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The Journal of Antimicrobial... Jun 2019Drug-resistant TB remains a public health challenge. Rifamycins are among the most potent anti-TB drugs. They are known to target the RpoB subunit of RNA polymerase;...
OBJECTIVES
Drug-resistant TB remains a public health challenge. Rifamycins are among the most potent anti-TB drugs. They are known to target the RpoB subunit of RNA polymerase; however, our understanding of how rifamycin resistance is genetically encoded remains incomplete. Here we investigated rpoB genetic diversity and cross-resistance between the two rifamycin drugs rifampicin and rifabutin.
METHODS
We performed WGS of 1003 Mycobacterium tuberculosis clinical isolates and determined MICs of both rifamycin agents on 7H10 agar using the indirect proportion method. We generated rpoB mutants in a laboratory strain and measured their antibiotic susceptibility using the alamarBlue reduction assay.
RESULTS
Of the 1003 isolates, 766 were rifampicin resistant and 210 (27%) of these were rifabutin susceptible; 102/210 isolates had the rpoB mutation D435V (Escherichia coli D516V). Isolates with discordant resistance were 17.2 times more likely to harbour a D435V mutation than those resistant to both agents (OR 17.2, 95% CI 10.5-27.9, P value <10-40). Compared with WT, the D435V in vitro mutant had an increased IC50 of both rifamycins; however, in both cases to a lesser degree than the S450L (E. coli S531L) mutation.
CONCLUSIONS
The observation that the rpoB D435V mutation produces an increase in the IC50 of both drugs contrasts with findings from previous smaller studies that suggested that isolates with the D435V mutation remain rifabutin susceptible despite being rifampicin resistant. Our finding thus suggests that the recommended critical testing concentration for rifabutin should be revised.
Topics: Antitubercular Agents; Bacterial Proteins; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifabutin; Rifampin; Tuberculosis
PubMed: 30793747
DOI: 10.1093/jac/dkz048 -
Antimicrobial Agents and Chemotherapy Apr 2019Infections caused by the difficult-to-treat bacterium are increasing in frequency. Rifabutin, in contrast to rifampin, appears to be active against , especially...
Infections caused by the difficult-to-treat bacterium are increasing in frequency. Rifabutin, in contrast to rifampin, appears to be active against , especially against clarithromycin-resistant strains. However, explorations for potential synergy between rifabutin and available antimicrobials are currently limited. synergism between rifabutin and 10 antimicrobials was evaluated in 31 mycobacterial strains by the checkerboard method. The fractional inhibitory concentration index (FICI) was calculated for each rifabutin-based combination. The colony morphology was recorded. Molecular methods for determination of the subspecies and analysis of macrolide resistance were performed by sequencing of the , , (41), and genes. Rifabutin yielded an MIC of 16 mg/liter (range, 2 to 32 mg/liter) against 26 clinical isolates (comprising 13 subsp. and 13 subsp. isolates) and 5 reference strains, including subsp. ATCC 19977, subsp. BCRC 16915, subsp. BCRC 16916, ATCC 35752, and ATCC 700686. Significant synergism, classified by an FICI of ≤0.5, was demonstrated for the combinations of rifabutin and imipenem in 100% of subsp. and 69% of subsp. isolates, and significant synergism for rifabutin and tigecycline was demonstrated in 77% of subsp. and 69% of subsp. isolates. Among the 6 clarithromycin-resistant (MICs ≥ 8 mg/liter) subsp. isolates, the combination of rifabutin and clarithromycin was 100% synergistic. Rifabutin showed promising synergism with first-line anti- agents, especially for macrolide-resistant subsp. isolates.
Topics: Anti-Bacterial Agents; Clarithromycin; Drug Resistance, Bacterial; Drug Synergism; Humans; Imipenem; Macrolides; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Rifabutin; Tigecycline
PubMed: 30670428
DOI: 10.1128/AAC.02234-18 -
Frontiers in Cellular and Infection... 2023We aimed to evaluate the activity of PBTZ169 and pretomanid against non-tuberculous mycobacteriosis (NTM) and .
