Antituberculous Agents Research Articles

Protective effect of vitamin C and or vitamin E on micronuclei induction by rifampicin in mice

Rifampicin which is a known antituberculous agent has been reported to induce both chromosomal breakage and numerical chromosomal abnormalities. This study was carried out to determine the mutagenicity of rifampicin and more importantly to investigate the protective roles of antioxidants-vitamin C and E individually and in-combination therapy against rifampicin mutagenicity using micronucleus assay. Therapeutic concentrations of rifampicin alone (9mg/kg), rifampicin plus vitamin E (5mg/kg), rifampicin plus vitamin C (8mg/kg) and rifampicin plus vitamin C plus vitamin E were administered orally for 28 consecutive days using 6 mice in each group. The negative and positive control mice received same volume of distilled water and cyclophosphamide (40 mg/kg) intraperitoneally 6 hours before sacrifice, respectively. The results showed rifampicin alone treated group to demonstrate significant ( P P ≤0.05) in the proportion of MPCE to PCE was demonstrated in the rifampicin plus vitamin E; rifampicin plus vitamin C plus E and rifampicin plus vitamin C groups compared with cyclophosphamide treated group and rifampicin treated group. These findings suggest that rifampicin has damaging effects on the deoxyribonucleic acid (DNA). However, co-administration of rifampicin and antioxidants (vitamin C and E) has protective effect on the damaging potentials of rifampicin.

Endoscopic classification of healing process in tracheobronchial tuberculosis

Out of 404 patients with pulmonary and/or tracheobronchial tuberculosis treated during the last 10 years at Kurume University Hospital and St. Mary Hospital, in 41 patients, who had been histopathologically or bacteriologically diagnosed as having active tracheobronchial tuberculosis, tracheobronchial lesions were examined by use of bronchofiberscope. Most patients were treated by a combination of three antituberculous agents (INH, RFP and SM or EB). In 31 patients out of the 41 patients, broncho-fiberscopic examinations were performed twice or more. We observed the ulcerous lesions of bronchial tuberculosis at various stages of healing, and could classify the ulcerous lesions into the following three stages. Active Stage: stage A; ulcer formation without regenerating epithelium, Healing Stage: stage H; ulcer formation with regenerating epithelium, Scarring Stage: stage S; and no ulcer formation. Only the lesions of stage A were observed before treatment. In many patients during the first and second month of treatment, the lesions were stage A or H. It was found that healing of the lesions of tracheobronchial tuberculosis progressed through the stages A, H, and S, in this order. The smear positive rates in sputum were 88.5% in stage A, 12.9% in stage H and 5.0% in stage S. The culture positive rates in sputum were 88.5% in stage A, 20.0% in stage H, and 0% in stage S. We conclude that at least 3 months were generally required for the healing of tracheobronchial tuberculosis with ulcerous lesion. However, it seems that the period of time for healing of ulcerous lesions is shorter in patients who are treated by aerosol therapy with SM.(ABSTRACT TRUNCATED AT 250 WORDS)

Pericarditis

Pericarditis

頸部リンパ節結核をともなった軟口蓋部上皮筋上皮癌の1例

We present a rare case of epithelial-myoepithelial carcinoma (EMC) arising in right side of the soft palate that was accompanied by cervical lymph node tuberculosis.A 72-year-old woman was referred to our hospital because of swelling of the right side of the soft palate. Intraoral examination revealed a submucosal mass lesion measuring 14 × 15mm in the soft palate. Contrast enhanced computed tomography showed a mass on the soft palate and cervical lymph node enlargement with ring enhancement. Magnetic resonance imaging and ultrasonography also revealed cervical lymphadenopathy. Fluorodeoxyglucose positron emission tomography (FDG-PET) showed intense focal FDG uptake in the enlarged lymph nodes, but not in the soft palate. Before surgery, the soft palate lesion underwent a biopsy, and the histopathological diagnosis was EMC. Thus, the enlarged cervical lymph nodes were diagnosed as EMC metastasis. Tumor resection of the soft palate and ipsilateral radical neck dissection were performed. Postoperative histopathological examination revealed EMC of the right soft palate and cervical lymph node tuberculosis. After surgery, antituberculous agents were administered to treat cervical lymph node tuberculosis.

