Rifabutina: terapia de rescate eficaz para la infección por Helicobacter pylori, revisión de la literatura actual / Rifabutin: therapeutic alternative for Helicobacter pylori infection, actual literature review

Resumen La infección por Helicobacter pylori se asocia con enfermedades gastroduodenales como gastritis crónica, úlcera péptica y adenocarcinoma gástrico. Actualmente se dispone de diferentes esquemas terapéuticos, sin embargo, el uso indiscriminado de antibióticos generó resistencia en este agente, razón para estudiar alternativas y reevaluar los criterios que determinan la selección de un esquema en específico. El objetivo de esta revisión fue describir los principios generales de tratamiento de acuerdo a guías de referencia y recomendaciones de autores independientes, y exponer el uso de la rifabutina como alternativa terapéutica. En la búsqueda bibliográfica se usaron los términos "Helicobacter pylori" AND "rifabutin", en las bases de datos PubMed, SciELO y el motor de búsqueda Google Scholar®. La evidencia actual sugiere que el uso de rifabutina como terapia de rescate es apropiado y seguro, y sería la alternativa ideal en casos de multirresistencia o difícil acceso a pruebas de susceptibilidad antibiótica. MÉD.UIS.2022;35(1): 31-42.

Abstract Helicobacter pylori infection is associated with gastroduodenal diseases such as chronic gastritis, peptic ulcer, and gastric adenocarcinoma. Nowadays, there are different therapeutic regimens, however, the indiscriminate use of antibiotics generated resistance in this agent, reason to study alternatives and reevaluate the criteria that determines the selection of a specific regimen. The aim of this review was to describe the general principles of treatment according to reference guidelines and recommendations of independent authors, and to present the use of rifabutin as a therapeutic alternative. The bibliographic search was performed using the terms "Helicobacter pylori" AND "rifabutin" in the databases PubMed, SciELO and the search engine Google Scholar®. Current evidence suggests that the use of rifabutin as rescue therapy is appropriate and safe, and would be an ideal alternative in cases of multidrug resistance or difficult access to antibiotic susceptibility tests. MÉD.UIS.2022;35(1): 31-42.

Tuberculosis-HIV treatment with rifampicin or rifabutin: are the outcomes different?

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.

Determination of Related Substances in Rifabutin Crude Drug and Capsules by HPLC / 中国药房

OBJECTIVE： To establish a method for the determination of related substances in rifabutin crude drug and capsules by HPLC. METHODS： HPLC method was adopted. The determination was performed on Agilent XDB-C8 column with mobile phase consisted of acetonitrile-0.1 mol/L potassium dihydrogen phosphate solution （pH 6.5±0.1） （50 ∶ 50， V/V） at the flow rate of 1.0 mL/min. The detection wavelength was set at 254 nm， the column temperature was 30 ℃， and sample size was 20 μL. The mobile phase was used as solvent to prepare the sample solution with a mass concentration of 1.0 mg/mL. The system suitability test was performed by using newly established method and current method （mass concentration of sample solution 0.5 mg/mL， C18 column） stated in quality standard of rifabutin crude drug and capsules. Related substance test was conducted for 6 batches of rifabutin crude drug and capsule （peak area normalization method）. RESULTS： The linear range of rifabutin was 0.8-16 μg/mL（r＝1.000 0）， RSDs of precision， reproducibility and stability tests （12 h） were all lower than 2.0％ （n＝6）； the limits of detection and quantification were 0.025 4， 0.085 2 μg/mL. In system suitability test， by using new method and current method， separation degree of rifabutin peak and pre-degradation product peak were 7.50 and 3.47. When 6 batches of samples were determined， the number of impurities detected by this method was 1-5 more than that by the current method， and the total amount of impurities was 0.19％-0.55％ higher. CONCLUSIONS： Established new method is well-separated and sensitive， and can be used for the determination of related substance in rifabutin crude drug and capsules， which helps the quality control of drugs.