OBJECTIVES
We aimed to evaluate the activity of PBTZ169 and pretomanid against non-tuberculous mycobacteriosis (NTM) and .
METHODS
The minimum inhibitory concentrations (MICs) of 11 antibiotics, against slow-growing mycobacteria (SGMs) and rapid-growing mycobacteria (RGMs) were tested using the microplate alamarBlue assay. The activities of bedaquiline, clofazimine, moxifloxacin, rifabutin, PBTZ169 and pretomanid against four common NTMs were assessed in murine models.
RESULTS
PBTZ169 and pretomanid had MICs of >32 μg/mL against most NTM reference and clinical strains. However, PBTZ169 was bactericidal against (3.33 and 1.49 log10 CFU reductions in the lungs and spleen, respectively) and (2.29 and 2.24 CFU reductions in the lungs and spleen, respectively) in mice, and bacteriostatic against Mycobacterium avium and . Pretomanid dramatically decreased the CFU counts of (3.12 and 2.30 log10 CFU reductions in the lungs and spleen, respectively), whereas it showed moderate inhibition of and . Bedaquiline, clofazimine, and moxifloxacin showed good activities against four NTMs and . Rifabutin did not inhibit and in mice.
CONCLUSION
PBTZ169 appears to be a candidate for treating four common NTM infections. Pretomanid was more active against , and than against .
Topics: Animals; Mice; Mycobacterium abscessus; Mycobacterium avium; Mycobacterium fortuitum; Mycobacterium chelonae; Clofazimine; Moxifloxacin; Mice, Inbred BALB C; Anti-Bacterial Agents; Nontuberculous Mycobacteria; Mycobacterium Infections; Rifabutin; Mycobacterium Infections, Nontuberculous; Microbial Sensitivity Tests
PubMed: 37077530
DOI: 10.3389/fcimb.2023.1115530 -
Journal of Clinical Microbiology Jun 2014Resistance to rifampin (RIF) and rifabutin (RFB) in Mycobacterium tuberculosis is associated with mutations within an 81-bp region of the rpoB gene (RIF...
Resistance to rifampin (RIF) and rifabutin (RFB) in Mycobacterium tuberculosis is associated with mutations within an 81-bp region of the rpoB gene (RIF resistance-determining region [RRDR]). Previous studies have shown that certain mutations in this region are more likely to confer high levels of RIF resistance, while others may be found in phenotypically susceptible isolates. In this study, we sought to determine the relationship between the MICs of RIF and RFB and rpoB RRDR mutations in 32 multidrug-resistant (MDR), 4 RIF-monoresistant, and 5 susceptible M. tuberculosis clinical isolates. The MICs were determined using the MGIT 960 system. Mutations in the rpoB RRDR were determined by Sanger sequencing. RpoB proteins with mutations S531L (a change of S to L at position 531), S531W, H526Y, and H526D and the double mutation D516A-R529Q were associated with high MICs for RIF and RFB. Five isolates carrying the mutations L511P, H526L, H526N, and D516G-S522L were found to be susceptible to RIF. Several mutations were associated with resistance to RIF and susceptibility to RFB (F514FF, D516V, and S522L). Whole-genome sequencing of two MDR isolates without rpoB RRDR mutations revealed a mutation outside the RRDR (V146F; RIF MIC of 50 μg/ml). The implications of the polymorphisms identified in the second of these isolates in RIF resistance need to be further explored. Our study further establishes a correlation between the mutations and the MICs of RIF and, also, RFB in M. tuberculosis. Several rpoB mutations were identified in RIF- and RFB-susceptible isolates. The clinical significance of these findings requires further exploration. Until then, a combination of phenotypic and molecular testing is advisable for drug susceptibility testing.