Corticosteroids in the treatment of hepatic tuberculosis: Case report and review of the literature

The role of corticosteroid therapy in addition to anti-tuberculous agents in the treatment of hepatic tuberculosis is unclear. We describe a 54-y-old female with hepatic tuberculosis and worsening hepatitis after initiation of anti-tuberculosis therapy. She experienced considerable clinical improvement and ultimately a complete recovery upon the receipt of adjunctive corticosteroids.

Mycobacterium drug susceptibility testing – an update

Due to the slow growth and relative resistance of mycobacteria to many antimicrobial agents, drug susceptibility testing (DST) has been technically difficult in the past, and is now mostly performed in regional reference laboratories.Currently, phenotypic DST for Mycobacterium tuberculosis is performed using a semi-automated broth culture system under internationally standardised protocols. With rising rates of drug resistance being reported worldwide, all new (and potential relapse) isolates of M. tuberculosis should be tested against first-line anti-tuberculous agents, and should any resistance be detected, representative second line agents should also be tested. DST methods are well established for several other mycobacterial species, but are of limited value in some, especially the M. avium complex (MAC). Recently commercial assays have started appearing that directly detect resistance mutations in M. tuberculosis genes encoding anti-tuberculous drug targets. Advantages and limitations of this approach will be discussed.

Incidence, Clinical and Epidemiological Risk Factors, and Outcome of Drug-Induced Hepatitis Due to Antituberculous Agents in New Tuberculosis Cases

Drug-induced hepatitis (DIH) is an important issue in tuberculosis (TB) treatment. We intend to assess the incidence, risk factors, and outcome of hepatitis due to anti-TB drugs. The study is carried out at the national TB referral center 2006-2008 including all documented new cases of TB. All patients received standard anti-TB treatment. If DIH occurred, all drugs were discontinued and reinitiated after liver function tests (LFT) normalization in a stepwise way. Of total 761 patients, 99 (13.0%) patients developed DIH during anti-TB treatment. There was no difference in sex, nationality, smoking, or opium use history between the hepatitis group and the control group (P > 0.05). DIH was significantly higher in patients older than 65 years (P = 0.019). The mean duration of DIH from the beginning of treatment was 17.53 +/- 19.42 days (median = 12; 1-125 days). Also, the mean of the time elapsed from DIH till the (LFT) normalization was 10.26 +/- 5.95 (median = 9; 0-32 days). Anorexia, nausea, vomiting, abdominal pain, jaundice, diarrhea, decreased level of consciousness, and fever were significantly higher in patients with DIH. In DIH group, 13 patients (13.4%) died, whereas in the control group, death occurred just in 21 cases (3.2%) (P < 0.001, 95% confidence interval = 2.26-9.70, odds ratio = 4.7). After adjusting with logistic regression, all the anticipated factors retained the statistical significance. Our study indicated that DIH most often occurs during the first 2 weeks of anti-TB treatment. DIH development is associated with old age, certain clinical manifestations, and higher death rates.

Nontuberculous Mycobacteria in Solid Organ Transplant Recipients

Nontuberculous Mycobacteria in Solid Organ Transplant Recipients

Laryngeal tuberculosis presenting as a supraglottic carcinoma: a case report and review of the literature

IntroductionLaryngeal tuberculosis used to be a common complication in advanced pulmonary tuberculosis. However, it has become a rare occurrence in developed countries since the introduction of antituberculous agents. Moreover, the pattern of the disease has changed over the years. Nowadays, it more closely resembles a laryngeal carcinoma than any other laryngeal illness.Case presentationWe describe the case of a 50-year-old Caucasian man who presented with the clinical picture of laryngeal cancer, but which turned out to be tuberculosis. We illustrate the difficulty of recognizing laryngeal tuberculosis both clinically and even with radiological examination.ConclusionAlthough laryngeal tuberculosis is uncommon, especially in developed countries, it still occurs and should be considered as a differential diagnosis in any laryngeal disease, in particular in the case of a laryngeal carcinoma.

