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Antimicrobial Agents and Chemotherapy Aug 2021Rifampicin is an effective drug for treating tuberculosis (TB) but is not used to treat Mycobacterium abscessus infections due to poor activity. While rifabutin,...
Rifampicin is an effective drug for treating tuberculosis (TB) but is not used to treat Mycobacterium abscessus infections due to poor activity. While rifabutin, another rifamycin, has better anti-M. abscessus activity, its activity is far from the nanomolar potencies of rifamycins against Mycobacterium tuberculosis. Here, we asked (i) why is rifabutin more active against M. abscessus than rifampicin, and (ii) why is rifabutin's anti-M. abscessus activity poorer than its anti-TB activity? Comparative analysis of naphthoquinone- versus naphthohydroquinone-containing rifamycins suggested that the improved activity of rifabutin over rifampicin is linked to its less readily oxidizable naphthoquinone core. Although rifabutin is resistant to bacterial oxidation, metabolite and genetic analyses showed that this rifamycin is metabolized by the ADP-ribosyltransferase Arr like rifampicin, preventing it from achieving the nanomolar activity that it displays against M. tuberculosis. Based on the identified dual mechanism of intrinsic rifamycin resistance, we hypothesized that rifamycins more potent than rifabutin should contain the molecule's naphthoquinone core plus a modification that blocks ADP-ribosylation at its C-23. To test these predictions, we performed a blinded screen of a diverse collection of 189 rifamycins and identified two molecules more potent than rifabutin. As predicted, these compounds contained both a more oxidatively resistant naphthoquinone core and C-25 modifications that blocked ADP-ribosylation. Together, this work revealed dual bacterial metabolism as the mechanism of intrinsic resistance of M. abscessus to rifamycins and provides proof of concept for the repositioning of rifamycins for M. abscessus disease by developing derivatives that resist both bacterial oxidation and ADP-ribosylation.
Topics: ADP-Ribosylation; Microbial Sensitivity Tests; Mycobacterium abscessus; Rifabutin; Rifamycins
PubMed: 34228543
DOI: 10.1128/AAC.00978-21 -
Annals of Oncology : Official Journal... Aug 2003Heat shock protein 90 (Hsp90) is responsible for chaperoning proteins involved in cell signaling, proliferation and survival. 17-allylamino-17-demethoxygeldanamycin... (Review)
Review
BACKGROUND
Heat shock protein 90 (Hsp90) is responsible for chaperoning proteins involved in cell signaling, proliferation and survival. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is an anticancer agent currently in phase I trials in the USA and UK. It represents a class of drugs, the benzoquinone ansamycin antibiotics, capable of binding and disrupting the function of Hsp90, leading to the depletion of multiple oncogenic client proteins.
MATERIALS AND METHODS
Studies were identified through a PubMed search, review of bibliographies of relevant articles and review of abstracts from national meetings.
RESULTS
Preclinical studies have demonstrated that disruption of many client proteins chaperoned by Hsp90 is achievable and associated with significant growth inhibition, both in vitro and in tumor xenografts. Following an overview of the mechanism of action of ansamycin antibiotics and the pathways they disrupt, we review the current clinical status of 17-AAG, and discuss future directions for combinations of traditional antineoplastics with 17-AAG.
CONCLUSIONS
17-AAG represents a class of drugs capable of affecting multiple targets in the signal transduction pathway involved in tumor cell proliferation and survival. Early results from phase I studies indicate that 17-AAG administration results in an acceptable toxicity profile while achieving in vivo disruption of client proteins.
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Benzoquinones; Clinical Trials, Phase I as Topic; Disease Models, Animal; Female; Forecasting; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Male; Mice; Neoplasms; Quinones; Research; Rifabutin; Sensitivity and Specificity; Signal Transduction
PubMed: 12881371
DOI: 10.1093/annonc/mdg316 -
Antimicrobial Agents and Chemotherapy Aug 2018is a rapidly emerging mycobacterial pathogen causing dangerous pulmonary infections. Because these bacteria are intrinsically multidrug resistant, treatment options are...