Topics: Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; Genome, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifabutin; Rifampin; Sequence Analysis, DNA; Tuberculosis
PubMed: 24740074
DOI: 10.1128/JCM.00691-14 -
The Cochrane Database of Systematic... Jul 2016There have been a number of studies with conflicting results which have examined the effect of anti-tuberculous therapy in Crohn's disease. A meta-analysis was performed... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
There have been a number of studies with conflicting results which have examined the effect of anti-tuberculous therapy in Crohn's disease. A meta-analysis was performed to evaluate the use of anti-tuberculous therapy for the maintenance of remission in Crohn's disease.
OBJECTIVES
To evaluate the effects of anti-tuberculous therapy for the maintenance of remission in patients with Crohn's disease.
SEARCH METHODS
We searched MEDLINE, EMBASE, the Cochrane LIbrary, and the Cochrane IBD Group Specialized Register from inception to June 22, 2015.
SELECTION CRITERIA
Randomized controlled trials (RCTs) of anti-tuberculous therapy compared to placebo or another active therapy in patients with quiescent Crohn's disease were considered for inclusion.
DATA COLLECTION AND ANALYSIS
At least two authors independently extracted data and assessed the quality of included studies using the Cochrane risk of bias tool. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for dichotomous outcomes.. The primary outcome was relapse. Secondary outcomes included adverse events, withdrawals due to adverse events and serious adverse events. All data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the primary and secondary outcomes was evaluated using the GRADE criteria.
MAIN RESULTS
Four placebo-controlled RCTs including 206 participants were included. Three trials included an 8 to 16 week induction phase with tapering corticosteroids (prednisone, prednisolone or methylprednisolone) as induction therapy. Anti-tuberculous therapy included monotherapy with clofazimine, combination therapy with clofazimine, rifampin, ethambutol, and dapsone or combination therapy with clarithromycin, rifabutin and clofazimine. All of the studies were rated as unclear risk of bias for allocation concealment, three were rated as unclear risk of bias for random sequence generation and two were rated as unclear risk of bias for blinding or participants and personnel. There was a statistically significant difference in relapse rates favoring anti-tuberculous therapy over placebo. Thirty-nine per cent (44/112) of patients in the anti-tuberculous therapy group relapsed at 9 months to 2 years compared to 67% (63/94) of placebo patients (RR 0.58, 95% CI 0.45 to 0.75, I(2) = 47%). A GRADE analysis indicates that the overall quality of the evidence supporting this outcome was very low due to unknown risk of bias and sparse data. Adverse events occurred more frequently in the anti-tuberculous therapy group (37/159) compared to the placebo group (14/163) with a pooled RR of 2.57 (95% CI 1.45 to 4.55; N=322; studies=4, I(2)=64%). A GRADE analysis indicates that the overall quality of the evidence supporting this outcome was very low due to unknown risk of bias, unexplained heterogeneity and sparse data. There was no difference in withdrawals due to adverse events. Nine per cent (14/159) of anti-tuberculous therapy patients withdrew due to adverse events compared to 7% (11/163) of placebo patients (RR 1.29, 95% CI 0.60 to 2.77, I(2) = 0%). Common adverse events included increased skin pigmentation and rashes. No serious adverse events were reported in any of the included studies.
AUTHORS' CONCLUSIONS
Anti-tuberculous therapy may provide a benefit over placebo for the prevention of relapse in participants with Crohn's disease in remission. However, this result is very uncertain due to unclear study quality and the small numbers of patients assessed. Further studies are needed to provide better quality evidence for the use of anti-tuberculous therapy for maintaining remission in people with quiescent Crohn's disease.
