responses to drug treatment and avoiding adverse drug reactions. A simple and sensitive liquid chromatography/tandem mass spectrometry method was developed to measure the plasma concentrations of 14 anti-TB drugs: ethambutol, isoniazid, pyrazinamide, levofloxacin, gatifloxacin, moxifloxacin, prothionamide, linezolid, rifampin, rifapentine, Rifabutin, cycloserine, p-aminosalicylic acid, and clofazimine.Human plasma was precipitated by acetonitrile and was subsequently separated by an AQ-C18 column with a gradient elution. Drug concentrations were determined using multiple reaction monitoring in positive ion electrospray ionization mode. According to pharmacokinetic data of patients, the peak concentration ranges and the timing of blood collection were determined.Intra- and interday precision was < 14.8%. Linearity, accuracy, extraction recovery, and matrix effect were acceptable for each drug. The stability of the method satisfied different storage conditions.The method allowed the sensitive and reproducible determination of 14 frequently used anti-TB drugs which has already been of benefit for some TB patients. |
| 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 | Activity of Rifampin, Rifabutin, Rifapentine, and Rifaximin against Planktonic and Biofilm States of Staphylococci Isolated from Periprosthetic Joint Infection. | Antimicrob Agents Chemother | The activities of rifampin, Rifabutin, rifapentine, and rifaximin were tested against 200 periprosthetic joint infection (PJI)-associated staphylococci. Seven rifampin-resistant isolates had MICs of ≥4 μg/ml. Three isolates had rifampin MICs of 0.25 to 1 μg/ml and harbored an Asp471Gly RpoB variant, suggesting that the CLSI rifampin-susceptible staphylococcal breakpoint of ≤1 μg/ml may be too high. The remaining isolates had rifampin MICs of ≤0.016 μg/ml, and the rifampin, Rifabutin, rifapentine, and rifaximin minimum biofilm bactericidal concentrations (MBBC) for ≥50% of isolates were 8, 1, 2, and 4 μg/ml (for ) and 2, 0.06, 0.25, and 0.5 μg/ml (for ), respectively, for rifampin-susceptible isolates. Nonrifampin rifamycins have promising staphylococcal activity, including antibiofilm activity. |
| 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. |
| 2019 | Evolution of Rifampin Resistance in Escherichia coli and Mycobacterium smegmatis Due to Substandard Drugs. | Antimicrob Agents Chemother | Poor-quality medicines undermine the treatment of infectious diseases, such as tuberculosis, which require months of treatment with rifampin and other drugs. Rifampin resistance is a critical concern for tuberculosis treatment. While subtherapeutic doses of medicine are known to select for antibiotic resistance, the effect of drug degradation products on the evolution of resistance is unknown. Here, we demonstrate that substandard drugs that contain degraded active pharmaceutical ingredients select for gene alterations that confer resistance to standard drugs. We generated drug-resistant and strains by serially culturing bacteria in the presence of the rifampin degradation product rifampin quinone. We conducted Sanger sequencing to identify mutations in rifampin-resistant populations. Strains resistant to rifampin quinone developed cross-resistance to the standard drug rifampin, with some populations showing no growth inhibition at maximum concentrations of rifampin. Sequencing of the rifampin quinone-treated strains indicated that they acquired mutations in the DNA-dependent RNA polymerase B subunit. These mutations were localized in the rifampin resistance-determining region (RRDR), consistent with other reports of rifampin-resistant and mycobacteria. Rifampin quinone-treated mycobacteria also had cross-resistance to other rifamycin class drugs, including Rifabutin and rifapentine. Our results strongly suggest that substandard drugs not only hinder individual patient outcomes but also restrict future treatment options by actively contributing to the development of resistance to standard medicines. |
| 2018 | Deciphering the late steps of rifamycin biosynthesis. | Nat Commun | Rifamycin-derived drugs, including rifampin, Rifabutin, rifapentine, and rifaximin, have long been used as first-line therapies for the treatment of tuberculosis and other deadly infections. However, the late steps leading to the biosynthesis of the industrially important rifamycin SV and B remain largely unknown. Here, we characterize a network of reactions underlying the biosynthesis of rifamycin SV, S, L, O, and B. The two-subunit transketolase Rif15 and the cytochrome P450 enzyme Rif16 are found to mediate, respectively, a unique C-O bond formation in rifamycin L and an atypical P450 ester-to-ether transformation from rifamycin L to B. Both reactions showcase interesting chemistries for these two widespread and well-studied enzyme families. |
| 2018 | A human xenobiotic nuclear receptor contributes to nonresponsiveness of to the antituberculosis drug rifampicin. | J Biol Chem | is the causative agent of tuberculosis (TB). It acquires phenotypic drug resistance inside macrophages, and this resistance mainly arises from host-induced stress. However, whether cellular drug-efflux mechanisms in macrophages contribute to nonresponsiveness of to anti-TB drugs is unclear. Here, we report that xenobiotic nuclear receptors mediate TB drug nonresponsiveness by modulating drug-efflux transporters in macrophages. This was evident from expression analysis of drug-efflux transporters in macrophages isolated from TB patients. Among patients harboring rifampicin-susceptible we observed increased intracellular survival of upon rifampicin treatment of macrophages isolated from patients not responding to anti-TB drugs compared with macrophages from patients who did respond. Of note, infection and rifampicin exposure synergistically modulated macrophage drug-efflux transporters We also found that the xenobiotic nuclear receptor pregnane X receptor (PXR) modulates macrophage drug-efflux transporter expression and activity, which compromised the anti-TB efficacy of rifampicin. We further validated this finding in a TB mouse model in which use of the PXR antagonist ketoconazole rescued rifampicin anti-TB activity. We conclude that PXR activation in macrophages compromises the efficacy of the anti-TB drug rifampicin. Alternative therapeutic strategies, such as use of the rifampicin derivatives rifapentine and Rifabutin, which do not activate PXR, or of a PXR antagonist, may be effective for tackling drug nonresponsiveness of that arises from drug-efflux systems of the host. |