Rifabutin Acts in Synergy and Is Bactericidal with Frontline Mycobacterium abscessus Antibiotics Clarithromycin and Tigecycline, Suggesting a Potent Treatment Combination.
is a rapidly emerging mycobacterial pathogen causing dangerous pulmonary infections. Because these bacteria are intrinsically multidrug resistant, treatment options are limited and have questionable efficacy. The current treatment regimen relies on a combination of antibiotics, including clarithromycin paired with amikacin and either imipenem or cefoxitin. Tigecycline may be added when triple therapy is ineffective. We initially screened a library containing the majority of clinically available antibiotics for anti- activity. The screen identified rifabutin, which was then investigated for its interactions with antibiotics used in drug regimens. Combination of rifabutin with either clarithromycin or tigecycline generated synergistic anti- activity, dropping the rifabutin MIC below concentrations found in the lung. Importantly, these combinations generated bactericidal activity. The triple combination of clarithromycin, tigecycline, and rifabutin was also synergistic, and clinically relevant concentrations had a sterilizing effect on cultures. We suggest that combinations including rifabutin should be further investigated for treatment of pulmonary infections.
Topics: Anti-Bacterial Agents; Clarithromycin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; High-Throughput Screening Assays; Humans; Microbial Sensitivity Tests; Microbial Viability; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Rifabutin; Small Molecule Libraries; Tigecycline
PubMed: 29760147
DOI: 10.1128/AAC.00283-18 -
Helicobacter Dec 2014Rifabutin has been known to be effective in multidrug-resistant Helicobacter pylori-harboring patients undergoing treatment failure for H. pylori infection. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Rifabutin has been known to be effective in multidrug-resistant Helicobacter pylori-harboring patients undergoing treatment failure for H. pylori infection.
AIM
To evaluate the efficacy of 7-day treatment regimen consisting rifabutin daily but increasing the dose of amoxicillin and lansoprazole in patients who have failed first and second eradication and to assess the side effect profiles in South Korea.
METHODS
From December 2007 to May 2013, 59 H. pylori-infected patients with two previous eradication failures were enrolled for this study prospectively. The eligible patients were randomly assigned to either group A or B. Group A received lansoprazole 30 mg bid, amoxicillin 1.0 g tid and rifabutin 150 mg bid during 7 days, whereas group B received lansoprazole 60 mg bid, amoxicillin 1.0 g tid and rifabutin 150 mg bid during 7 days.
RESULTS
In group A, H. pylori eradication was achieved in 25 (78.1%) of the 32 patients in the ITT analysis and in 25 (80.6%) of the 31 patients in the PP analysis. In group B, H. pylori eradication was achieved in 26 (96.3%) of the 27 patients in the ITT analysis and in 27 (100%) of the 26 patients in the PP analysis. There was statistically significant difference between the two groups in terms of the eradication rates in PP analysis (p = .047), whereas a marginally statistical significance was found in terms of the eradication rates in ITT analysis (p = .051). Reported side effects were mild, and treatment was well tolerated. No major changes in physical examination or in standard laboratory parameters were observed after treatment.
CONCLUSIONS
Rifabutin-based high-dose proton-pump inhibitor (PPI)-combined therapy as empirical rescue treatment is more effective than standard dose PPI-combined rifabutin-based therapy, safe and best tolerable in third-line therapy in the Korean population. The key to successful rescue therapy with rifabutin-amoxicillin-PPI regimen may be to increase doses of PPI.
Topics: Adult; Aged; Amoxicillin; Anti-Bacterial Agents; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Helicobacter Infections; Helicobacter pylori; Humans; Male; Prospective Studies; Proton Pump Inhibitors; Republic of Korea; Rifabutin; Treatment Outcome
PubMed: 25231089
DOI: 10.1111/hel.12147 -
Computational and Mathematical Methods... 2022To compare the clinical efficacy and adverse drug reactions of four different schemes in the treatment of pleural tuberculoma.
OBJECTIVE
To compare the clinical efficacy and adverse drug reactions of four different schemes in the treatment of pleural tuberculoma.
METHODS
A total of 120 patients with pleural tuberculoma admitted to the Tuberculosis Department of our hospital from January 2018 to January 2021 were selected as the research subjects. According to different treatment methods, the patients were divided into four groups, with 30 cases in each group. They were as follows: group A received classical HRZE regimen, group B received HRZE+pleural injection, group C received HZE+rifabutin, and group D received HZE+rifabutin+pleural injection. All patients were treated intensively for 3 months and then consolidated treatment for 6 months according to the patient's condition. The absorption of lesions in the four groups at different time was compared, and the occurrences of adverse drug reactions and treatment outcomes during treatment were recorded.