Topics: Antitubercular Agents; Clarithromycin; Clofazimine; Crohn Disease; Ethambutol; Glucocorticoids; Humans; Maintenance Chemotherapy; Methylprednisolone; Prednisone; Randomized Controlled Trials as Topic; Recurrence; Remission Induction; Rifabutin; Rifampin; Secondary Prevention
PubMed: 27444319
DOI: 10.1002/14651858.CD000299.pub3 -
Antimicrobial Agents and Chemotherapy Mar 1998This study evaluated the tolerance and potential pharmacokinetic interactions between clarithromycin (500 mg every 12 h) and rifabutin (300 mg daily) in clinically... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
This study evaluated the tolerance and potential pharmacokinetic interactions between clarithromycin (500 mg every 12 h) and rifabutin (300 mg daily) in clinically stable human immunodeficiency virus-infected volunteers with CD4 counts of <200 cells/mm3. Thirty-four subjects were randomized equally to either regimen A or regimen B. On days 1 to 14, subjects assigned to regimen A received clarithromycin and subjects assigned to regimen B received rifabutin, and then both groups received both drugs on days 15 to 42. Of the 14 regimen A and the 15 regimen B subjects who started combination therapy, 1 subject in each group prematurely discontinued therapy due to toxicity, but 19 of 29 subjects reported nausea, vomiting, and/or diarrhea. Pharmacokinetic analysis included data for 11 regimen A and 14 regimen B subjects. Steady-state pharmacokinetic parameters for single-agent therapy (day 14) and combination therapy (day 42) were compared. Regimen A resulted in a mean decrease of 44% (P = 0.003) in the clarithromycin area under the plasma concentration-time curve (AUC), while there was a mean increase of 57% (P = 0.004) in the AUC of the clarithromycin metabolite 14-OH-clarithromycin. Regimen B resulted in a mean increase of 99% (P = 0.001) in the rifabutin AUC and a mean increase of 375% (P < 0.001) in the AUC of the rifabutin metabolite 25-O-desacetyl-rifabutin. The usefulness of this combination for prophylaxis of Mycobacterium avium infections is limited by frequent gastrointestinal adverse events. Coadministration of clarithromycin and rifabutin results in significant bidirectional pharmacokinetic interactions. The resulting increase in rifabutin levels may explain the increased frequency of uveitis observed with concomitant use of these drugs.
Topics: Acquired Immunodeficiency Syndrome; Adult; Area Under Curve; CD4 Lymphocyte Count; Clarithromycin; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Rifabutin
PubMed: 9517944
DOI: 10.1128/AAC.42.3.631 -
Memorias Do Instituto Oswaldo Cruz Feb 2019Rifamycins are a group of antibiotics mainly used in the treatment of tuberculosis (TB), however they interact with antiretroviral therapy (ART). Rifabutin allows more... (Comparative Study)
Comparative Study
BACKGROUND
Rifamycins are a group of antibiotics mainly used in the treatment of tuberculosis (TB), however they interact with antiretroviral therapy (ART). Rifabutin allows more regimens options for concomitant imunodeficiency virus (HIV) treatment compared to rifampicin.
OBJECTIVE
Compare the outcomes of TB-HIV co-infected patients who used rifampicin or rifabutin.
METHODS
We analysed data from a prospective cohort study at National Institute of Infectious Diseases Evandro Chagas, Rio de Janeiro (RJ), Brazil. Patients who were treated for TB and HIV with rifampicin or rifabutin, from February 2011 to September 2016 were included.
FINDINGS
There were 130 TB-HIV patients, of whom 102 were treated with rifampicin and 28 with rifabutin. All patients in the rifabutin-treated group and 55% of the rifampicin-treated group patients were ART-experienced. Patients treated with rifampicin had similar abandon and cure rates, interruptions in treatment due to adverse reactions, immune reconstitution inflammatory syndrome and a similar mortality rate as those treated with rifabutin. However, rifampicin-treated patients had higher CD4 counts and more frequently undetectable HIV viral load by the end of treatment (67% versus 18%, p < 0.001) compared to rifabutin-treated patients, even when only ART-experienced patients were evaluated (66,6% versus 36,3%, p = 0.039).