Efficacy and safety of rifabutin and furazolidone included triple regimen and minocycline plus furazolidone included quadruple regimen in eradicating refractory Helicobacter pylori infection / 中华消化杂志

Objective To observe the efficacy and safety of rifabutin and furazolidone included triple regimen and minocycline plus furazolidone included quadruple regimen in eradicating refractory H.pylori infection.Methods A total of 146 patients who failed (≥ two times) to treat H.pylori with standard antiH.pylori therapy were selected and divided into esomeprazole,rifabutin and furazolidone treatment group (ERF group,n =74) and esomeprazole,minocycline,furazolidone and bismuth potassium citrate group (EMFB group,n =72).The duration of treatment were both 10 days.Liver and renal functions were examined within three days after therapy.13C or 14 C-urease breath test was performed one month after the medication withdrawal.The patients were followed up once every two weeks during the treatment period.The medication and adverse reactions were recorded in detail.The compliance and rates of adverse events in two groups were compared and analyzed.The eradication rates of the two groups and subgroups were compared by intention-to-treat (ITT) and per-protocol (PP) analyses.The cost-effectiveness of the two groups was evaluated with cost effectiveness analysis (CEA).The cost/effectiveness (C/E) ratio was calculated by PP.Chi-square test and t test were used for statistical analysis.Results There was no significant difference in complicance between ERF group and EMFB group (90.5％ vs.90.3％,P ＞0.05).There was no significant difference in H.pylori eradication rate between ERF group and EMFB group analyzed by ITT (82.4％ vs.84.7％,P ＞0.05).Analyzed by PP,there were no significant differences in H.pylori eradication rate between ERF group and EMFB group (91.0％ vs.93.8％),between male subgroup and female subgroup of ERF group (87.9％ vs.94.1％),between subgroup with age less than 60 years and subgroup with age over 60 years of ERF group (89.7％ vs.92.9％),between male subgroup and female subgroup of EMFB group (89.7％ vs.97.2％) and between subgroup with age less than 60 years and subgroup with age over 60 years of EMFB group (93.6％ vs.94.4％) (all P ＞ 0.05).There were no statistically significant differences in the rate of adverse events between ERF group and EMFB group (20.3％ vs.22.2％),between male subgroup and female subgroup of ERF group (25.0％ vs.15.8％),between subgroup with age less than 60 years and subgroup with age over 60 years of ERF group (26.2％ vs.12.5％),between male subgroup and female subgroup of EMFB group (19.4％ vs.24.4％) and between subgroup with age less than 60 years and subgroup with age over 60 years of EMFB group (24.5％ vs.15.8％)(all P ＞ 0.05).Fixed daily cost,total cost and C/E of ERF group was RMB 59.0 yuan,RMB 590.5 yuan and 648.9,respectively;and the eradication rate was 91.0％ (61/67).Fixed daily cost,total cost and C/E of EMFB group was RMB 32.9 yuan,RMB 329.1 yuan and 350.9,respectively;and the eradication rate was 93.8％ (61/65).Conclusions Rifabutin and furazolidone included triple regimen and minocycline plus furazolidone included quadruple regimen both have good efficacy,safety and compliance in the eradication of refractory H.pylori infection,and the latter is better.

Efficacy and safety of rifabutin and furazolidone included triple regimen and minocycline plus furazolidone included quadruple regimen in eradicating refractory Helicobacter pylori infection / 中华消化杂志

