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Nature Communications Aug 2022Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (Mtb) and is a major cause of morbidity and mortality. Successful treatment requires...
Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (Mtb) and is a major cause of morbidity and mortality. Successful treatment requires strict adherence to drug regimens for prolonged periods of time. Long-acting (LA) delivery systems have the potential to improve adherence. Here, we show the development of LA injectable drug formulations of the anti-TB drug rifabutin made of biodegradable polymers and biocompatible solvents that solidifies after subcutaneous injection. Addition of amphiphilic compounds increases drug solubility, allowing to significantly increase formulation drug load. Solidified implants have organized microstructures that change with formulation composition. Higher drug load results in smaller pore size that alters implant erosion and allows sustained drug release. The translational relevance of these observations in BALB/c mice is demonstrated by (1) delivering high plasma drug concentrations for 16 weeks, (2) preventing acquisition of Mtb infection, and (3) clearing acute Mtb infection from the lung and other tissues.
Topics: Animals; Antitubercular Agents; Drug Delivery Systems; Mice; Mycobacterium tuberculosis; Rifabutin; Tuberculosis
PubMed: 35941109
DOI: 10.1038/s41467-022-32043-3 -
Antimicrobial Agents and Chemotherapy Aug 2021Rifamycins are widely used for treating mycobacterial and staphylococcal infections. Drug-drug interactions (DDI) caused by rifampicin (RIF) are a major issue. We used a...
Rifamycins are widely used for treating mycobacterial and staphylococcal infections. Drug-drug interactions (DDI) caused by rifampicin (RIF) are a major issue. We used a model-based approach to predict the magnitude of DDI with RIF and rifabutin (RBT) for 217 cytochrome P450 (CYP) substrates. On average, DDI caused by low-dose RIF were twice as potent as those caused by RBT. Contrary to RIF, RBT appears unlikely to cause severe DDI, even with sensitive CYP substrates.
Topics: Drug Interactions; Pharmaceutical Preparations; Rifabutin; Rifampin; Rifamycins
PubMed: 34228545
DOI: 10.1128/AAC.01043-21 -
International Journal of Molecular... Jul 2022The cytotoxicity of various antibiotics at low doses in drug-resistant cancer cells was evaluated. Low doses of rifabutin were found to markedly increase the...
The cytotoxicity of various antibiotics at low doses in drug-resistant cancer cells was evaluated. Low doses of rifabutin were found to markedly increase the cytotoxicity of various antimitotic drugs, such as vincristine (VIC), to P-glycoprotein (P-gp)-overexpressing antimitotic-drug-resistant KBV20C cells. Rifabutin was also found to exert high levels of P-gp-inhibitory activity at 4 and 24 h posttreatment, suggesting that the cytotoxicity of VIC + rifabutin was mainly due to the direct binding of rifabutin to P-gp and the reduction of VIC efflux by P-gp. The combination of VIC + rifabutin also increased early apoptosis, G2 arrest, and the DNA damaging marker, pH2AX protein. Interestingly, only the combination of VIC + rifabutin induced remarkable levels of cytotoxicity in resistant KBV20C cells, whereas other combinations (VIC + rifampin, VIC + rifapentine, and VIC + rifaximin) induced less cytotoxicity. Such finding suggests that rifabutin specifically increases the cytotoxicity of VIC in KBV20C cells, independent of the toxic effect of the ansamycin antibiotic. Only rifabutin had high P-gp-inhibitory activity, which suggests that its high P-gp-inhibitory activity led to the increased cytotoxicity of VIC + rifabutin. As rifabutin has long been used in the clinic, repositioning this drug for P-gp-overexpressing resistant cancer could increase the availability of treatments for patients with drug-resistant cancer.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antimitotic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Humans; Neoplasms; Rifabutin; Vincristine
PubMed: 35806386
DOI: 10.3390/ijms23137383 -
Effects of fluconazole and clarithromycin on rifabutin and 25-O-desacetylrifabutin pharmacokinetics.Antimicrobial Agents and Chemotherapy Aug 2000Ten human immunodeficiency virus-infected patients were given rifabutin in addition to fluconazole and clarithromycin. There was a 76% increase in the area under the... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Ten human immunodeficiency virus-infected patients were given rifabutin in addition to fluconazole and clarithromycin. There was a 76% increase in the area under the concentration-time curve of rifabutin when either fluconazole or clarithromycin was given alone and a 152% increase when both drugs were given together with rifabutin. Patients should be monitored for adverse effects of rifabutin administered concomitantly with clarithromycin and/or fluconazole.
Topics: Adult; Anti-Bacterial Agents; Antibiotics, Antitubercular; Antifungal Agents; Clarithromycin; Drug Interactions; Drug Therapy, Combination; Female; Fluconazole; HIV Infections; Humans; Male; Middle Aged; Rifabutin
PubMed: 10898693
DOI: 10.1128/AAC.44.8.2170-2172.2000 -
Mycobacterium abscessus HelR interacts with RNA polymerase to confer intrinsic rifamycin resistance.Molecular Cell Sep 2022Rifampicin (RIF), the frontline drug against M. tuberculosis, is completely ineffective against M. abscessus, partially due to the presence of an...