| 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 | Drug Susceptibility of 33 Reference Strains of Slowly Growing Mycobacteria to 19 Antimicrobial Agents. | Biomed Res Int | . Slowly growing mycobacteria (SGM) are prevalent worldwide and cause an extensive spectrum of diseases. . In this study, the antimicrobial susceptibility of 33 reference strains of SGM to 19 antimicrobial agents was tested using a modified microdilution method. . Cefmetazole (32/33) and azithromycin (32/33) exhibited the highest antimicrobial activity, and dapsone (9/33) exhibited the lowest activity against the tested strains. Cefoxitin (30/33), cefoperazone (28/33), and cefepime (28/33) were effective against a high proportion of strains, and macrolides were also highly effective as well as offering the benefit of convenient oral administration to patients. Linezolid (27/33), meropenem (26/33), sulfamethoxazole (26/33), and tigecycline (25/33) showed the highest activity; clofazimine (20/33) and doxycycline (18/33) showed intermediate activity; and rifapentine (13/33), Rifabutin (13/33), and minocycline (11/33) showed low antimicrobial activity, closely followed by thioacetazone (10/33) and pasiniazid (10/33), against the tested organisms. According to their susceptibility profiles, the slowly growing species and were the least susceptible to the tested drugs, whereas , , , , , and were the most susceptible. . In summary, cephalosporins and macrolides, particularly cefmetazole, azithromycin, clarithromycin, and roxithromycin, showed good antimicrobial activity against the reference strains of SGM. |
| 2017 | Antimicrobial susceptibility and MIC distribution of 41 drugs against clinical isolates from China and reference strains of nontuberculous mycobacteria. | Int J Antimicrob Agents | To treat nontuberculous mycobacteria (NTM) infections more optimally, further research pertaining to mycobacterial susceptibility to antimicrobial agents is required. A total of 82 species of NTM reference strains and 23 species of NTM clinical isolates were included. Minimum inhibitory concentrations (MICs) for 41 drugs were determined using the microdilution method in cation-adjusted Mueller-Hinton broth. The results showed that most of the NTM were susceptible to aminoglycosides, quinolones, three macrolides (clarithromycin, azithromycin and roxithromycin), cefmetazole, linezolid and capreomycin. Rapidly growing mycobacterium strains were additionally susceptible to cefoxitin, clofazimine, rifapentine, doxycycline, minocycline, tigecycline, meropenem and sulfamethoxazole, whereas slowly growing mycobacterium strains were additionally susceptible to Rifabutin. This study on the susceptibility of NTM includes the largest sample size of Chinese clinical isolates and reference strains. NTM species-specific drug susceptibility patterns suggested that it is urgent to identify the species of NTM, to normalise the treatment of NTM infectious disease and to clarify the resistance mechanisms of NTM. |
| 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. |
| 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 | Characterization of 22 Antituberculosis Drugs for Inhibitory Interaction Potential on Organic Anionic Transporter Polypeptide (OATP)-Mediated Uptake. | Antimicrob Agents Chemother | We investigated the inhibitory interaction potential of 22 currently marketed antituberculosis (TB) drugs on organic anion-transporting polypeptide 1B1 (OATP1B1)-, OATP2B1-, and OATP1B3-mediated uptake using in vitro Xenopus oocytes and HEK cells. Rifabutin, ethambutol, amoxicillin, linezolid, p-amino salicylic acid, and rifapentine exhibited mild to moderate inhibitory effects on OATP-mediated uptake of estrone-3 sulfate, estradiol 17β-d-glucuronide, and rosuvastatin. The 50% inhibitory concentration (IC50) values of Rifabutin, amoxicillin, ethambutol, p-amino salicylic acid, and linezolid were 35.4, 36.2, 57.6, 72.6, and 65.9 μM, respectively, for uptake mediated by organic anionic transporter polypeptide 1B1 (OATP1B1) and 28.8, 28.9, 53.9, 31.5, and 61.0 μM, respectively, for uptake mediated by organic anionic transporter polypeptide 1B3 (OATP1B3). Streptomycin and linezolid showed greater inhibition of organic anionic transporter polypeptide 2B1 (OATP2B1)-mediated uptake, with IC50 values of 33.2 and 35.6 μM, respectively, along with mild inhibition of other drugs. Furthermore, Rifabutin, amoxicillin, and rifapentine significantly inhibited OATP1B1-mediated rosuvastatin uptake, with IC50 values of 12.3, 13.0, and 11.0 μM, respectively, which showed a similar profile to estrone-3 sulfate uptake. The calculated R values ([I]u inlet,max/Ki, where [I]u inlet,max represents the maximum estimated inhibitor concentration inlet to the liver and Ki is the inhibition constant) as the drug-drug interaction (DDI) indexes of PAS, ethambutol, and amoxicillin were 26.1, 6.5, and 4.3 for OATP1B1 and 52.0, 8.0, and 4.6 for OATP1B3, and those for streptomycin, amikacin, and linezolid were 5.0, 4.2, and 4.4 for OATP2B1, respectively, suggesting a higher possibility of in vivo DDIs. This study is the first comprehensive report to show the novel inhibitory potential of 22 marketed anti-TB drugs on OATP-mediated uptake, providing evidence for future in vivo clinical DDI studies. |
| 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 | Drug Susceptibility Testing of 31 Antimicrobial Agents on Rapidly Growing Mycobacteria Isolates from China. | Biomed Res Int | Several species of rapidly growing mycobacteria (RGM) are now recognized as human pathogens. However, limited data on effective drug treatments against these organisms exists. Here, we describe the species distribution and drug susceptibility profiles of RGM clinical isolates collected from four southern Chinese provinces from January 2005 to December 2012.Clinical isolates (73) were subjected to in vitro testing with 31 antimicrobial agents using the cation-adjusted Mueller-Hinton broth microdilution method. The isolates included 55 M. abscessus, 11 M. fortuitum, 3 M. chelonae, 2 M. neoaurum, and 2 M. septicum isolates.M. abscessus (75.34%) and M. fortuitum (15.07%), the most common species, exhibited greater antibiotic resistance than the other three species. The isolates had low resistance to amikacin, linezolid, and tigecycline, and high resistance to first-line antituberculous agents, amoxicillin-clavulanic acid, rifapentine, dapsone, thioacetazone, and pasiniazid. M. abscessus and M. fortuitum were highly resistant to ofloxacin and Rifabutin, respectively. The isolates showed moderate resistance to the other antimicrobial agents.Our results suggest that tigecycline, linezolid, clofazimine, and cefmetazole are appropriate choices for M. abscessus infections. Capreomycin, sulfamethoxazole, tigecycline, clofazimine, and cefmetazole are potentially good choices for M. fortuitum infections. Our drug susceptibility data should be useful to clinicians. |