Objective@#To observe the efficacy and safety of rifabutin and furazolidone included triple regimen and minocycline plus furazolidone included quadruple regimen in eradicating refractory H. pylori infection.@*Methods@#A total of 146 patients who failed (≥two times) to treat H. pylori with standard anti-H.pylori therapy were selected and divided into esomeprazole, rifabutin and furazolidone treatment group (ERF group, n=74) and esomeprazole, minocycline, furazolidone and bismuth potassium citrate group (EMFB group, n=72). The duration of treatment were both 10 days. Liver and renal functions were examined within three days after therapy. 13C or 14C-urease breath test was performed one month after the medication withdrawal. The patients were followed up once every two weeks during the treatment period. The medication and adverse reactions were recorded in detail. The compliance and rates of adverse events in two groups were compared and analyzed. The eradication rates of the two groups and subgroups were compared by intention-to-treat (ITT) and per-protocol (PP) analyses. The cost-effectiveness of the two groups was evaluated with cost effectiveness analysis (CEA). The cost/effectiveness (C/E) ratio was calculated by PP. Chi-square test and t test were used for statistical analysis.@*Results@#There was no significant difference in complicance between ERF group and EMFB group (90.5% vs. 90.3%, P>0.05). There was no significant difference in H. pylori eradication rate between ERF group and EMFB group analyzed by ITT (82.4% vs. 84.7%, P>0.05). Analyzed by PP, there were no significant differences in H. pylori eradication rate between ERF group and EMFB group (91.0% vs. 93.8%), between male subgroup and female subgroup of ERF group (87.9% vs. 94.1%), between subgroup with age less than 60 years and subgroup with age over 60 years of ERF group (89.7% vs. 92.9%), between male subgroup and female subgroup of EMFB group (89.7% vs. 97.2%) and between subgroup with age less than 60 years and subgroup with age over 60 years of EMFB group (93.6% vs. 94.4%) (all P>0.05). There were no statistically significant differences in the rate of adverse events between ERF group and EMFB group (20.3% vs. 22.2%), between male subgroup and female subgroup of ERF group (25.0% vs. 15.8%), between subgroup with age less than 60 years and subgroup with age over 60 years of ERF group (26.2% vs. 12.5%), between male subgroup and female subgroup of EMFB group (19.4% vs. 24.4%) and between subgroup with age less than 60 years and subgroup with age over 60 years of EMFB group (24.5% vs. 15.8%) (all P>0.05). Fixed daily cost, total cost and C/E of ERF group was RMB 59.0 yuan, RMB 590.5 yuan and 648.9, respectively; and the eradication rate was 91.0%(61/67). Fixed daily cost, total cost and C/E of EMFB group was RMB 32.9 yuan, RMB 329.1 yuan and 350.9, respectively; and the eradication rate was 93.8%(61/65).@*Conclusions@#Rifabutin and furazolidone included triple regimen and minocycline plus furazolidone included quadruple regimen both have good efficacy, safety and compliance in the eradication of refractory H. pylori infection, and the latter is better.

Therapeutic implications of nano-encapsulated rifabutin, azithromycin & ethambutol against experimental Mycobacterium avium infection in mice

Background & objectives: Mycobacterium avium causes atypical infection in both immunocompetent and immunocompromised individuals. Conventional chemotherapy for M. avium infection is not efficient due to lengthy course of treatment and drug-associated toxic side effects. The present study was aimed at reducing dosing frequency of antimicrobial regimen consisting of azithromycin (AZM), rifabutin (RBT) and ethambutol (EMB) by encapsulation of drugs in nanoparticles (NPs) in experimental M. avium infection in mice. Methods: Poly (DL-lactide-co-glycolide) NPs containing anti-M. avium drugs were prepared, characterized and studied for their pharmacokinetics and pharmacodynamics parameters. Drug-loaded NPs were further analyzed for their therapeutic efficacy against experimental M. avium infection in mice. Results: Drug-loaded NPs were of size 227.3�.4 for RBT, 334.35�.7 for AZM and 509.85�.5 for EMB with smooth surface morphology and negative zeta potential. AZM, EMB and RBT from NPs were detectable for 6, 4 and 5 days, respectively, in the mice plasma, whereas free drugs were cleared from mice circulation within 24 h. Chemotherapeutic effects of weekly administered drug-loaded NPs were equivalent to daily administered free drugs. Interpretation & conclusions: Our findings showed that NPs gave sustained release of drugs inside plasma and organs, thus decreasing dosage frequency, and their weekly dosage had therapeutic efficacy equivalent to daily dosage of free drugs.