Successful Antiviral and Antituberculosis Treatment With Pegylated Interferon-alfa and Ribavirin in a Chronic Hepatitis C Patient With Pulmonary Tuberculosis

Pulmonary tuberculosis is a rare side effect of antiviral treatment for chronic hepatitis C. We present the case of 55-year-old woman with chronic hepatitis C, who developed pulmonary tuberculosis after receiving 8 weeks of peginterferon alfa-2a plus ribavirin therapy. Antituberculous treatment was started and antiviral agents were given continually at adjusted doses. Her symptoms of cough with blood-tinged sputum improved 1 month after antituberculous therapy. Treatment for hepatitis C and pulmonary tuberculosis were completed after 6 months. At 6 months after antiviral therapy, a sustained virological response was achieved and follow-up chest radiography showed a marked regressive change. This is believed to be the first case report of complete remission from hepatitis C and pulmonary tuberculosis treated concurrently with antiviral and antituberculous agents.

Multiple mycotic aneurysms due to Mycobacterium bovis after intravesical bacillus Calmette-Guérin therapy

Mycotic aneurysms are exceptional complications after intravesical instillations of bacillus Calmette-Guérin (BCG) for bladder carcinoma. We report a patient who underwent an emergency operation for a ruptured carotid aneurysm 16 months after BCG therapy. Postoperative investigations discovered multiple other synchronous aneurysms. Culture of an abscess surrounding the right carotid artery identified Mycobacterium bovis var BCG. The patient improved clinically with antituberculous agents prescribed for 9 months but died from recurrence of bladder carcinoma 16 months later. A mycotic origin should be evoked when an aneurysm is discovered after BCG therapy. Microbiologic investigation of the artery wall is diagnostic.

Crescentic glomerulonephritis associated with miliary tuberculosis

We report a 70-year-old man who presented with cervical lymphadenopathy, hypercalcemia, and acute renal failure. Lymph node biopsy revealed caseating granulomas. Renal biopsy showed immune complex-mediated diffuse proliferative glomerulonephritis with crescentic formation. Ultrastructural features of the glomerular disease were compatible with the description in infectious glomerulonephritis. Disseminated tuberculosis was diagnosed when sputum, urine, and bone marrow cultures confirmed the presence of Mycobacterium tuberculosis. Successful treatment with antituberculous agents accompanied by recovery of renal function. As far as we know, the association of tuberculosis with glomerulonephritis appears to be exceedingly rare. In addition to describing this case, we also review cases of tuberculosis-associated glomerulonephritis retrieved from the literature.

A Prospective Study of Hepatitis During Antituberculous Treatment in Taiwanese Patients and a Review of the Literature

The present study prospectively investigated the incidence of and factors associated with hepatitis during antituberculous treatment in patients with tuberculosis and various underlying diseases. The results were compared with those of previously published studies. Patients treated with antituberculous agents were enrolled from July 1, 2000 to July 31, 2001, in the divisions of chest and infectious diseases at National Taiwan University Hospital and followed until November 30, 2001. Hepatitis was defined as an aminotransferase level>5 times the upper limit of normal (ULN), or >3 times ULN in the presence of symptoms of hepatitis, or total bilirubin level>3 mg/dL. Studies reporting the incidence of hepatitis during antituberculous treatment were reviewed for comparison. Among 261 patients, median age was 58 years (range, 17-90 years), 17.7% had abnormal baseline liver function tests and 18.4% had concurrent hepatotoxic drug use. Fifteen patients (5.7%) had hepatitis B virus infection, 17 (6.5%) had hepatitis C virus infection, 14 (5.4%) had liver cirrhosis, and 15 (5.7%) had human immunodeficiency virus infection. Hepatitis occurred in 42 patients (16.1%), with 60% of the events in the first 2 months of treatment. Such an incidence was comparable to that in other Asian countries (5.3-18.2%) and slightly higher than that in Western countries (2.4-19%). In multivariate analysis, abnormal liver function tests at baseline and liver cirrhosis were independent factors for development of hepatitis. Elevation of liver function tests was not uncommon during antituberculous treatment, especially in the first 2 months. Patients with abnormal liver function tests at baseline or liver cirrhosis should be closely monitored.

