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.

Three new polyketides from vasR2 gene over-expressed mutant strain of Verrucosispora sp. NS0172 / 中国天然药物

Over-expression of the pathway specific positive regulator gene is an effective way to activate silent gene cluster. In the curret study, the SARP family regulatory gene, vasR2, was over-expressed in strain Verrucosispora sp. NS0172 and the cryptic gene cluster responsible for the biosynthesis of pentaketide ansamycin was partially activated. Two tetraketides (1 and 2) and a triketide (3) ansamycins, together with five known compounds (4-8), were isolated and elucidated from strain NS0172OEvasR2. Their NMR data were completely assigned by analysis of their HR-ESI-MS and

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.

Traditional and Novel Mechanisms of Heat Shock Protein 90 (HSP90) Inhibition in Cancer Chemotherapy Including HSP90 Cleavage

HSP90 is a molecular chaperone that increases the stability of client proteins. Cancer cells show higher HSP90 expression than normal cells because many client proteins play an important role in the growth and survival of cancer cells. HSP90 inhibitors mainly bind to the ATP binding site of HSP90 and inhibit HSP90 activity, and these inhibitors can be distinguished as ansamycin and non-ansamycin depending on the structure. In addition, the histone deacetylase inhibitors inhibit the activity of HSP90 through acetylation of HSP90. These HSP90 inhibitors have undergone or are undergoing clinical trials for the treatment of cancer. On the other hand, recent studies have reported that various reagents induce cleavage of HSP90, resulting in reduced HSP90 client proteins and growth suppression in cancer cells. Cleavage of HSP90 can be divided into enzymatic cleavage and non-enzymatic cleavage. Therefore, reagents inducing cleavage of HSP90 can be classified as another class of HSP90 inhibitors. We discuss that the cleavage of HSP90 can be another mechanism in the cancer treatment by HSP90 inhibition.

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.

Mycobacterium avium Complex Peritonitis in an Acquired Immune Deficiency Syndrome Patient / 대한내과학회지

Mycobacterium avium complex (MAC) is an opportunistic bacterium that primarily infects acquired immune deficiency syndrome (AIDS) patients with low CD4+ T cell counts; however, peritonitis caused by MAC in AIDS patients is rare. Here, we report the first case of peritonitis caused by MAC in AIDS patients in Korea. A 41-year-old female with poor adherence to antiretroviral therapy was admitted to hospital with nonspecific symptoms; an abdominal computed tomography (CT) scan revealed substantial ascites, splenomegaly, and lymphadenopathy. Based on the CT scan and ascitic fluid cultures, MAC peritonitis was diagnosed. In addition to antiretroviral therapy, clarithromycin, rifabutin, and ethambutol were administered to treat the MAC infection, and the patient's symptoms improved.

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.

Historical Perspective of Helicobacter pylori Treatment in Korea

Since the discovery of Helicobacter pylori in 1983 by Warren and Marshall, it has been recognized as one of the most significant risk factors for gastric cancer and has been associated with various gastrointestinal disorders such as peptic ulcer disease. In Korea, the triple therapy of proton pump inhibitor, clarithromycin, and amoxicillin has been recommended as a primary regimen since 1998. However, the eradication rate of conventional first line therapy of H. pylori infection has been decreasing progressively, primarily due to increased resistance to antibiotics. A recent meta-analysis showed that the overall eradication rates were 74.6% by intention-to-treat analysis and 82.0% by per-protocol analysis. Therefore, the need for alternative first line eradication regimens has been rising. Sequential therapy, concomitant therapy, and various combinations of new antibiotics such as quinolone and rifabutin have been introduced as new options, but they have yet to be proven as standard first line therapy. Further nation-wide surveillance regarding the antibiotic resistance rates and well-designed prospective randomized controlled multicenter trials on the empirical first line therapy are necessary to establish the appropriate treatment for H. pylori in Korea.