Rifabutin-based Fourth and Fifth-line Rescue Therapy in Patients with for Helicobacter pylori Eradication Failure / 대한소화기학회지

BACKGROUND/AIMS: Optimized regimen has not yet been established for failures of multiple Helicobacter pylori (H. pylori) eradication. Hence, we aimed to evaluate the efficacy of rifabutin-based rescue therapy, at least after three eradication failures. METHODS: Twelve patients, who failed in the treatment for H. pylori eradication at least three times, were consecutively enrolled between 2007 and 2015 at Seoul National University Bundang Hospital. The rifabutin-based rescue regimen was consisted of proton pump inhibitor (PPI), rifabutin (150 mg b.i.d.), and amoxicillin (1 g b.i.d.), given for 7 or 14 days. MIC concentration test by the agar dilution method was performed on six patients prior to rifabutin-based rescue therapy. RESULTS: One patient did not take this regimen, and per-protocol (PP) analysis was performed in 11 patients. The overall eradication rate by intention-to-treat and PP analysis with rifabutin-based rescue therapy was 50.0% (6/12 patients) and 54.5% (6/11 patients), respectively. There was no difference of the eradication rate depending on the underlying disease, smoking, alcohol, number of previous eradication failures, and CYP2C19 genotype. All of the six patients were susceptible to rifabutin, but only three of them succeeded in eradicating with H. pylori. Side effects occurred in two patients (18.2%), and compliance was 90.9%. CONCLUSIONS: Even the eradication rate of rifabutin-based rescue therapy was not very good. Rifabutin-based rescue therapy could be considered as a rescue therapy, perhaps as the fourth or the fifth-line treatment option. No correlation of rifabutin sensitivity with eradication success rate of H. pylori suggests that frequent administration of high dose PPI and amoxicillin might be important.

Neutropenia grave secundaria al tratamiento médico de una adenitis por micobacterias no tuberculosas / Severe neutropenia as side effect of medical treatment in nontuberculous mycobacterial adenitis

Non-tuberculous mycobacterial adenitis is getting more common in our environment. Epidemiologic studies and clinical trials published nowadays are limited. We present a 2-years-old boy diagnosed of Mycobacterium intracellulare adenitis and severe neutropenia as side effect of combined treatment with oral azythromycin and rifabutin, which recovers after suspending the second one. Liver metabolism of macrolide seems to increase other drugs toxicity, in this case, rifabutin. The patient eventually needed surgery due to persistence of the adenitis despite treatment with antibiotics.

Las adenopatías por micobacterias no tuberculosas (AMNT) son cada vez más frecuentes en nuestro medio. Los estudios epidemiológicos y ensayos clínicos controlados publicados hasta la fecha son escasos. Presentamos el caso de un niño de 2 años con el diagnóstico de una adenitis por Mycobacterium intracellulare que desarrolló una neutropenia grave secundaria a la terapia combinada de azitromicina y rifabutina oral. La metabolización hepática de los macrólidos parece aumentar la toxicidad de otros fármacos, en este caso, la rifabutina. Finalmente, al paciente se le realizó una exéresis quirúrgica por persistencia de la adenitis a pesar de la antibioterapia.

Effect of Rifabutin Combined with Multi-drugs in the Treatment of Multi-drug Resistant Tuberculosis with Long-term Therapy / 中国药师