CONCLUSIONS
Patients who used rifabutin had worst immune and virological control. This group had more ART-experienced patients. New and simpler regimens are needed for patients who do not respond to previous antiretroviral therapies.
Topics: Adult; Anti-HIV Agents; Antibiotics, Antitubercular; Cohort Studies; Drug Interactions; Female; HIV Infections; Humans; Male; Middle Aged; Prospective Studies; Rifabutin; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary
PubMed: 30758392
DOI: 10.1590/0074-02760180420 -
The Journal of Antimicrobial... Dec 2020Rifabutin, an oral drug approved to treat Mycobacterium avium infections, demonstrated potent activity against Acinetobacter baumannii in nutrient-limited medium enabled...
In vitro activity of rifabutin against 293 contemporary carbapenem-resistant Acinetobacter baumannii clinical isolates and characterization of rifabutin mode of action and resistance mechanisms.
BACKGROUND
Rifabutin, an oral drug approved to treat Mycobacterium avium infections, demonstrated potent activity against Acinetobacter baumannii in nutrient-limited medium enabled by rifabutin cellular uptake through the siderophore receptor FhuE.
OBJECTIVES
To determine rifabutin in vitro activity and resistance mechanisms in a large panel of A. baumannii isolates.
METHODS
Two hundred and ninety-three carbapenem-resistant A. baumannii clinical isolates collected from Europe, the USA and Asia during 2017-19 were used for MIC determination. Sequencing/genotyping of fhuE, rpoB and arr-2 genes in isolates with elevated rifabutin MIC combined with genetic engineering and gene expression quantification was used to characterize rifabutin's mode of action and resistance mechanisms.
RESULTS
Rifabutin showed excellent activity on the strain panel, with an MIC50/90 of 0.008/1 mg/L, and was superior to all other antibiotics tested, including colistin, tigecycline and cefiderocol (MIC90 of 8 mg/L). Rifabutin remained active on resistant subpopulations, including strains resistant to the siderophore-drug conjugate cefiderocol (MIC90 of 2 mg/L, n = 23). At least two independent resistance mechanisms were required to abolish rifabutin activity, which is in line with the dose-dependent mutational resistance frequency reaching 10-9 at rifabutin concentrations at or above 2 mg/L.
CONCLUSIONS
This study demonstrated the potent activity of rifabutin against carbapenem-resistant A. baumannii. We propose that FhuE-mediated active uptake of rifabutin enables activity against rifampicin-resistant isolates. To achieve clinically meaningful strain coverage and to avoid rapid resistance development, rifabutin concentrations ≥2 mg/L are required, something rifabutin oral formulations cannot deliver.
Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Asia; Carbapenems; Drug Resistance, Multiple, Bacterial; Europe; Microbial Sensitivity Tests; Rifabutin
PubMed: 32869081
DOI: 10.1093/jac/dkaa370 -
Annals of Medicine Dec 2022To determine the minimum inhibitory concentration (MIC) distribution of antibacterial drugs and the susceptibility of non-tuberculous mycobacterial (NTM) isolates to...
Antimicrobial susceptibility and minimum inhibitory concentration distribution of common clinically relevant non-tuberculous mycobacterial isolates from the respiratory tract.