| 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 | Bacteriological and virulence study of a Mycobacterium chimaera isolate from a patient in China. | Antonie Van Leeuwenhoek | A clinical isolate from a patient was identified as Mycobacterium chimaera, a recently identified species of nontuberculous Mycobacteria. The biochemical and molecular identity, drug sensitivity and virulence of this isolated strain were investigated. 16S rRNA, the 16S-23S ITS, hsp65 and rpoB were amplified, and their sequence similarities with other mycobacteria were analyzed. The minimum inhibitory concentrations of 22 anti-microbial agents against this isolate were established, and the virulence of the isolate was evaluated by intravenous injection into C57BL/6 mice using Mycobacterium tuberculosis H37Rv as a control strain. Growth and morphological characteristics and mycolic acid profile analysis revealed that this isolated strain was a member of the Mycobacterium avium complex. BLAST analysis of the amplified sequences showed that the isolated strain was closely related to M. chimaera. Susceptibility testing showed that the isolate was sensitive to Rifabutin, rifapentine, clarithromycin, azithromycin, imipenem and cefoxitin. Bacterial load determination and tissue histopathology of the infected mice indicated that the isolate was highly virulent. The first case of M. chimaera infection in China was evaluated. The information derived from this case may offer valuable guidance for clinical diagnosis and treatment. |
| 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. |
| 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 | Bacteriological characterization of a Mycobacterium parascrofulaceum strain isolated from a Chinese pneumonia patient. | Int J Infect Dis | A Mycobacterium parascrofulaceum strain was isolated from a pneumonia patient-the first such reported case from China. The bacteriological characteristics of the strain were determined.Species identification was performed by homologue gene sequence comparison, then a series of biochemical tests was conducted to elucidate the bacteriological characteristics. Drug susceptibility and pathogenicity to mice of the strain were tested.The clinical M. parascrofulaceum strain presented a very similar phenotypic profile to that of Mycobacterium scrofulaceum. The M. parascrofulaceum strain was sensitive to Rifabutin, rifapentine, clarithromycin, azithromycin, cefoxitin, and moxifloxacin in vitro. At week 2 post-infection, the lung tissues of mice demonstrated a local inflammatory response denoted by peri-bronchiolar inflammatory infiltrates. At weeks 4 and 8, the lung tissues showed peri-bronchiolar inflammatory infiltrates with large aggregates of lymphocytes and part of the tissue showed granulomatous lesions; there was no appreciable necrosis. The colony-forming units (CFU) count of infected lung and spleen increased gradually during the 8 weeks of the experiment.The M. parascrofulaceum strain isolated in China was sensitive to Rifabutin, rifapentine, clarithromycin, azithromycin, cefoxitin, and moxifloxacin. The mycobacteria were capable of proliferating in mice and could lead to pathological changes in the lungs of the mice. |
| 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. |
| 2013 | Induction of influx and efflux transporters and cytochrome P450 3A4 in primary human hepatocytes by rifampin, rifabutin, and rifapentine. | Antimicrob Agents Chemother | Rifampin is a potent inducer of cytochrome P450 (CYP) enzymes and transporters. Drug-drug interactions during tuberculosis treatment are common. Induction by rifapentine and Rifabutin is understudied. Rifampin and Rifabutin significantly induced CYP3A4 (80-fold and 20-fold, respectively) in primary human hepatocytes. The induction was concentration dependent. Rifapentine induced CYP3A4 in hepatocytes from 3 of 6 donors. Data were also generated for ABCB1, ABCC1, ABCC2, organic anion-transporting polypeptide 1B1 (OATP1B1), and OATP1B3. This work serves as a basis for further study of the extent to which rifamycins induce key metabolism and transporter genes. |
| 2013 | Update on rifampin, rifabutin, and rifapentine drug interactions. | Curr Med Res Opin | Rifampin is a potent inducer of both cytochrome P-450 oxidative enzymes and the P-glycoprotein transport system. Among numerous well documented, clinically significant interactions, examples include warfarin, oral contraceptives, itraconazole, digoxin, verapamil, simvastatin, and human immunodeficiency virus-related protease inhibitors. Rifabutin reduces serum concentrations of antiretroviral agents, but less so than rifampin. Rifapentine is also an inducer of drug metabolism.A literature search of English language journals from 2008 to March 2012 was completed using several databases, including PubMed, EMBASE, and SCOPUS. Search terms included rifampin, Rifabutin, rifapentine AND drug interactions.Examples of clinically relevant interactions with rifampin demonstrated by recent reports include posaconazole, voriconazole, oxycodone, risperidone, mirodenafil, and ebastine.To avoid a reduced therapeutic response, therapeutic failure, or toxic reactions when rifampin, Rifabutin, or rifapentine are added to or discontinued from medication regimens, clinicians need to be aware of these interactions. Recent studies have indicated that other transporter systems play a role in these drug interactions. As reports of rifampin drug interactions continue to grow, this review is a reminder to clinicians to be vigilant. |
| 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 | 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 | 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 | Rifamycins--obstacles and opportunities. | Tuberculosis (Edinb) | With nearly one-third of the global population infected by Mycobacterium tuberculosis, TB remains a major cause of death (1.7 million in 2006). TB is particularly severe in parts of Asia and Africa where it is often present in AIDS patients. Difficulties in treatment are exacerbated by the 6-9 month treatment times and numerous side effects. There is significant concern about the multi-drug-resistant (MDR) strains of TB (0.5 million MDR-TB cases worldwide in 2006). The rifamycins, long considered a mainstay of TB treatment, were a tremendous breakthrough when they were developed in the 1960's. While the rifamycins display many admirable qualities, they still have a number of shortfalls including: rapid selection of resistant mutants, hepatotoxicity, a flu-like syndrome (especially at higher doses), potent induction of cytochromes P450 (CYP) and inhibition of hepatic transporters. This review of the state-of-the-art regarding rifamycins suggests that it is quite possible to devise improved rifamycin analogs. Studies showing the potential of shortening the duration of treatment if higher doses could be tolerated, also suggest that more potent (or less toxic) rifamycin analogs might accomplish the same end. The improved activity against rifampin-resistant strains by some analogs promises that further work in this area, especially if the information from co-crystal structures with RNA polymerase is applied, should lead to even better analogs. The extensive drug-drug interactions seen with rifampin have already been somewhat ameliorated with Rifabutin and rifalazil, and the use of a CYP-induction screening assay should serve to efficiently identify even better analogs. The toxicity due to the flu-like syndrome is an issue that needs effective resolution, particularly for analogs in the rifalazil class. It would be of interest to profile rifalazil and analogs in relation to rifampin, rifapentine, and Rifabutin in a variety of screens, particularly those that might relate to hypersensitivity or immunomodulatory processes. |