Recent Update on Third-line Helicobacter pylori Eradication

The eradication rate of Helicobacter pylori has been decreasing progressively, primarily due to increased resistance to antibiotics. The widely used standard clarithromycin-based triple therapy regimen is no longer achieving eradication rate of 80% in intent-to-treat analysis in many countries. Due to the primary and secondary resistance to metronidazole, the key antibiotic for second line regimen, eradication rate of standard metronidazole based quadruple therapy is also decreasing. It is rational to check antibiotic resistance for selecting regimens in third-line rescue eradication therapy, but it requires time and resource. Limited studies regarding the efficacy of a dual regimen consisting of high dose proton pump inhibitor and amoxicillin showed controversial results. Efficacy of rescue regimens containing fluoroquinolones, such as levofloxacin and moxifloxacin, were reported to be insufficient due to increasing incidence of primary and secondary resistance. Eradication result of third-line rescue regimens with sitafloxacin, a novel quinolone of which the antibacterial activity towards H. pylori is more than 100-fold that of ciprofloxacin in vitro, is promising. Although prevalence of serious side effect such as myelotoxicity with rifabutin-based rescue regimen is reported to be lower than expected, wider use of rifabutin is still concerned regarding the emergence of resistant mycobacterial species. Rifaximin based rescue regimen is safer and cheaper than rifabuitin based regimen. However, further investigation for better eradication rates by enhancing higher drug concentration in the gastric mucus layer needs to be evaluated.

Recurrent neutropenia induced by rifabutin in a renal transplant recipient

No abstract available.

A Case of Vertebral Osteomyelitis With Epidural Abscess Caused by Mycobacterium intracellulare in a Rheumatoid Arthritis Patient

Mycobacterium avium complex (MAC) is the most common pathogen in nontuberculous mycobacterial lung diseases, but vertebral osteomyelitis caused by MAC is rare. We experienced a case of vertebral osteomyelitis with epidural abscess in a rheumatoid arthritis patient who received immunosuppressive agents. Initial assessment was tuberculous vertebral osteomyelitis, and then treated with antituberculous drugs. Fifty-six days later, Mycobacterium intracellulare was identified from abscess culture and drugs were altered to clarithromycin, rifabutin, and ethambutol. After 3 months of M. intracellulare treatment, the radiological findings showed increases of epidural abscess. According to the suseptibility, the patient received intravenous amikacin for four weeks, and then, oral ciprofloxacin in addition to clarithromycin, rifabutin, and ethambutol. The patient is being treated with the medication for 13 months and currently showing slow improvements.

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.

Development of Multidrug Resistance during Standardized Treatment in a Patient with Drug-Sensitive Tuberculosis / 대한내과학회지

Standard short-course chemotherapy (SSC) is recommended for new patients with pulmonary tuberculosis (TB). This approach has been regarded as among the most effective tools for preventing the development of resistance to anti-TB drugs. We report on the development of multidrug-resistance during SSC in a patient with drug-susceptible TB. Isoniazid, rifampin, pyrazinamide, and ethambutol were started, and negative culture conversion was obtained. Ethambutol was discontinued after 5 weeks of treatment due to visual dysfunction, and pyrazinamide was discontinued after a 2-month phase of intensive treatment. However, M. tuberculosis was cultivated from sputum collected after 9 weeks of treatment. Drug-susceptibility testing revealed resistance to isoniazid, rifampin, ethambutol, and rifabutin. Given that the patient took medication regularly, this observation suggests the possibility that some patients acquire drug resistance during SCC.

Comparison of the Antibiotic Resistance of Helicobacter pylori Isolated in Jinju Over a 15-year Period