Objective:To evaluate the effect and safety of rifabutin combined with multi-drugs in the treatment of multi-drug resist-ant tuberculosis with long-term therapy. Methods:Totally 86 cases of patients with multi-drug resistant tuberculosis were divided into the control group and the treatment group with 43 ones in each according to a random number table method. The two groups were trea-ted with levofloxacin, pasiniazid, ethambutol, protionamide and amikacin etc. The control group was treated with rifapentine, and the treatment group was treated with rifabutin additionally. After 18-month treatment, the negative conversion ratio of sputum smear and sputum mycobacterium tuberculosis culture, lesion absorption rate and cavity closure rate of X-ray chest radiograph and adverse reac-tions in the two groups were compared. Results:The negative conversion ratio of sputum smear and sputum mycobacterium tuberculosis culture in the treatment group was 41. 86% and 32. 56%, respectively, which were similar with those in the control group ( P >0. 05). There were no significant differences in lesion absorption rate and cavity closure rate of X-ray chest radiograph and adverse re-actions between the two groups (P>0. 05). Conclusion:Rifapentine or rifabutin combined with multi-drugs in the treatment of multi-drug resistant tuberculosis can improve the negative conversion rate of sputum mycobacterium and lesion absorption and cavity closure with high safety.

Recurrent neutropenia induced by rifabutin in a renal transplant recipient

No abstract available.

Preparation and in vitro evaluation of uniform-sized rifabutin-loaded PL-GA microspheres / 中国药学杂志

OBJECTIVE: To prepare uniform-sized rifabutin-loaded PLGA microspheres and evaluate the characteristics of the microspheres. METHODS: The particle size uniformity of the microspheres prepared by premix membrane emulsification method and homogenization method was compared. Preparation technology was optimized by orthogonal design. Then the drug loading, entrapment efficiency and in vitro drug release were studied. RESULTS: The average particle size and PDI of the microspheres prepared by homogenization method were (4242±175.6) nm and 0.330. The microspheres prepared by premix membrane emulsification method were round, complete and smooth, and their particle sizes were well-distributed with mean value of (1330±64) nm and PDI of 0.168. Besides, the drug loading was (46.83±0.29)% and the entrapment efficiency was (93.66±0.58)%. Accumulative drug release rate was 66% in 15 d. CONCLUSION: The rifabutin-loaded PLGA microspheres prepared by premix membrane emulsification method have narrow particle size distribution, high drug loading, high entrapment efficiency, and ideal in vitro sustained-release effect.

Comparison of Rifabutin- and Levofloxacin-based Third-line Rescue Therapies for Helicobacter pylori / 대한소화기학회지

BACKGROUND/AIMS: There is increasing need for third-line therapy of Helicobacter pylori due to increasing level of antibiotics resistance. The aim of this study was to compare rifabutin and levofloxacin rescue regimens in patients with first- and second-line Helicobacter pylori eradication failures. METHODS: Patients, in whom a first treatment with proton pump inhibitor-clarithromycin-amoxicillin and a second trial with proton pump inhibitor-bismuth-tetracycline-metronidazole had failed, received treatment with either rifabutin or levofloxacin, plus amoxicillin (1 g twice daily) and standard dose proton pump inhibitor. Eradication rates were confirmed with 13C-urea breath test or rapid urease test 4 weeks after the cessation of therapy. RESULTS: Eradication rates were 71.4% in the rifabutin group, and 57.1% in the levofloxacin group, respectively. Although there was no significant difference in Helicobacter pylori eradication rates between two groups (p=0.656), rifabutin based regimen showed relatively higher eradication rate. CONCLUSIONS: Helicobacter pylori eradication rates of rifabutin- or levofloxacin-based triple therapy could not achieve enough eradication rate. Further studies would be needed on combination of levofloxacin and rifabutin-based regimen or culture based treatment.