To determine the minimum inhibitory concentration (MIC) distribution of antibacterial drugs and the susceptibility of non-tuberculous mycobacterial (NTM) isolates to provide a reference basis for the clinical selection of an effective starting regimen. The common clinical isolates of NTM in the respiratory tract, which met the standards of the American Thoracic Society for NTM lung disease, were collected. The MICs of 81 isolates were determined using the microbroth dilution method (Thermo Fisher Scientific, USA), as recommended by the Clinical and Laboratory Standards Institute, USA. Included were 43 complex (MAC) strains, 24 complex (MAB) strains, and 14 strains. The sensitivity rates of MAC to clarithromycin and amikacin were 81.4% and 79.1%, respectively, while the sensitivity rates to linezolid and moxifloxacin were only 20.9% and 9.3%; the MIC of rifabutin was the lowest (MIC50% was just 2 μg/mL). After incubation for 3-5 days, the sensitivity rate of MAB to clarithromycin was 87.5%; this decreased to 50% after 14 days' incubation. Most of them were susceptible to amikacin (91.6%), and most were resistant to moxifloxacin (95.8%), ciprofloxacin (95.8%), imipenem (95.8%), amoxicillin/clavulanate (95.8%), tobramycin (79.1%), doxycycline (95.8%) and trimethoprim/sulfamethoxazole (95.8%). intermediate (83.3%) and resistant (16.7%) to cefoxitin. The susceptibility to linezolid was only 33.3%. The sensitivity and resistance breakpoints of tigecycline were set to ≤0.5 and ≥8 μg/mL, respectively, and the sensitivity and resistance rates were 50% and 0%, respectively. was susceptible to clarithromycin, amikacin, linezolid, moxifloxacin, rifampicin and rifabutin (100%). In Wenzhou, clarithromycin, amikacin and rifabutin have good antibacterial activity against MAC, while linezolid and moxifloxacin have high resistance. Amikacin and tigecycline have strong antibacterial activity against MAB, while most other antibacterial drugs are resistant to varying degrees. Most antibacterial drugs are susceptible to . and have good antibacterial activity. The identification of NTM species and the detection of their MICs have certain guiding values for the treatment of NTM lung disease.Key MessageThe three most common respiratory non-tuberculous mycobacterial (NTM) isolates with clinical significance in the Wenzhou area were tested for drug susceptibility. The broth microdilution method was used to determine the minimum inhibitory concentration distribution of antibacterial drugs and the susceptibility of NTM isolates to provide a reference basis for the clinical selection of an effective starting regimen.
Topics: Amikacin; Amoxicillin; Anti-Bacterial Agents; Cefoxitin; Ciprofloxacin; Clarithromycin; Clavulanic Acid; Doxycycline; Humans; Imipenem; Linezolid; Lung Diseases; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Respiratory System; Rifabutin; Rifampin; Sulfamethoxazole; Tigecycline; Tobramycin; Trimethoprim
PubMed: 36120867
DOI: 10.1080/07853890.2022.2121984 -
Environmental Health Perspectives Nov 1994Animal studies have demonstrated that the mouse and rabbit are far more responsive to the inductive properties of rifamycin derivatives than the rat and guinea pig. The... (Review)
Review
Animal studies have demonstrated that the mouse and rabbit are far more responsive to the inductive properties of rifamycin derivatives than the rat and guinea pig. The rat hepatic cytochrome P450 system seems to be resistant to the action of rifampicin unless very high doses are used. Mouse hepatic microsomal mixed-function oxidase activity is markedly increased by repeated dosing with rifampicin, whereas administration of rifabutin may be ineffective. In humans, both rifampicin and rifabutin are extensively metabolized and induce their own metabolism. The induced metabolic pathways remain essentially unknown. Under autoinduction conditions, the elimination half-life of rifampicin decreases, whereas that of rifabutin is not altered. Although the effects of repeated administration of rifampicin and rifabutin on the various forms of cytochrome P450 in humans have not been extensively examined, there is convincing evidence that the P4503A subfamily is induced by either drug, whereas the P4501A subfamily and P4502D6 do not appear to be affected by rifampicin. Limited reliable information is available concerning the induction of human glucuronyltransferase activities by rifampicin and rifabutin which, however, do not seem to influence zidovudine glucuronide formation in healthy subjects.
Topics: Animals; Cytochrome P-450 Enzyme System; Enzyme Induction; Female; Humans; Male; Mice; Microsomes, Liver; Rabbits; Rats; Rifabutin; Rifampin; Species Specificity
PubMed: 7698069
DOI: 10.1289/ehp.94102s9101