Rifampicin (RIF), the frontline drug against M. tuberculosis, is completely ineffective against M. abscessus, partially due to the presence of an ADP-ribosyltransferase (Arr) that inactivates RIF. Using RNA-seq, we show that exposure of M. abscessus to sublethal doses of RIF and Rifabutin (RBT), a close analog of RIF, results in an ∼25-fold upregulation of Mab_helR in laboratory and clinical isolates. An isogenic deletion in Mab_helR results in RIF/RBT hypersensitivity, and overexpression of Mab_helR confers RIF tolerance in M. tuberculosis. We demonstrate an increased HelR-RNAP association in RIF-exposed bacteria and a MabHelR-mediated dissociation of RNAP from stalled initiation complexes in vitro. Finally, we show that the tip of the PCh-loop of Mab_helR, present in proximity to RIF, is critical for conferring RIF resistance but dispensable for dissociation of stalled RNAP complexes, suggesting that HelR-mediated RIF resistance requires a step in addition to displacement of RIF-stalled RNAP.
Topics: DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium abscessus; Mycobacterium tuberculosis; Rifabutin; Rifampin; Rifamycins; Tuberculosis
PubMed: 35905736
DOI: 10.1016/j.molcel.2022.06.034 -
Microbiology Spectrum Jun 2022This case series describes seven patients who received rifabutin in place of rifampin combined with conventional antimicrobial therapy for treatment of...
This case series describes seven patients who received rifabutin in place of rifampin combined with conventional antimicrobial therapy for treatment of hardware-associated staphylococcal infections. Infection recurrence, defined as need for unplanned surgical intervention within the evaluable follow up period after starting rifabutin, occurred in two patients. Two patients experienced possible treatment-associated adverse effects. Findings support future work to examine rifabutin use, when rifampin is not suitable, for adjunctive treatment of staphylococcal hardware infections. This work evaluates real-world data and clinical outcomes when rifabutin is used in place of rifampin for adjunctive management of staphylococcal hardware-associated infections. This is the second case study looking at this specific use of rifabutin, signifying the current lack of clinical data in this area. Assessing use of rifabutin in this capacity is clinically important given its lower propensity for drug interactions compared to rifampin.
Topics: Anti-Bacterial Agents; Drug Interactions; Humans; Rifabutin; Rifampin; Staphylococcal Infections
PubMed: 35543561
DOI: 10.1128/spectrum.00384-22 -
Antimicrobial Agents and Chemotherapy Nov 2019The activities of rifampin, rifabutin, rifapentine, and rifaximin were tested against 200 periprosthetic joint infection (PJI)-associated staphylococci. Seven...
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.
Topics: Anti-Bacterial Agents; Arthritis, Infectious; Biofilms; Humans; Microbial Sensitivity Tests; Plankton; Prosthesis-Related Infections; Rifabutin; Rifampin; Rifaximin; Staphylococcal Infections; Staphylococcus
PubMed: 31451499
DOI: 10.1128/AAC.00959-19 -
Antimicrobial Agents and Chemotherapy Jul 2023Administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use...
Administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use of long-acting injectable (LAI) drug formulations may simplify and shorten regimens for this indication. Rifapentine and rifabutin have antituberculosis activity and physiochemical properties suitable for LAI formulation, but there are limited data available for determining the target exposure profiles required for efficacy in TPT regimens. The objective of this study was to determine exposure-activity profiles of rifapentine and rifabutin to inform development of LAI formulations for TPT. We used a validated paucibacillary mouse model of TPT in combination with dynamic oral dosing of both drugs to simulate and understand exposure-activity relationships to inform posology for future LAI formulations. This work identified several LAI-like exposure profiles of rifapentine and rifabutin that, if achieved by LAI formulations, could be efficacious as TPT regimens and thus can serve as experimentally determined targets for novel LAI formulations of these drugs. We present novel methodology to understand the exposure-response relationship and inform the value proposition for investment in development of LAI formulations that have utility beyond latent tuberculosis infection.
Topics: Animals; Mice; Rifabutin; Antitubercular Agents; Latent Tuberculosis; Rifampin
PubMed: 37338374
DOI: 10.1128/aac.00481-23 -
Journal of Gastroenterology Mar 2018Helicobacter pylori-associated gastritis leads to the development of gastric cancer. Kyoto global consensus report on H. pylori gastritis recommended H. pylori... (Review)
Review
Helicobacter pylori-associated gastritis leads to the development of gastric cancer. Kyoto global consensus report on H. pylori gastritis recommended H. pylori eradication therapy to prevent gastric cancer. To manage H. pylori infection, it is important to choose the appropriate regimen considering regional differences in resistance to clarithromycin and metronidazole. Quinolones and rifabutin-containing regimens are useful as third- and fourth-line rescue therapies.
Topics: Anti-Bacterial Agents; Clarithromycin; Consensus; Disease Eradication; Drug Resistance, Bacterial; Gastritis; Health Planning Guidelines; Helicobacter Infections; Helicobacter pylori; Humans; Incidence; Japan; Metronidazole; National Health Programs; Quinolones; Rifabutin; Stomach Neoplasms
PubMed: 29138921
DOI: 10.1007/s00535-017-1407-1 -
Antimicrobial Agents and Chemotherapy Apr 2019infections are difficult to treat because of their resistance to many antibiotics. , tedizolid combined with imipenem displayed a moderate synergistic effect...
infections are difficult to treat because of their resistance to many antibiotics. , tedizolid combined with imipenem displayed a moderate synergistic effect (fractional inhibitory concentration index, 0.41) but no bactericidal activity. Intracellularly, tedizolid 2 μg/ml (half of the MIC), corresponding to the peak serum concentration, increased the efficacy of imipenem at 8 and 32 μg/ml. Addition of avibactam and rifabutin, alone or in combination, improved the activity of the imipenem-tedizolid combination.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Humans; Imipenem; Macrophages; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Oxazolidinones; Rifabutin; Tetrazoles; beta-Lactamases
PubMed: 30745387
DOI: 10.1128/AAC.01915-18