| 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 | 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. |
| 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 | [A controlled clinical trial of long course chemotherapy regimens containing rifabutin in the treatment of multi-drug resistant pulmonary tuberculosis]. | Zhonghua Jie He He Hu Xi Za Zhi | To evaluate the curative effect and safety of a long course regimen containing Chinese-made Rifabutin as compared to the regimen containing rifapentine in the treatment of multi-drug resistant pulmonary tuberculosis.During 18 month treatment, 130 patients with multi-drug resistant pulmonary tuberculosis were divided into a treatment group (Rifabutin, pasiniazide, levofloxacin, ethambutol, ethionamide, amikacin for 3 months, Rifabutin, pasiniazide, levofloxacin, ethambutol, ethionamide for 6 months, Rifabutin, pasiniazide, levofloxacin, ethambutol for 9 months), and a control group (rifapentine, pasiniazide, levofloxacin, ethambutol, ethionamide, amikacin for 3 months, Rifabutin, pasiniazide, levofloxacin, ethambutol, ethionamide for 6 months, Rifabutin, pasiniazide, levofloxacin, ethambutol for 9 months) with proportion 1:1 random, and parallel compared method.After intensive phase, the sputum negative conversion rates (smear negative, culture negative) of the treatment group and the control group were 41.54% (27/65) and 35.94% (23/65), chi(2) = 2.42, P > 0.05, respectively. The remarkable effective rates in chest X-ray of the two groups were all 10.77% (7/65), chi(2) = 0.01, P > 0.05, and the effective rates were 67.69% (44/65) and 56.92% (37/65), chi(2) = 1.44, P > 0.05, respectively. At the end of the treatment, the sputum negative conversion rate (smear negative, culture negative) of the treatment group was 75.0% (48/65), and of the control group was 65.08% (41/65), chi(2) = 1.88, P > 0.05. The remarkable effective rates in chest X-ray of the two groups were 46.15% (30/65) and 44.62% (29/65), chi(2) = 0.02, P > 0.05, and the effective rates were 76.92% (50/65) and 73.85% (48/65), chi(2) = 0.19, P > 0.05, respectively. The cavity closure rates were 23.64% (13/55) and 33.33% (17/51), chi(2) = 0.00, P > 0.05, respectively.Regimens containing Rifabutin or rifapentine. are very effective in sputum negative conversion rate, lesion absorption and cavity closing for the treatment of multi-drug resistant pulmonary tuberculosis, with good safety and tolerance. |
| 2006 | Advances in the diagnosis and treatment of tuberculosis. | Proc Am Thorac Soc | Although truly major advances that would revolutionize tuberculosis (TB) diagnosis and treatment have not been realized, we are beginning to see the innovations that have been prompted by the recognition of the economic potential of the market for new diagnostic tests and treatments for TB and considerably increased public and private funding. Despite the enormous global burden of TB and the overall low rates of case detection worldwide, conventional approaches to diagnosis have, until recently, relied on tests that have major limitations. In this review of advances in diagnosis, we focus on strengths and limitations of newer tests that are available for the diagnosis of latent and active tuberculosis and rapid detection of drug resistance, specifically, tests that measure release of IFN-gamma in response to stimulation by Mycobacterium tuberculosis antigens, nucleic acid amplification for identification of M. tuberculosis complex, and rapid tests for detecting drug resistance. Standard regimens for treating TB have not changed for more than 30 yr and still require a minimum of 6 mo to have a high likelihood of a lasting cure. In this article, we focus on important changes in the philosophy of treatment, emphasizing the responsibility of the provider to assure successful completion of treatment, and on the roles of existing anti-TB agents and newer drugs such as Rifabutin, rifapentine, and fluoroquinolones. |
| 2005 | Cross-resistance of Escherichia coli RNA polymerases conferring rifampin resistance to different antibiotics. | J Bacteriol | In this study we further defined the rifampin-binding sites in Escherichia coli RNA polymerase (RNAP) and determined the relationship between rifampin-binding sites and the binding sites of other antibiotics, including two rifamycin derivatives, Rifabutin and rifapentine, and streptolydigin and sorangicin A, which are unrelated to rifampin, using a purified in vitro system. We found that there is almost a complete correlation between resistance to rifampin (Rif(r)) and reduced rifampin binding to 12 RNAPs purified from different rpoB Rif(r) mutants and a complete cross-resistance among the different rifamycin derivatives. Most Rif(r) RNAPs were sensitive to streptolydigin, although some exhibited weak resistance to this antibiotic. However, 5 out of the 12 Rif(r) RNAPs were partially resistant to sorangicin A, and one was completely cross-resistant to sorangicin A, indicating that the binding site(s) for these two antibiotics overlaps. Both rifampin and sorangicin A inhibited the transition step between transcription initiation and elongation; however, longer abortive initiation products were produced in the presence of the latter, indicating that the binding site for sorangicin A is within the rifampin-binding site. Competition experiments of different antibiotics with (3)H-labeled rifampin for binding to wild-type RNAP further confirmed that the binding sites for rifampin, Rifabutin, rifapentine, and sorangicin A are shared, whereas the binding sites for rifampin and streptolydigin are distinct. Because Rif(r) mutations are highly conserved in eubacteria, our results indicate that this set of Rif(r) mutant RNAPs can be used to screen for new antibiotics that will inhibit the growth of Rif(r) pathogenic bacteria. |
| 2004 | In vitro and in vivo activities of new rifamycin derivatives against mycobacterial infections. | Curr Pharm Des | Several rifamycin derivatives have been developed during the last 15 years for the treatment of mycobacterial infections. For tuberculosis, Rifabutin (RFB) showed strong activity and seemed to be suitable when tuberculosis patients were also treated for their AIDS infection. Rifapentine (RPT) was evaluated in patients with or without AIDS for its intermittent use. It displayed promising activity but must be strengthened in situations, such as AIDS or patients without AIDS but with cavities. Rifalazil (RLZ) has been evaluated in mice but the dosages used were much higher than those tolerated by patients. Regarding Mycobacterium avium infections, RFB showed significant prophylactic activity in humans, RPT displayed some activity in mice and RLZ showed modest activity in mice. |
| 2003 | Rapid detection of rifampin resistance in Mycobacterium tuberculosis isolates by heteroduplex analysis and determination of rifamycin cross-resistance in rifampin-resistant isolates. | J Clin Microbiol | Direct heteroduplex analysis and a universal heteroduplex generator assay were performed to detect rifampin resistance rapidly in Turkish Mycobacterium tuberculosis isolates. Cross-resistance to rifapentine, Rifabutin, and rifalazil was investigated. A relationship between specific mutations and resistance patterns, which can guide the choice of an appropriate therapeutic regimen for tuberculosis patients, was identified. |