抗結核薬投与患者における皮疹発現に関する研究

It is not uncommon for tuberculosis patients taking 3 or 4 kinds of antituberculous agents long-term to develop adverse effects such as rash or hepatic dysfunction.However,the frequency of rash is unclear because many cases are based on patients' self-reports.The purpose of this study was to clarify the incidence of rash caused by antituberculous agent as well as the relationship between rash and other factors such as other adverse effects,clinical test values and period of taking antituberculous agents until appearance of rash.We conducted a retrospective search of medical records for inpatients with tuberculosis at Tokyo Hospital from October 1,2004 to September 30,2006.There were 266 subjects and rash developed in 100 of them (38%).In most cases,the rash was only mild and easily controlled with antiallergics.However,rash was severe in 26 patients requiring the reduction or discontinuation of antituberculous agents.We noted no difference in rash occurrence rate among prescriptions for antituberculous agents and no relationship between rash and other factors was observed.These results indicate that the frequency of rash caused by antituberculous agents is high and that it is important to judge the severity of each case in order to perform appropriate treatment.

Disseminated BCG infection in patients with urinary bladder carcinoma

Bacillus Calmette-Guërin--a live, attenuated strain of Mycobacterium bovis has been used in immunotherapy of patients with superficial urinary bladder carcinoma. Some patients develop complications after intravesical instillation of BCG: high temperature followed by hematuria or granulomatous prostatits, epidydimoorchitis, urethral obstruction, and less than 1% have a systemic disease followed by dissemination of bacteria into other organs. A 50-year-old man underwent transurethral resection of a bladder tumor. One month after the operation BCG intravesical installations were administered for three weeks. After the fourth installation, our patient developed high fever, fatigue, vomiting, dark urine, light stools, and jaundice. On admission he was jaundiced with a high fever, enlarged liver and spleen and laboratory findings which included high erythrocyte sedimentation rate, pancytopenia, elevated liver enzymes, especially alkaline phosphatase and aminotranspherases. The bone-marrow biopsy showed granulomatous inflamation suggesting mycobacterial spread in the bone marrow, liver and spleen and sepsis. The patient was initially treated with antituberculous therapy, but his state did not improve until corticosteroids were added to the antituberculous treatment regimen. Although dissemination of BCG is a rare complication of intravesical BCG treatment of the bladder carcinoma, it may result in prolonged fever and granulomatous inflamation of the liver, spleen, lungs, bone marrow and BCG sepsis. Antituberclous agents in combination with corticosteroids comprise the treatment of choice for disseminated BCG infection.

Addison's Disease Induced by Miliary Tuberculosis and the Administration of Rifampicin

We herein report a rare occurrence of Addison's disease caused by acute adrenal gland tuberculosis occurring in association with miliary tuberculosis and the administration of rifampicin. An 82-year-old woman with miliary tuberculosis was treated with antituberculous chemotherapeutic agents including rifampicin (RFP), but she still demonstrated general malaise in addition to hyponatremia. Abdominal CT showed an enlargement of the right adrenal gland. However, after discontinuing RFP, the patient's symptoms improved. We carefully reinitiated the administration of RFP. The patient's condition thereafter did not worsen, and the treatment could thus be maintained. It is extremely important to immediately recognize adrenal crisis precipitated by the administration of RFP.