RESULTS
After 3 months of treatment, compared with groups A, B, and C, the number of significantly absorbed cases and effective cases in group D increased, while the number of invalid cases decreased. However, there was no statistical significance in the absorption of lesions between the four groups ( = 8.272, = 0.507). In addition, pairwise comparison showed no significant difference in the absorption of lesions ( > 0.05). After 9 months of treatment, there was no significant difference in the absorption of lesions among the four groups ( = 8.795, = 0.185), but the absorption of lesions in group D was significantly better than that in group A ( < 0.05). During treatment, the incidence of adverse reactions in the four groups was significantly different ( = 8.779, = 0.032). Pairwise comparison showed that the incidence of adverse reactions in groups C and D was significantly lower than that in group A ( < 0.05). The total treatment course of group A was 9-16 months, and 10 cases (33.33%) still had residual lesions or pleural thickening at the end of treatment. The total course of treatment in group B was 9-12 months, and 7 cases (23.33%) still had residual lesions or pleural thickening at the end of the course of treatment. The total treatment course of group C was 9-16 months, and 8 cases (26.67%) still had residual lesions or pleural thickening at the end of treatment. The total course of treatment in group D was 9-12months, and there were still 2 cases of residual lesions (6.67%) at the end of the course.
CONCLUSIONS
HZE+rifabutin+pleural injection against tuberculosis therapy has a significant clinical efficacy in the treatment of pleural tuberculoma, which can more effectively improve the clinical symptoms of patients, improve the efficacy, and reduce complications, with a good prognosis, worthy of clinical promotion.
Topics: Disease Progression; Drug-Related Side Effects and Adverse Reactions; Humans; Pleurisy; Rifabutin; Tuberculoma; Tuberculosis, Pleural
PubMed: 36065379
DOI: 10.1155/2022/5666067 -
Antimicrobial Agents and Chemotherapy Oct 2020is increasingly recognized as an emerging opportunistic pathogen causing severe lung diseases. As it is intrinsically resistant to most conventional antibiotics, there...
is increasingly recognized as an emerging opportunistic pathogen causing severe lung diseases. As it is intrinsically resistant to most conventional antibiotics, there is an unmet medical need for effective treatments. Repurposing of clinically validated pharmaceuticals represents an attractive option for the development of chemotherapeutic alternatives against infections. In this context, rifabutin (RFB) has been shown to be active against and has raised renewed interest in using rifamycins for the treatment of pulmonary diseases. Here, we compared the and activity of RFB against the smooth and rough variants of , differing in their susceptibility profiles to several drugs and physiopathologial characteristics. While the activity of RFB is greater against rough strains than in smooth strains , suggesting a role of the glycopeptidolipid layer in susceptibility to RFB, both variants were equally susceptible to RFB inside human macrophages. RFB treatment also led to a reduction in the number and size of intracellular and extracellular mycobacterial cords. Furthermore, RFB was highly effective in a zebrafish model of infection and protected the infected larvae from -induced killing. This was corroborated by a significant reduction in the overall bacterial burden, as well as decreased numbers of abscesses and cords, two major pathophysiological traits in infected zebrafish. This study indicates that RFB is active against both and , further supporting its potential usefulness as part of combination regimens targeting this difficult-to-treat mycobacterium.