| 2002 | [Prospects for development of new antituberculous drugs]. | Kekkaku | Tuberculosis (TB) is a growing international health concern, since it is the leading infectious cause of death in the world today. Moreover, the resurgence of TB in industrialized countries and the worldwide increase in the prevalence of Mycobacterium avium complex (MAC) infections in immunocompromised hosts have prompted the quest for new antimycobacterial drugs. In particular, the appearance of multidrug-resistant (MDR) strains of M. tuberculosis, which exhibit in vitro resistance to at least two major antituberculous drug (usually INH and RFP) and cause intractable TB, has greatly contributed to the increased incidence of TB. Because of the global health problems of TB, the increasing rate of MDR-TB and the high rate of a co-infection with HIV, the development of potent new antituberculous drugs without cross-resistance with known antimycobacterial agents is urgently needed. In this article, I reviewed the following areas. First, I briefly reviewed some new findings (mainly reported after 2000) on the pharmacological status of rifamycin derivatives (Rifabutin, rifapentine, and rifalazil), fluoroquinolones (ciprofloxacin, ofloxacin, sparfloxacin, levofloxacin, gatifloxacin, sitafloxacin, moxifloxacin, and others), and new macrolides (clarithromycin, azithromycin, and roxithromycin). Second, I described other types of agents which are being developed as antimycobacterial drugs. Some of the agents discussed are already under preliminary clinical investigation, and others appear to be promising candidates for future development. In this review, the status of the development of new antimycobacterial, especially antituberculous agents including oxazolidinone (PNU-100480), 5'-nitroimidazole (CGI 17341), 2-pyridone (ABT-255), new riminophenazines, nitroimidazopyran (PA-824), new ketolides (ABT-773, telithromycin) and defensins (human neutrophil peptide-I), was examined. Third, the development of new antitubercular drugs was discussed according to the potential pharmacological target. New critical information on the whole genome of M. tuberculosis recently elucidated and increasing knowledge on various mycobacterial virulence genes will promote the progression in the identification of genes that code for new drug targets. Using such findings on mycobacterial genomes, drug development using quantitative structure-activity relationship may be possible in the near future. In this review, I described the screening of drugs that have an inhibitory activity against dTDP-rhamnose synthesis of M. tuberculosis, as a new drug target of the organism. In addition, I discussed the usefulness of antisense oligo DNAs specific to mycobacterial genes encoding certain metabolic enzymes or virulence factors that play roles in the bacterial escape from antimicrobial mechanisms of host macrophages. Fourth, I reviewed the drug vehicles which enable efficacious drug delivery to their target in vivo. The usefulness of poly (DL-lactide-co-glycolide) microsphere technology, which enables the encapsulated drugs to deliver the requested doses of them for prolonged time periods by a single shot without causing any toxicity and, moreover, enables the highly targeted delivery of the drugs to host macrophages, was discussed. Fifth, I described adjunctive immunotherapy for the management of patients with mycobacterial infections by giving certain immunomodulators in combination with antimycobacterial drugs. Adjuvant clinical trials using IL-2 or GM-CSF have been found to be efficacious to some extent in improving patients with tuberculosis or disseminated MAC infections. However, it seems that these immunopotentiating cytokines as well as IFN-gamma and IL-12 are not so promising for the therapeutic agents of mycobacterial infections because of the possible induction of immunosuppressive cytokines during adjuvant therapy and, in some cases, severe side-effect. Thus, the development of new classes of immuno-modulators other than cytokines, particularly those with no severe side-effect, is needed. This review dealt with ATP and its analogues which potentiate macrophage antimycobacterial activity via a purinergic P2X7 receptor. Finally, I described the roles of type II alveolar epithelial cells in the establishment of mycobacterial infections in the host lungs and the profiles of drug susceptibilities of M. tuberculosis and MAC organisms replicating within the type II pneumocytes. These findings are useful to precisely assess or predict the in vivo therapeutic activity of a given antimycobacterial drug from its in vitro activity. In this article, I have thoroughly reviewed the status of the development of new antimycobacterial drugs. There are a number of difficulties in the 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 tuberculosis 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 tuberculosis is rapidly increasing in the latter. |
| 2002 | Acquired rifamycin resistance in persons with advanced HIV disease being treated for active tuberculosis with intermittent rifamycin-based regimens. | MMWR Morb Mortal Wkly Rep | Rifamycin drugs (i.e., rifampin, Rifabutin, and rifapentine) are essential for short-course chemotherapy in persons with active tuberculosis (TB). However, adverse drug-drug interactions complicate the concurrent use of rifamycins and protease inhibitor drugs in persons with active TB who also are infected with human immunodeficiency virus (HIV-TB). CDC has recommended use of Rifabutin in place of rifampin in multidrug regimens for the treatment of active TB in HIV-TB because Rifabutin can be administered with antiretroviral treatment regimens that include protease inhibitors (1,2). These recommendations included twice-weekly intermittent therapy. Because intermittent Rifabutin-based regimens had not been evaluated in clinical trials of HIV-TB, CDC's TB Trials Consortium (TBTC) initiated TBTC Study 23, a single-arm trial of twice-weekly Rifabutin-based therapy for treatment of HIV-TB. |
| 2000 | Prospects for development of new antimycobacterial drugs. | J Infect Chemother | In this article, I have thoroughly reviewed the status of development of new antimycobacterial drugs, particularly fluoroquinolones (ciprofloxacin, ofloxacin, sparfloxacin, levofloxacin, gatifloxacin, sitafloxacin, and moxifloxacin), new macrolides (clarithromycin, azithromycin, and roxithromycin), rifamycin derivatives (Rifabutin, rifapentine, and KRM-1648), and others. The main purpose of this review was to describe the in-vitro and in-vivo activities of these drugs against Mycobacterium tuberculosis and Mycobacterium avium complex. In addition, the therapeutic efficacy of these drugs in the clinical treatment of mycobacterial infections has also been briefly mentioned. |