A Once-Weekly R207910-containing Regimen Exceeds Activity of the Standard Daily Regimen in Murine Tuberculosis

R207910 (TMC207 or J) is a member of the diarylquinolines, a new family of antituberculous drugs with high bactericidal activity when given daily in the murine model of tuberculosis. R207910 exhibits a long half-life and thus is a good candidate for once-weekly therapy of tuberculosis. To study the activity of once-weekly R207910 monotherapy and combinations of R207910 with other antituberculous agents (isoniazid, rifapentine, moxifloxacin, and pyrazinamide). The established infection model of murine tuberculosis was used. Colony counts were determined in the lungs. Eight weeks of monotherapy reduced the bacillary load by 3 to 4 log(10) for rifapentine and by 5 to 6 log(10) for R207910 (P < 0.05). The addition of rifapentine and isoniazid or moxifloxacin did not improve the bactericidal activity of R207910 monotherapy. In contrast, the triple combination of R207910 plus rifapentine plus pyrazinamide given once weekly for 2 months (i.e., a total of only eight administrations), was significantly (P < 0.05) more active than R207910 monotherapy or other R207910 combinations, and led to lung culture negativity in 9 of 10 mice, whereas all lungs were culture positive in the groups treated with other drug combinations. Moreover, R207910 plus rifapentine plus pyrazinamide given once weekly was more active than the current standard regimen of rifampin plus isoniazid plus pyrazinamide given five times per week. The unprecedented activity of the triple combination of R207910 plus rifapentine plus pyrazinamide suggests that it may be feasible to develop a fully intermittent once-weekly regimen.

Recent advances in antituberculous drug development and novel drug targets

TB, especially multidrug-resistant TB and extensively drug-resistant TB, is an important global health concern, and the novel development of effective anti-tuberculous drugs is urgently needed. Newly elucidated, critical information on the entire genome of Mycobacterium tuberculosis (MTB) and advances in knowledge regarding various mycobacterial virulence genes are promoting progression in the identification of genes that code for new drug targets. With this background, this review deals with the following areas: first, the future development of new anti-tuberculous drugs is discussed according to the potential pharmacological targets of MTB; and second, a review of the present development status of new anti-tuberculous drugs is conducted, particularly focusing on some promising new anti-tuberculous agents, such as nitroimidazoles, diarylquinolines and oxazolidinones.

Inhibition of M. tuberculosis in vitro in monocytes and in mice by aminomethylene pyrazinamide analogs

Pyrazinamide is unusual among anti-tuberculous agents in its ability to promote a durable cure and shorten the duration of therapy. Yet the basis for this effect is not well understood. A particularly effective strategy for the development of new drugs can be to synthetically manipulate the well-established structures to improve either the spectrum of activity or some pharmacological properties. Similar to previously described aminomethylene amides such as morphazinamide, it was found that novel aminomethylene amides can have in vitro activity at higher than the very acidic pH conditions where pyrazinamide is inactive as well as retaining activity against pyrazinamide-resistant M. tuberculosis. These new compounds have shown an improved anti-tuberculous activity in infected human macrophages relative to pyrazinamide. Compound 1, in combination with rifamycin, was especially effective in both infected human macrophages and in a murine model of infection. The activity of these analogs against pyrazinamide-resistant strains suggests that the development of second generation pyrazinamide analogs may be especially fruitful.

흉쇄 관절에 발생된 결핵성 관절염의 수술적 치료 - 2예 보고 -

Tuberculous arthritis on the sternoclavicular joint is an uncommon disease and a delayed diagnosis can be due to the obscure clinical symptoms. We should suspect tuberculous arthritis in patients with slowly progressive pain, swelling, mild fever and a previous history of tuberculosis. Early diagnosis is important through conducting a thorough physical examination and performing laboratory tests and radiologic study. Tuberculous arthritis on the sternoclavicular joint should be treated with a combination of systemic antituberculous agents and thorough surgical debridement in marked damaged joints. When performing this operation, it is important not only to minimized the injury of the costoclavicular ligament, but also to avoid injury to the surrounding the vital structures such as the mediastinum and pleura after aggressive resection or radical debridement. We describe here 2 cases of the tuberculous arthritis on the sternoclavicular joint: one case had a good result after surgical debridement with using an anti-tuberculous agent, and the other had fatal complications such as mediastinal abscess and pleural effusion after the operation.