The aims of this study were to investigate the changing pattern of Helicobacter pylori antibiotic resistance in Jinju over a 15-year period. H. pylori strains were isolated from 170 adults living in Jinju from 1985-1989, 1990-1994 and 1995-1999, and from 23 adults living in Cheongju from 1995 to 1999. Susceptibility to erythromycin, clarithromycin, azithromycin, amoxicillin, tetracycline, metronidazole, furazolidone, levofloxacin, ciprofloxacin, moxifloxacin, and rifabutin was tested using the serial two-fold agar dilution method. Moxifloxacin resistance significantly increased in Jinju from 1985-1989 (0%) to 1995-1999 (14.9%) (p < 0.0001). Resistance to amoxicillin was increasesed trend to decreased trend from 1985 to 1999 (p = 0.033), whereas metronidazole resistance decreased from 37.5% to 21.3%. Resistance to furazolidone was greater from 1985-1989 (9.4%) than in 1995-1999 (2.1%). In comparing Jinju and Cheongju, minimal inhibitory concentrations (MICs) of tetracycline and levofloxacin among H. pylori isolated from Jinju were lower than for isolates from Cheonju (p < 0.05). The levofloxacin resistance rate was higher in Cheongju than in Jinju (p = 0.02). No macrolide resistance was observed in Cheongju. Overall, we did not observe any remarkable antimicrobial resistance increase of H. pylori strains isolated from Jinju over 15 years. The MIC distributions of antimicrobials and antimicrobial resistant rates were time- and region-specific among different strains. Future anti-H. pylori eradication regimens should be designed based on the changing patterns of antimicrobial resistance according to the resident area.

Development of Multidrug Resistance during Standardized Treatment in a Patient with Drug-Sensitive Tuberculosis / 대한내과학회지

Standard short-course chemotherapy (SSC) is recommended for new patients with pulmonary tuberculosis (TB). This approach has been regarded as among the most effective tools for preventing the development of resistance to anti-TB drugs. We report on the development of multidrug-resistance during SSC in a patient with drug-susceptible TB. Isoniazid, rifampin, pyrazinamide, and ethambutol were started, and negative culture conversion was obtained. Ethambutol was discontinued after 5 weeks of treatment due to visual dysfunction, and pyrazinamide was discontinued after a 2-month phase of intensive treatment. However, M. tuberculosis was cultivated from sputum collected after 9 weeks of treatment. Drug-susceptibility testing revealed resistance to isoniazid, rifampin, ethambutol, and rifabutin. Given that the patient took medication regularly, this observation suggests the possibility that some patients acquire drug resistance during SCC.

Regulation of invasion behavior of ERK-mediated trophoblast by focal adhesion kinase / 中南大学学报(医学版)

OBJECTIVE@#To investigate the role of focal adhesion kinase (FAK) in extracellular signal-regulated kinase (ERK) signaling pathway mediated invadsion of trophoblasts.@*METHODS@#We established a human extravillous cytotrophoblasts in vitro invasion model. Different concentrations of herbimycin A(FAK inhibitor)and PD98059 (ERK inhibitor) were given to observe the influence on the growth of trophoblast cells, FAK, ERK phosphorylation, and trophoblast invasion abilities.@*RESULTS@#The expression of phosphorylated FAK in the extravillous cytotrophoblasts (EVCT) was inhibited by herbimycin A in a concentration-dependent manner and expression of phosphorylated ERK1/2 was also partially reduced. PD98059 had no effect on the expression of phosphorylated FAK. Herbimycin A and PD98059 suppressed the in vitro invasion of EVCT to various degrees.@*CONCLUSION@#ERK signaling pathway may be the common pathway for many invasive signals,and play a key role in the regulation of trophoblast invasion.

Treatment of Helicobacter pylori

The seroprevalence of Helicobacter pylori (H. pylori) in Korea was found to be decreased. However eradication rate of 1st line therapy has become lower and antimicrobial resistance has increased, recently. Therefore we must also be prepared to face treatment failure and in designing a treatment strategy we should not focus on the results of 1st line therapy alone, but also on the rescue therapy. Some studies have demonstrated that levofloxacine-based triple regimen shows favourable results in 2nd or 3rd line therapy. However, it has shown that resistance to quinolones is easily acquired, and in Korea with a high consumption of these drugs, the resistance rate is increasing and is already relatively high. Therefore it should be reserved for final rescue treatment. Another potential regimen for final rescue therapy is rifabutin-based regimen which is known to be effective for H. pylori strains resistant to clarithromycin or metronidazole. Several concerns still remain, however, regarding rifabutin treatment. Firstly it is very expensive. Secondly myelotoxicity such as leukopenia and thrombocytopenia have been reported in some patients treated with rifabutin. Finally because of multiresistant strains of Mycobacterium tuberculosis increasing in numbers, indications for these drugs should be chosen very carefully to avoid further acceleration of development of resistance. Therefore refabutin should be considered only as the last option. It is difficult to choose proper treatment in Korea after failure of 2nd line treatment, because only a few study about 3rd line rescue therapy have been reported. Therefore we need more well designed randomized controlled studies.