| 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 | 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 | Prospects for development of new antimycobacterial drugs, with special reference to a new benzoxazinorifamycin, KRM-1648. | Arch Immunol Ther Exp (Warsz) | In this article, I have thoroughly reviewed the status of development of new antimycobacterial drugs, in particular, rifamycin derivatives (Rifabutin, rifapentine, and a new benzoxazinorifamycin, KRM-1648), fluoroquinolones (ciprofloxacin, ofloxacin, sparfloxacin, levofloxacin, gatifloxacin, sitafloxacin, moxifloxacin, and others), new macrolides (clarithromycin, azithromycin, roxithromycin), and others. In this review, I have mainly described the in vitro and in vivo activities of these drugs against Mycobacterium tuberculosis and atypical mycobacteria, especially Mycobacterium avium complex. In addition, therapeutic efficacy of these drugs in cases of clinical treatment of mycobacterial infections have also been briefly mentioned. |
| 1999 | Molecular characterization of rpoB mutations conferring cross-resistance to rifamycins on methicillin-resistant Staphylococcus aureus. | Antimicrob Agents Chemother | Mutations of the rpoB gene conferring resistance to rifampin were analyzed in 40 methicillin-resistant Staphylococcus aureus isolates obtained from six countries. Interestingly, the majority of clinical isolates showed multiple mutations within rpoB. The amino acid substitution 481His-->Asn was the most prevalent one, capable of conferring low-level resistance on its own. Cross-resistance to rifampin, Rifabutin, and rifapentine was demonstrated for all mutants identified. The level of resistance to rifamycins correlated with both the mutation position and type of amino acid substitution. |
| 1999 | Pharmacokinetics of rifapentine in subjects seropositive for the human immunodeficiency virus: a phase I study. | Antimicrob Agents Chemother | Rifapentine is undergoing development for the treatment of pulmonary tuberculosis. This study was conducted to characterize the single-dose pharmacokinetics of rifapentine and its 25-desacetyl metabolite and to assess the effect of food on the rate and extent of absorption in participants infected with human immunodeficiency virus (HIV). Twelve men and four women, mean age, 38.6 +/- 6.9 years, received a single 600-mg oral dose of rifapentine in an open-label, randomized two-way, complete crossover study. Each volunteer received rifapentine following a high-fat breakfast or during a fasting period. Serial blood samples were collected for 72 h and both rifapentine and its metabolite were assayed by a validated high-performance liquid chromatography method. Pharmacokinetics of rifapentine and 25-desacetylrifapentine were determined by noncompartmental methods. Mean (+/- the standard deviation) maximum concentrations of rifapentine in serum and areas under the curve from time zero to infinity following a high-fat breakfast were 14.09 +/- 2.81 and 373.63 +/- 78.19 micrograms/ml, respectively, and following a fasting period they were 9.42 +/- 2.67 and 256.10 +/- 86.39 micrograms. h/ml, respectively. Pharmacokinetic data from a previously published healthy volunteer study were used for comparison. Administration of rifapentine with a high-fat breakfast resulted in a 51% increase in rifapentine bioavailability, an effect also observed in healthy volunteers. Although food increased the exposure of these patients to rifapentine, the infrequent dosing schedule for the treatment of tuberculosis (e.g., once- or twice-weekly dosing) would be unlikely to lead to accumulation. Additionally, autoinduction has been previously studied and has not been demonstrated with this compound, unlike with Rifabutin and rifampin. Rifapentine was well tolerated by HIV-infected study participants. The results of our study suggest that no dosage adjustments may be required for rifapentine in HIV-infected patients (Centers for Disease Control and Prevention classification A1, A2, B1, or B2) undergoing treatment for tuberculosis. |
| 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. |
| 1998 | Contribution of rpoB mutations to development of rifamycin cross-resistance in Mycobacterium tuberculosis. | Antimicrob Agents Chemother | The contributions of 23 insertion, deletion, or missense mutations within an 81-bp fragment of rpoB, the gene encoding the beta-subunit of the DNA-dependent RNA polymerase of Mycobacterium tuberculosis, to the development of resistance to rifamycins (rifampin, Rifabutin, rifapentine, and KRM-1648) in 29 rifampin-resistant clinical isolates were defined. Specific mutant rpoB alleles led to the development of cross-resistance to all rifamycins tested, while a subset of mutations were associated with resistance to rifampin and rifapentine but not to KRM-1648 or Rifabutin. To further study the impact of specific rpoB mutant alleles on the development of rifamycin resistance, mutations were incorporated into the rpoB gene of M. tuberculosis H37Rv, contained on a mycobacterial shuttle plasmid, by in vitro mutagenesis. Recombinant M. tuberculosis clones containing plasmids with specific mutations in either codon 531 or 526 of rpoB exhibited high-level resistance to all rifamycins tested, whereas clones containing a plasmid with a mutation in codon 516 exhibited high-level resistance to rifampin and rifapentine but were susceptible to both Rifabutin and KRM-1648. These results provided additional proof of the association of specific rpoB mutations with the development of rifamycin resistance and corroborate previous reports of the usefulness of rpoB genotyping for predicting rifamycin-resistant phenotypes. |
| 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. |
| 1997 | Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin. | Chem Biol Interact | In our laboratory, primary human hepatocytes are being investigated as an in vitro experimental system for the evaluation of pharmacokinetic drug-drug interactions. Our study here represents the first reported study that directly compares the cytochrome P450 isozyme 3A (CYP3A) induction potential of three antimicrobials derived from rifamycin B, namely, rifampin, rifapentine and Rifabutin. Two endpoints of CYP3A activity, testosterone 6 beta-hydroxylation and midazolam 1-hydroxylation have been used. Results obtained with hepatocytes from four different human donors show consistently that rifampin and rifapentine are potent inducers of CYP3A, while a significantly lower induction potential is observed for Rifabutin. The relative induction potency of the three antimicrobials (rifampin > rifapentine >> Rifabutin) is consistent with the available human in vivo data. For CYP1A measured as ethoxyresorufin O-deethylase activity, CYP2C8/9 measured as tolbutamide 4-hydroxylation activity, CYP2D6 measured as dextromethorphan O-demethylation, and AZT glucuronidation, there is either no effect or, where induction is found to be statistically significant in these other endpoints, the maximum induction values are consistently < 100% of the control. Our results suggest that CYP3A is the major CYP induced by these rifamycin B derivatives. These studies illustrate the application of human hepatocytes in the evaluation of the structure-activity relationships in CYP induction for this class of chemicals and as an in vitro screen for drug-drug interaction potential via CYP induction. |