Topics: Animals; Anti-Bacterial Agents; Humans; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Rifabutin; Zebrafish
PubMed: 32816730
DOI: 10.1128/AAC.00363-20 -
Antimicrobial Agents and Chemotherapy Sep 2021
Topics: Anti-Infective Agents; Antitubercular Agents; Clofazimine; Diarylquinolines; Fluoroquinolones; Microbial Sensitivity Tests; Mycobacterium fortuitum; Rifabutin; Tetracyclines
PubMed: 34280021
DOI: 10.1128/AAC.00593-21 -
Antimicrobial Agents and Chemotherapy Feb 2001The objective of this study was to determine if there is a pharmacokinetic interaction when amprenavir is given with rifabutin or rifampin and to determine the effects... (Clinical Trial)
Clinical Trial
The objective of this study was to determine if there is a pharmacokinetic interaction when amprenavir is given with rifabutin or rifampin and to determine the effects of these drugs on the erythromycin breath test (ERMBT). Twenty-four healthy male subjects were randomized to one of two cohorts. All subjects received amprenavir (1,200 mg twice a day) for 4 days, followed by a 7-day washout period, followed by either rifabutin (300 mg once a day [QD]) (cohort 1) or rifampin (600 mg QD) (cohort 2) for 14 days. Cohort 1 then received amprenavir plus rifabutin for 10 days, and cohort 2 received amprenavir plus rifampin for 4 days. Serial plasma and urine samples for measurement of amprenavir, rifabutin, and rifampin and their 25-O-desacetyl metabolites, were measured by high-performance liquid chromatography. Rifabutin did not significantly affect amprenavir's pharmacokinetics. Amprenavir significantly increased the area under the curve at steady state (AUC(ss)) of rifabutin by 2.93-fold and the AUC(ss) of 25-O-desacetylrifabutin by 13.3-fold. Rifampin significantly decreased the AUC(ss) of amprenavir by 82%, but amprenavir had no effect on rifampin pharmacokinetics. Amprenavir decreased the results of the ERMBT by 83%. The results of the ERMBT after 2 weeks of rifabutin and rifampin therapy were increased 187 and 156%, respectively. Amprenavir plus rifampin was well tolerated. Amprenavir plus rifabutin was poorly tolerated, and 5 of 11 subjects discontinued therapy. Rifampin markedly increases the metabolic clearance of amprenavir, and coadministration is contraindicated. Amprenavir significantly decreases clearance of rifabutin and 25-O-desacetylrifabutin, and the combination is poorly tolerated. Amprenavir inhibits the ERMBT, and rifampin and rifabutin are equipotent inducers of the ERMBT.
Topics: Adolescent; Adult; Anti-Bacterial Agents; Antibiotics, Antitubercular; Biotransformation; Breath Tests; Carbamates; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dealkylation; Drug Interactions; Erythromycin; Furans; Humans; Male; Middle Aged; Mixed Function Oxygenases; Rifabutin; Rifampin; Sulfonamides
PubMed: 11158747
DOI: 10.1128/AAC.45.2.502-508.2001 -
Antimicrobial Agents and Chemotherapy Feb 1994The dose-response activity of rifabutin and the comparative activities of rifabutin and rifapentine were evaluated in the beige mouse model of disseminated Mycobacterium... (Comparative Study)
Comparative Study
The dose-response activity of rifabutin and the comparative activities of rifabutin and rifapentine were evaluated in the beige mouse model of disseminated Mycobacterium avium complex (MAC) infection. In the dose-response study, mice were infected intravenously with approximately 10(7) viable M. avium ATCC 49601. Treatment with rifabutin at 10, 20, or 40 mg/kg of body weight was started 7 days postinfection and was administered daily for 10 days. The mice were sacrificed 3 to 5 days after the last dose. Spleens, livers, and lungs were homogenized, and viable cell counts were determined by serial dilution and plating onto Middlebrook 7H10 agar. A dose-related reduction in MAC cell counts in the organs was noted for this MAC isolate. The comparative activities of rifabutin and rifapentine were determined against a total of five MAC isolates in the beige mouse model. Rifabutin or rifapentine (20 mg/kg each) was administered to infected mice for 10 days. Groups of treated mice were compared with untreated control animals. Despite favorable in vitro susceptibility results, rifabutin and rifapentine had activities in the spleens against only two of the five MAC isolates. For these two MAC isolates, rifabutin was more active than rifapentine. These agents had activities in the lungs against three of five isolates. Further study of rifabutin or rifapentine against a broader range of clinical isolates in a murine infection model may be useful as part of the continuing development of newer rifamycins as anti-MAC agents.
Topics: Animals; Antitubercular Agents; Colony Count, Microbial; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Lung; Mice; Mice, Inbred C57BL; Mycobacterium avium; Mycobacterium avium Complex; Rifabutin; Rifampin; Tuberculosis
PubMed: 8192449
DOI: 10.1128/AAC.38.2.234 -
Antimicrobial Agents and Chemotherapy Feb 2021exhibits Arr (ADP-ribosyltransferase)-dependent rifampin resistance. In apparent contrast, rifabutin (RBT) has demonstrated promising activity in infection models,...
exhibits Arr (ADP-ribosyltransferase)-dependent rifampin resistance. In apparent contrast, rifabutin (RBT) has demonstrated promising activity in infection models, implying that RBT might not be inactivated by Arr. RBT susceptibility testing of revealed a strongly decreased MIC. Our findings suggest that the efficacy of RBT might be enhanced by rendering RBT resilient to Arr-dependent modification or by blocking Arr activity.
Topics: ADP Ribose Transferases; Humans; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Rifabutin; Rifampin
PubMed: 33318008
DOI: 10.1128/AAC.02215-20