The differences of rpoB mutations in rifampicin/rifabutin cross-resistant clinical isolates of Mycobacterium tuberculosis / 中华检验医学杂志

ObjectiveTo learn the rpoB mutation difference in rifampicin/rifabutin cross-resistant (RIF/Rfb-R)clinical isolates and in rifampicin-resistant/rifabutin-susceptible (RIF-R/Rbo-S)clinical isolates of Mycobacterium tuberculosis.Methods To sequence the full-length genome of rpoB gene,and analyze the rpoB full-length gene mutation differences in 278 RIF/Rfb-R clinical isolates,40 RIF-R/Rfb-S clinical isolates,30 rifampicin-susceptible/rifabutin-susceptible (RIF-S/Rfb-S) and in 1 reference strain ofH37Rv.ResultsNo mutations of rpoB full-length gene were found in H37Rv reference strain and RIF-S/Rfb-S clinical isolates.In RIF/Rfb-R clinical isolates,531 (70.5％ ) and 526 (20.9％ ) were the most frequent mutation codons.223 (80.2％ ) isolates possesed single mutations as S531L,S531W,H526D,H526Y,H526R,Q513K,Q513P,Q510H,V176F,P287R,Y395C and H404Y.55 (19.8％) isolates had multiple mutations,and among these the S531L,H526 R,H526Y,H526D,D516G and Q513K were the main substitutions which were in combination with other points.In RIF-R/Rfb-S clinical isolates,516 (65.0％),526 ( 17.5％ ) and 533 ( 10.0％ ) were the most frequent mutation codons.21 (52.5％ ) isolates possesed single mutations as L533P,H526L,H526S,S522L,D516V,D516Y and D516F.19 (47.5％)isolates had multiple mutations and among these the D516V and L533P were the main substitutions which were in combination with other points.CondusionsIn our study,100％ rifamycin-resistant clinical isolates of Mycobacterium tuberculosis had rpoB mutations,but the mutations in RIF/Rfb-R clinical isolates were sharply different from RIF-R/Rfb-S clinical isolates in mutation positions or amino acids substitutions of single mutations strains,mutation positions or combination types and the most frequently mutation codons or amino acids substitutions of multiple mutations strains.Thus,DNA sequencing is instructive and meaningful to choose rifampicin or rifabutin for tuberculosis treatment.

Rifabutin Related Uveitis in AIDS: A Case Report

PURPOSE: To describe a case of symptomatic rifabutin-related uveitis with hypopyon and vitreous opacity in apatient with acquired immunodeficiency syndrome infected with Mycobacterium tuberculosis. CASE SUMMARY: A 33-year-old male patient with acquired immunodeficiency syndrome was referred to our clinic for abruptly decreased vision in his right eye. Multi-drug therapy with rifabutin was administered for 5 weeks to treat tuberculosis enteritis and pulmonary tuberculosis. Visual acuity of the right eye was hand motion and hypopyon as well as vitreous opacity was found in ocular examinations. Other serologic tests, anterior chamber paracentesis and lumbar puncture test were normal. Rifabutin was immediately stopped and topical steroid and cycloplegics were administered, which resulted in resolution of the hypopyon, vitreous opacity and visual acuity. Four weeks after the initial episode, rifabutin was restarted to treat the pulmonary tuberculosis and rifabutin-related uveitis relapsed in the opposite eye. CONCLUSIONS: Rifabutin-related uveitis should be considered in cases of uveitis in immunosuppressive patients, especially in acquired immunodeficiency syndrome patients. Underlying disease and medication history should be carefully assessed.

Cross-resistance Between Rifampicin and Rifabutin and Its Relationship with rpoB Gene Mutations in Clinically Isolated MDR-TB Strains / 결핵및호흡기질환