| 1996 | Low-dose aerosol infection model for testing drugs for efficacy against Mycobacterium tuberculosis. | Antimicrob Agents Chemother | As a paradigm for chronic infectious diseases, tuberculosis exhibits a variety of clinical presentations, ranging from primary pulmonary tuberculosis to reactivation tuberculosis and cavitary disease. To date, the animal models used in evaluating chemotherapy of tuberculosis have been high-dose intravenous models that mimic the disseminated forms of the disease. In the present study, we have used a low-dose aerosol exposure model which we feel better reflects newly diagnosed tuberculosis in patients converting to tuberculin positivity. As appropriate examples of chemotherapy, four rifamycins (rifampin, Rifabutin, rifapentine, and KRM-1648) were tested, first in an in vitro murine macrophage model and then in the low-dose aerosol infection model, for their activity against Mycobacterium tuberculosis. In both models, KRM-1648 had the highest level of activity of the four compounds. In the infected-lung model, Rifabutin, rifapentine, and KRM-1648 all had sterilizing activity when given orally at 5 mg/kg of body weight per day. When given at 2.5 mg/kg/day, KRM-1648 had the highest level of activity of the four drugs, reducing the bacterial load by 2.7 logs over 35 days of therapy. |
| 1996 | Rifapentine is active in vitro and in vivo against Toxoplasma gondii. | Antimicrob Agents Chemother | Rifapentine, a derivative of rifamycin, was examined for its in vitro and in vivo activities against the protozoan parasite Toxoplasma gondii. The drug inhibited the intracellular replication of parasites and was not cytotoxic for the host cells at inhibitory concentrations. Mice infected either intraperitoneally with tachyzoites of the RH strain or orally with tissue cysts of the C56 strain were protected against death by treatment with rifapentine. The degree of protection was similar to that induced by atovaquone and apparently higher than that induced by Rifabutin. Rifapentine may be a useful drug for the treatment of toxoplasmosis in immunocompromised individuals. |
| 1995 | New drugs for tuberculosis. | Eur Respir J Suppl | Since the late 1960s, tuberculosis has been successfully cured with antibiotics. With the introduction of rifampin, "short course" regimens using isoniazid and rifampin together with either streptomycin, ethambutol or pyrazinamide, for 6-9 months, have been successfully adopted. The spread of drug resistant M. tuberculosis strains in large urban areas has made this armamentarium of drugs insufficient, calling for the development of new drugs. Among rifamycin derivatives, Rifabutin is more active than rifampin in vitro and in experimental animals, and allows sputum conversion rats of 95-100%. It is effective in treating multidrug-resistant tuberculosis. Rifapentine is more active than rifampin in vitro and has a longer half-life, but it is not active against rifampin-resistant strains. Fluoroquinolones concentrate within macrophages, are effective against M. tuberculosis and act synergistically with rifampin and isoniazid. Ofloxacin, ciprofloxacin, sparfloxacin and lomefloxacin have been evaluated as antimycobacterial agents, and no cross-resistance with major antituberculous drugs has been found. Several other drugs, including new inhibitors of beta-lactamase and new beta-lactamase-resistant antibiotics, the aminoglycoside antibiotic, paromomycin, and the new nitroimidazole, 2-ethyl-5-intro-2.3-dihydro imidazo-oxazole, have been found to be active in vitro against M. tuberculosis. |
| 1994 | Antimycobacterial drugs. | Semin Respir Infect | This review consists of the following three sections: (1) General principles in selecting antimycobacterial drugs for the treatment regimens, (2) The antimicrobial activity in vitro with an emphasis on inhibitory and bactericidal potency of various agents, and (3) Drug susceptibility testing including methodology and interpretation of the test results. Each of these sections addresses three groups of antimycobacterial agents: (1) against tuberculosis, (2) against Mycobacterium avium complex infections, and (3) against infections caused by M. fortuitum and M chelonae. The following are the drugs examined in the sections and subsections of this review: isoniazid, ethionamide, thiacetazone, rifampin, Rifabutin, rifapentine, KRM-1648, pyrazinamide, streptomycin, kanamycin, amikacin, capreomycin, gentamicin, tobramycin, ethambutol, para-aminosalicylic acid, D-cycloserine, ofloxacin, levofloxacin, ciprofloxacin, sparfloin, clofazimine, clarithromycin, azithromycin, erythromycin, cefoxitin, cefmetazole, imipenem, sulfamethoxazole, sulfisoxazole, sulfadiazine, sulfathiazole, trimethoprim, and doxycycline. |
| 1994 | Comparative in vivo activities of rifabutin and rifapentine against Mycobacterium avium complex. | Antimicrob Agents Chemother | The dose-response activity of Rifabutin and the comparative activities of Rifabutin and rifapentine were evaluated in the beige mouse model of disseminated Mycobacterium avium complex (MAC) infection. In the dose-response study, mice were infected intravenously with approximately 10(7) viable M. avium ATCC 49601. Treatment with Rifabutin at 10, 20, or 40 mg/kg of body weight was started 7 days postinfection and was administered daily for 10 days. The mice were sacrificed 3 to 5 days after the last dose. Spleens, livers, and lungs were homogenized, and viable cell counts were determined by serial dilution and plating onto Middlebrook 7H10 agar. A dose-related reduction in MAC cell counts in the organs was noted for this MAC isolate. The comparative activities of Rifabutin and rifapentine were determined against a total of five MAC isolates in the beige mouse model. Rifabutin or rifapentine (20 mg/kg each) was administered to infected mice for 10 days. Groups of treated mice were compared with untreated control animals. Despite favorable in vitro susceptibility results, Rifabutin and rifapentine had activities in the spleens against only two of the five MAC isolates. For these two MAC isolates, Rifabutin was more active than rifapentine. These agents had activities in the lungs against three of five isolates. Further study of Rifabutin or rifapentine against a broader range of clinical isolates in a murine infection model may be useful as part of the continuing development of newer rifamycins as anti-MAC agents. |