Correlation of seven biological factors (Hsp90a, p53, MDM2, Bcl-2, Bax, Cytochrome C, and Cleaved caspase3) with clinical outcomes of ALK+ anaplastic large-cell lymphoma / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To explore correlation of seven apoptosis-related proteins (Hsp90a, p53, MDM2, Bcl-2, Bax, Cytochrome C, and Cleaved caspase3) with clinical outcomes of ALK+ anaplastic large-cell lymphoma (ALCL).</p><p><b>METHODS</b>Using immunohistochemistry and immunofluorescence double staining methods, the expressions of these seven apoptosis-associated proteins were studied to clarify their relationship with clinical outcomes of 36 ALK+ and 25 ALK-systemic ALCL patients enrolled between 1996 and 2006. The relationship of these apoptosis-regulating proteins with NPM-ALK status was also evaluated with the tyrosine inhibitor herbimycin A (HA) in vitro by immunocytochemistry, Western blotting and flow cytometric assays.</p><p><b>RESULTS</b>The presence of Hsp90α-, MDM2-, Bax-, Cytochrome C, and Cleaved caspase3-positive tumor cells was found significantly different in ALK+ and ALK-ALCLs, which was correlated with highly favorable clinical outcome. The Bcl-2- and p53-positive tumor cells were found in groups of patients with unfavorable prognosis. Inhibition of NPM-ALK by HA could reactivate the p53 protein and subsequent apoptosis-related proteins and therefore induced apoptosis in ALK+ ALCL cells.</p><p><b>CONCLUSION</b>Our results suggest that these seven proteins might be involved in apoptosis regulation and associated with clinical outcome of ALK+ systemic ALCLs. We also reveal a dynamic chain relation that NPM-ALK regulates p53 expression and subsequent apoptosis cascade in ALK+ ALCLs.</p>

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.

Neutropenia crónica e infección por el virus de la inmunodeficiencia humana / Chronic neutropenia and human immunodeficiency virus infection

Se presenta el caso de un paciente masculino con neutropenia crónica e infección por el virus de immunodeficiencia humana, con una revisión de los posibles mecanismos patogénicos. Las alteraciones hematológicas como anemia, trombocitopenia y leucopenia se presentan asociadas con frecuencia a la infección aguda por el virus de inmunodeficiencia humana. Al establecer la terapia antirretroviral y disminuir la actividad del virus, estas alteraciones tienden a mejorar. Sin embargo, algunos fármacos antirretrovirales, como la zidovudina, poseen toxicidad medular y pueden producir o empeorar las alteraciones hematológicas en estos pacientes, lo cual lleva a cambios en los esquemas de tratamiento. Los citotóxicos y antimetabolitos empleados en el tratamiento de neoplasias asociadas tienen conocida actividad depresora sobre la médula ósea. Algunos antimicrobianos utilizados en la profilaxis de infecciones poseen también toxicidad hematológica conocida, como el trimetoprim-sulfametaxazol, por lo que deben ser utilizados con precaución en pacientes con infección por el virus de inmunodeficiencia humana. Por otro lado, se plantean mecanismos alternativos que causan neutropenia en estos pacientes, como la formación de anticuerpos antineutrófilos, daño primario del progenitor granulocítico, por desbalance en la producción de neutrófilos, por anticuerpos contra la glicoproteína gp 120 de la cápside viral del VIH, y deficiencias vitamínicas. En el caso del paciente neutropénico febril, en quien se sospecha infección bacteriana grave, se pueden utilizar los factores estimulantes de las colonias de granulocitos para aumentar los conteos absolutos de neutrófilos y mejorar la recuperación clínica.