BACKGROUND: Despite the emerging danger of MDR-TB to human beings, there have only been a limited number of drugs developed to treat MDR-TB since 1970. This study investigated the cross-resistance rate between rifampicin (RFP) and rifabutin (RBU) in order to determine the efficacy of rifabutin in treating MDR-TB. In addition, the results of rifabutin were correlated with the rpoB mutations, which are believed to be markers for MDR-TB and RFP resistance. METHODS: The MICs of RBU were tested against 126 clinical isolates of MDR-TB submitted to the clinical laboratory of National Masan TB Hospital in 2004. Five different concentrations (10-160 microgram/ml) were used for the MICs. The detection of the rpoB mutations was performed using a RFP resistance detection kit with a line probe assay(LiPA), which contains the oligonucleotide probes for 5 wide type and 3 specific mutations (513CCA, 516GTC, and 531TTG). The rpoB mutation was determined by direct sequencing. RESULTS: The rate of cross-resistance between RFP and RBU was 70.5%(74/105) at 20 microgram/ml RBU(ed note: How much RFP?) Most mutations (86.3%) occurred in the 524~534 codons. The His526Gln, His526Leu, Leu533Pro, Gln513Glu, and Leu511Pro mutations(Ed note: Is this correct?) were associated with the susceptibilty to RBU. CONCLUSION: Based on the cross-resistance rate between RFP and RBU, RBU may be used effectively in some MDR-TB patients. Therefore, a conventional drug susceptibility test for RBU and a determination of the critical concentration are needed. However, rpoB gene mutation test may be have limited clinical applications in detecting RBU resistance.

The Proportion of Rifabutin-susceptible Strains among Rifampicin- resistant Isolates and Its Specific rpoB Mutations / 결핵및호흡기질환

BACKGROUND: Rifabutin (ansamycin) is a spiro-piperidyl rifamycin, which is highly active against Mycobacterium tuberculosis. It has been found that some clinical isolates of tubercle bacilli that are resistant to rifampicin are susceptible to rifabutin, with some patients with multi-drug resistant pulmonary tuberculosis having shown favorable clinical and bacteriological responses to the rifabutin. This study was conducted to find the proportion of rifabutin- susceptible strains among rifampicin-resistant isolates from Korean MDR-TB patients, and investigate the presence of specific rpoB mutations, which may confer resistance to rifampicin, but not to rifabutin. METHODS: 201 rifampicin-resistant and 50 pan-susceptible M. tuberculosis isolates were randomly selected for this study. The isolates were retested at rifampicin and rifabutin concentrations of 0, 20, 40 and 80 microgram/ml, respectively. The isolates that grew at and/or over a rifabutin concentration of 20 microgram/ml were judged rifabutin-resistant. The rpoB gene was extracted from the isolates, and then amplified for direct sequencing to investigate specific rpoB mutations that conferred rifabutin- susceptibility but rifampicin-resistance. RESULTS: Out of the 201 rifampicin-resistant M. tuberculosis, 41 strains (20.4%) were susceptible to rifabutin using the absolute concentration method on Lowenstein-Jensen media. The rpoB mutation types that showed susceptibility to rifabutin were Leu511Pro, Ser512Arg, Gln513Glu, Asp516Ala, Asp516Gly, Asp516Val, Asp516Tyr, Ser522Leu, His526Asn, His526Leu, His526Cys, Arg529Pro and Leu533Pro. A reverse hybridization technique was able to detect 92.5% of the rifabutin-susceptible isolates, with a specificity of 96.1% among 195 M. tuberculosis isolates with the rpoB mutation. CONCLUSIONS: Around 20% of the rifampicin-resistant isolates in Korea showed susceptibility to rifabutin, which was associated with some specific mutations of rpoB. Rifabutin could be used for the treatment of MDR-TB patients, especially when drug susceptibility testing reveals susceptibility to rifabutin.

Detection of Point Mutations in the rpoB gene Related to Drug Susceptibility in Mycobacterium Tuberculosis using an Oligonucleotide Chip / 결핵