| 1993 | Effectiveness of rifampin, rifabutin, and rifapentine for preventive therapy of tuberculosis in mice. | Am Rev Respir Dis | To identify alternative regimens for preventive therapy of tuberculosis, the pharmacokinetics and antimicrobial activities of rifampin (RMP), Rifabutin (RBT), and rifapentine (RPT) were compared in BCG-vaccinated and M. tuberculosis-infected immunocompetent mice. RPT showed the highest serum peak level (Cmax) and the longest half-life (t1/2), whereas RBT displayed the lowest Cmax and the shortest t1/2. On weight-to-weight basis, both RPT and RBT were more bactericidal than RMP. The activity of RMP was significantly reduced when the frequency of administration was reduced from six to three times weekly, whereas significant bactericidal activity was still observed in mice treated with RPT, 10 mg/kg up to once fortnightly, or RBT, 10 mg/kg twice weekly. Because the bactericidal activity of RBT, 10 mg/kg six times/wk for 6 wk, or RPT, 10 mg/kg two times/wk for 12 wk, was comparable to that of RMP, 10 mg/kg six times/wk for 12 wk in mice, the two regimens are appropriate for clinical trials of preventive therapy of tuberculosis. |
| 1993 | Azithromycin, rifabutin, and rifapentine for treatment and prophylaxis of Mycobacterium avium complex in rats treated with cyclosporine. | Antimicrob Agents Chemother | Azithromycin, Rifabutin, and rifapentine were used to treat or prevent disseminated Mycobacterium avium complex (MAC) infections produced in rats immunosuppressed with cyclosporine. Animals with bacteremic infections were treated 1 week after intravenous inoculation with 10(7) CFU of MAC with azithromycin, 100 mg/kg of body weight administered subcutaneously for 5 days and then 75 mg/kg on Monday, Wednesday, and Friday, or with Rifabutin or rifapentine, 20 mg/kg administered intraperitoneally on Monday through Friday. All three drugs showed efficacy after 1 and 2 months. Rifabutin cleared the organisms from tissues more rapidly than azithromycin or rifapentine. To approximate prophylaxis, treatment was started 2 weeks before intravenous inoculation with 10(4) organisms. MAC infections were undetectable in treated animals after 4 months, while control animals had disseminated infections. These findings support the rationale for clinical trials of treatment and prophylaxis with these agents. The cyclosporine-treated rat appears to be a useful model in which to evaluate compounds for the treatment and prophylaxis of disseminated MAC infections. |
| 1992 | Activity of antimicrobial agents against Mycobacterium avium-intracellulare complex (MAC) strains isolated in Italy from AIDS-patients. | Zentralbl Bakteriol | Twenty-five strains of Mycobacterium avium-intracellulare (MAC) isolated from acquired immunodeficiency syndrome (AIDS) patients in three medical centres in Italy have been studied. Serotyping performed on eighteen strains showed various serovars within either M. avium or M. intracellulare serotypes and with serovars 1 and 21 being the most prevalent (four strains for each serovar). Among fourteen drugs used for testing the antibiotic sensitivity, rifapentine, Rifabutin and clofazimine showed to have the best in vitro activity. In an ex vivo model of infection using peritoneal resting macrophages from the C57BL/6 mouse, the intracellular viability of a strain of M. avium (strain 489, serovar 3) was reduced by clofazimine, amikacin, ciprofloxacin, Rifabutin and clarithromycin (99, 98, 93, 89 and 69%, respectively), thus indicating for clofazimine a good correlation between in vitro and ex vivo activity. |
| 1992 | Activity in vitro of rifabutin, FCE 22807, rifapentine, and rifampin against Mycobacterium microti and M. tuberculosis and their penetration into mouse peritoneal macrophages. | Am Rev Respir Dis | The activities of the rifamycins, Rifabutin, FCE 22807, rifapentine, and rifampin, were studied within unstimulated peritoneal macrophages infected with Mycobacterium microti and in cultures of M. microti and M. tuberculosis in 7H-9 medium without Tween 80. In macrophage cultures, serial rifamycin concentrations were added after a 2.5 h phagocytosis period, and viable counts were done after incubation for 5 to 6 days. To ensure comparability with the daily drug replacements in the macrophage experiments, the period of exposure to serial rifamycin concentrations in 7H-9 medium was kept to only 3 days. The MICs of M. microti and M. tuberculosis were similar. The MICs of Rifabutin and FCE 22807 were 2.5 times lower and that of rifapentine 1.7 times lower than the MIC of rifampin. None of the rifamycins were concentrated in macrophages, the MICs being higher in the macrophages than in vitro by a factor of 2-fold for Rifabutin, 6.7-fold for rifampin, 20-fold for FCE 22807, and 26-fold for rifapentine. |
| 1991 | In vivo activities of newer rifamycin analogs against Mycobacterium avium infection. | Antimicrob Agents Chemother | The comparative activities of newer rifamycin analogs and the activity of Rifabutin or rifapentine in combination with other antimycobacterial agents was evaluated in the beige (C57BL/6J; bgj/bgj) mouse model of disseminated Mycobacterium avium infection. Rifabutin and rifapentine at 20 mg/kg of body weight had comparable activities. P/DEA and CGP 7040 at 20 mg/kg were less active. The combination of ethambutol at 125 mg/kg and Rifabutin at 20 mg/kg resulted in a slight increase in activity beyond that seen with Rifabutin alone against organisms in the spleens. The combination of ethambutol and rifapentine at 20 mg/kg resulted in a modest increase in activity beyond that seen with rifapentine alone against organisms in the lungs. The combination of ethionamide at 125 mg/kg and rifapentine resulted in a decrease in activity compared with that for rifapentine alone. The combination of clofazimine at 20 mg/kg and rifapentine resulted in increased activity in the mouse model. The combination of clofazimine and rifapentine (or Rifabutin) appears to be an attractive regimen that should be evaluated for the treatment of human infections due to M. avium complex. |
| 1990 | Bactericidal activity in vitro of various rifamycins against Mycobacterium avium and Mycobacterium tuberculosis. | Am Rev Respir Dis | Minimal inhibitory and bactericidal concentrations (MICs and MBCs) of rifampin (RMP), Rifabutin (RBT), rifapentine (RPT), CGP-7040, and P-DEA, were determined for 50 M. avium strains in 7H12 liquid medium radiometrically under various pH conditions. Half were isolated from patients with AIDS and the other half from patients without AIDS but with pulmonary disease. The MICs and MBCs were also determined in 7H12 broth for M. tuberculosis strains. The MIC results obtained with M. tuberculosis strains, and the serum peak levels in humans, were used as standards for interpretation of the MICs and MBCs of the rifamycins for M. avium. The bactericidal activity of all rifamycins for M. avium was substantially lower than for M. tuberculosis. The majority of M. avium strains was within the "susceptible" category, e.g., comparable to susceptible M. tuberculosis strains, when tested with CGP-7040 and RPT, and all of them were "moderately susceptible" when tested with P-DEA. On the basis of in vitro bacteriostatic and bactericidal activity, it seems that three agents, RPT, P-DEA, and CGP-7040 have more potential than do RMP and RBT against M. avium disease. |
| 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. |