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Reactivation of tuberculosis after conversion from azathioprine to mycophenolate mofetil 16 years after renal transplantation.

The incidence of tuberculosis among transplant recipients is greater than in the general population. Mycophenolate mofetil (MMF) is a potent immunosuppressive agent that has become part of most standard immunosuppressive protocols after renal transplantation. We have recently shown that conversion from azathioprine (AZA) to MMF in patients with chronic allograft dysfunction may be beneficial. Here, we report a patient with a history of pulmonary tuberculosis during his childhood. This patient was converted from AZA to MMF therapy 16 years after allogenic renal transplantation because of chronic allograft dysfunction. Two months later, he developed axillary lymph node tuberculosis caused by Mycobacterium tuberculosis. Because he denied contact with infectious persons, we diagnosed reactivation of old dormant tuberculosis. After surgical extirpation, quadruple antituberculous therapy was administered for 3 months (isoniazid, rifampicin, ethambutol, and pyrazinamide), followed by dual therapy for 3 months (isoniazid and rifampicin), and monotherapy for another 3 months (isoniazid). In the follow-up period, he remained asymptomatic with stable graft function. We conclude that MMF therapy in renal allograft recipients may cause reactivation of old dormant tuberculosis, even in the very late posttransplantation period. In these patients, close monitoring and isoniazid prophylaxis may be useful.

Azathioprine↗

Optimal treatment and long-term outcome of tuberculous peritonitis complicating continuous ambulatory peritoneal dialysis.

A retrospective study of the treatment and short- and long-term outcomes of tuberculous peritonitis (TBP) complicating continuous ambulatory peritoneal dialysis (CAPD) among our dialysis patients over a 6-year period was performed. Ten cases of TBP complicating CAPD were identified among 601 dialysis patients between January 1988 and December 1994. There were four male and six female patients. The most common clinical features were abdominal pain, fever, and cloudy peritoneal fluid (PDF). Two patients had concurrent bacterial peritonitis. Extraperitoneal tuberculosis was not observed. The majority of the patients showed neutrophil predominance in the PDF. Only one patient had a positive acid-fast bacilli smear of the PDF. The acid-fast bacilli culture of the PDF was positive in all patients. The patients were treated with isoniazid, rifampicin, and pyrazinamide for 9 to 12 months (mean, 11 months). Continuous ambulatory peritoneal dialysis was continued in all patients. Two patients died, one from multiorgan failure at 2 months and the other from sudden cardiac death at 9 months. Two patients were converted to hemodialysis at 3 months. Six patients continued to receive CAPD after completion of the antituberculous treatment. Four of these six patients were still alive 5 years after the TBP. Three patients were still undergoing CAPD with satisfactory ultrafiltration and solute clearance. None of the patients developed relapse of TBP. We concluded that (1) TBP is a rare but important complication of CAPD, (2) removal of the Tenckhoff catheter is not mandatory in the management of TBP complicating CAPD, and (3) long-term continuation of CAPD is possible after TBP.

Antitubercular Agents↗

[Pulmonary disease caused by Mycobacterium kansasii. Analysis of 39 cases].

OBJECTIVE: To study the epidemiological, clinical, radiological, and microbiological characteristics as well as clinical course and response to treatment of patients with lung disease due to Mycobacterium kansasii. METHODS: All cases of lung disease caused by M. kansasii diagnosed between 1993 and 1998 in Santa Marina Hospital in Bilbao (Spain) were reviewed. RESULTS: The nurse identified 39 cases of lung disease caused by M. kansasii. The incidence in our practice is growing. Most patients were men (97.4%). Mean patient age was 55.9 years. Relevant features of patients' case histories were lung tuberculosis (38.4%), chronic airflow limitation (28.2%) and smoking (87%). Most patients lived in urban settings (94.8%). The most frequent symptoms were cough (87%) and general malaise (72%). Hemoptysis occurred in 31%. Chest images showed mainly a localized alveolar pattern (69%). Cavitation was present in 76.9%. Bacilli were observed in 76.9%. Antibiograms (for 30 cases) showed resistance to the following drugs: rifampicin 3.3%, isoniazid (1 microgram/ml 10%, isoniazid (0.2 microgram/ml 100%, ethambutol 6.6%, streptomycin 90%, pyrazinamide 90%. Eight patients (22% of 36) died; all had severe associated disease. In 33% of the 21 patients with cavitation, closure was not achieved according to follow-up images. Follow-up microbiological tests revealed one case (2.7% of 36 patients) of treatment failure and four cases (15.3% of 26 patients) of relapse. CONCLUSIONS: The number of patients with lung disease due to M. kansasii has increased significantly in recent years in our hospital. The mortality rate in these patients was high, but we believe it is explained by the severity of associated disease. The 15.3% rate of relapse calls for long-term follow-up of such patients.

Adult↗

[Primary Mycobacterium avium respiratory infection in nonimmunocompromised children].