BACKGROUND: The appearance of multiple-drug-resistant Mycobacterium tuberculosis strains has been seriously compromising successful control of tuberculosis. Rifampin-resistance, caused by mutations in the rpoB gene, can be indicative of multiple-drug-resistance, and its detection is of great importance. The present study aimed to develop an oligonucleotide chip for accurate and convenient screening of drug-resistance. METHODS: In order to detect point mutations in the rpoB gene, an oligonucleotide chip was prepared by immobilizing specific probe DNA to a microscopic slide glass by a chemical reaction. The probe DNA that was selected from the 81 bp core region of the rpoB gene was designed to have mutation sites at the center. A total of 17 mutant probes related to rifampin-resistance including 8 rifabutin-sensitive mutant probes were used in this study. For accurate determination, wild type probes were prepared for each mutation position with an equal length, which enabled a direct comparison of the hybridization intensities between the mutant and wild type. RESULTS: Mycobacterial genomic DNA from clinical samples was tested with the oligonucleotide chip and the results were compared with those of the drug-susceptibility test in addition to sequencing and INNO-LiPA Rif. TB kit test in some cases. Out of 15 samples, the oligonucleotide chip results of 13 samples showed good agreement with the rifabutin-sensitivity results. The two samples with conflicting result also showed a discrepancy between the other tests, suggesting such possibilities as existence of mixed strains and difference in drug-sensitivity. Further verification of these samples in addition to more case studies are required before the final evaluation of the oligonucleotide chip can be made. CONCLUSION: An oligonucleotide chip was developed for the detection of rpoB gene mutations related to drug-susceptibility. The results to date show the potential for using the oligonucleotide chip for accurate and convenient screening of drug-resistance to provide useful information in antituberculosis drug therapy.

Rifabutin susceptibility and rpoB gene mutations in multi-drug resistant mycobacterium tuberculosis / 결핵

BACKGROUND: Following several decades of decline, the incidence of tuberculosis has recently begun to increase in many countries and the control of this disease has been impeded by the emergence of multi-drug resistant tuberculosis (MDR-TB). The development of rapid diagnostic methods and effective new drugs are needed to control MDR-TB. One of the new drugs for MDR-TB is rifabutin (RBU) which has been known to be effective in some patients with MDR-TB. A few reports showed that some types of mutaitions of the rpoB gene, which were known to be present in 96-98% of rifampicin-resistant M. tuberculosis, were associated with the rifampicin-resistant but RBU-susceptible phenotype. This study was performed to investigate the correlation between RBU susceptibility and the patterns of rpoB gene mutations in Korean MDR-TB. METHODS: Sixty-five clinical isolates of multi-drug resistant Mycobacterium tuberculosis, gathered from patients two visited the Asan Medical Center from July 1997 to June 1999, were investigated. Clinical responses to rifabutin-containing regimen were evaluated. An RBU susceptibility test and sequencing analysis of rpoB gene were performed, and the result were analyzed to confirm which mutations correlated with RBU-susceptible MDR-TB. RESULTS: Fifty-three of 56 (95%) clinical isolates of MDR-TB had 60 mutations of the rpoB gene. The most frequent mutations were found at codon 531 (43%), and two mutations were combined in seven clinical isolates. Five of 53 (10%) clinical isolates showed the RBU-susceptible phenotype, and in them the characteristic patterns of point mutations were found at codon 509, 516, and 526. CONCLUSION: The frequency and pattern of mutations of the rpoB gene of Korean MDR-Tb isolates were similar to those in western countries, where the prevalence of tuberculosis is low, but some show RBU-susceptible phenotypes. RBU-susceptible MDR-TB isolates showed the characteristic pattern of mutations of the rpoB gene which could be used to rapidly diagnose RBU susceptibility.

Progress of clinical pharmacological study on rifabutin / 中国临床药理学与治疗学

Rifabutin(RBT) is a rifamycin derivative,like rifampicin(RIF),registered for the prophylaxis and treatment of mycobacterium avium complex (MAC)in patients with AIDS by FDA in 1992.Subsequently,the drug was approved by many other countries.But now,it is used not only in the prophlaxis and treatment of mycobacterium avium complex but also in the treatment of pulmonary tuberculosis and Helicobacter pylori.For its high lipophilic characteristic and weak inducing properties compare to other rifamycin derivative,it can be applied in treatment with many diseases successfully,especially when combine with other antibiotics,and can solve the problem of traditional antibiotics resistance and increase the clinical safety of combined medical treatment.This paper just shows the progress of clinical pharmacological study and related aspects on rifabutin in order to instruct prescription.