Mycobacterium avium is a common pathogen in barnyards, where it infects poultry and pigs. In human beings M. avium is most often found to cause disease in immunocompromised individuals, although it is also described fairly often as affecting patients with tuberculosis or chronic obstructive pulmonary disease; in recent years lung infections by M. avium have even been reported in elderly women with no underlying disease. Respiratory infection by this mycobacterium is unusual, however, in healthy children. We describe the case of a previously healthy 2-year-old boy with pneumonia whose course was complicated. After 6 months of treatment with various broad spectrum antibiotics there was no clinically or radiologically observable improvement. Other underlying diseases were ruled out, including infection by germs that cause atypical pneumonia. When all tests were negative, we investigated the possibility of primary infection by an atypical mycobacterium. A skin test was positive for M. avium. Acid-alcohol resistant bacilli were isolated from lung biopsy samples and the presence of tuberculoid granulomas were confirmed. Our patient then responded favorably after tuberculostatic treatment with 3 drugs (isoniazid, rifampicin and pyrazinamide).

Anti-Bacterial Agents↗

Treatment of pulmonary tuberculosis.

Recently the duration of treatment for pulmonary tuberculosis in The Netherlands was shortened from nine to six months. A six months regimen containing isoniazid (H), rifampicin (R) and pyrazinamid (Z) daily for two months, followed by H and R daily for another four months (2HRZ/2HR) has been proven effective for the treatment of pulmonary tuberculosis, provided the cause is a fully susceptible strain of M. tuberculosis. Worldwide there is an increase in drug-resistant tuberculosis. Since at the start of treatment susceptibility tests often are not available, a fourth drug must be added in the intensive phase. Ethambutol is the drug preferred. This means that one always starts with 4 drugs unless the patient is a contact of an index-case with proven susceptibility and one is sure that he will be compliant or the patient is infected in the past before 1940, he received never tuberculostatic drugs and one is sure that there is no exogenous reinfection. If the patient has been treated previously and anti-tuberculosis drug resistance is likely, treatment regimens should contain at least two drugs with which he has not been treated before, while a fifth drug routinely must be added in the intensive phase. Amikacin is preferred, since there is no cross-resistance to streptomycin. Consensus on the duration of treatment for extra-pulmonary tuberculosis has not yet been reached, but basically the principles for treatment are the same. This is also true for HIV infected tuberculosis patients. In some serious clinical situations (meningitis, miliary, spine tb) duration of treatment still is 9-12 months. Early involvement of the public health nurse of the municipal health department (GGD) is necessary to ensure patient compliance and treatment supervision.

AIDS-Related Opportunistic Infections↗

Therapeutic isoniazid monitoring using a simple high-performance liquid chromatographic method with ultraviolet detection.

Simultaneous measurement of isoniazid and its main acetylated metabolite acetylisoniazid in human plasma is realized by high-performance liquid chromatography. The technique used is evaluated by a factorial design of validation that proved to be convenient for routine drug monitoring. Plasma samples are deproteinized by trichloroacetic acid and then the analytes are separated on a microBondapak C18 column (Waters). Nicotinamide is used as an internal standard. The mobile phase is 0.05 M ammonium acetate buffer (pH 6)-acetonitrile (99:1, v/v). The detection is by ultraviolet absorbance at 275 nm. The validation, using the factorial design allows one to: (a) test the systematic factors of bias (linearity and matrix effect); (b) estimate the relative standard deviations (RSDs) related to extraction, measure and sessions assay. The linearity is confirmed to be within a range of 0.5 to 8 microg/ml of isoniazid and 1 to 16 microg/ml of acetylisoniazid. This method shows a good repeatability for both extraction and measurement (RSD INH=3.54% and 3.32%; RSD Ac.INH=0.00% and 5.97%), as well as a good intermediate precision (RSD INH=7.96%; RSD Ac.INH=15.86%). The method is also selective in cases of polytherapy as many drugs are associated (rifampicin, ethambutol, pyrazinamide, streptomycin). The matrix effect (plasma vs. water) is negligible for INH (3%), but statistically significant for Ac.INH (11%). The application of this validation design gave us the possibility to set up an easy and suitable method for INH therapeutic monitoring.

Antitubercular Agents↗

Pericarditis as primary manifestation of Mycobacterium bovis SSP. caprae infection.

A 76-year-old white male presented with progressive malaise, weight loss and dyspnea at rest. Echocardiography revealed a circular pericardial effusion and global hypokinesia. Pericardiocentesis showed a purulent exudate and microbiologic examination revealed Mycobacterium bovis fully sensitive to isoniazid, streptomycin, ethambutol, rifampin, and pyrazinamide. By spoligotyping the isolate could be further differentiated to M. bovis ssp. caprae. Antimycobacterial therapy was initiated but 3 weeks later the patient's circulation and renal function deteriorated and he died with clinical signs of sepsis despite intensive care treatment. Pericarditis is a rare manifestation of tuberculosis and can be fatal even when diagnosed and treated appropriately. In low incidence countries diagnosis is often delayed and even overlooked.

Animals↗

[Isoniazid-induced visual hallucinosis].

INTRODUCTION: Isoniazid is the antituberculosis drug that causes psychiatric manifestations most often. Their incidence is nonetheless rare: a review of the literature found only 16 cases. Only one author has reported hallucinosis, defined by isolated sensorial symptoms, and perceptions not believed to be the reality of the object. CASE: We report a case of a 42-year-old woman, a nonsmoker with no particular history and with lymph node tuberculosis. Three weeks after beginning antituberculosis treatment (isoniazid, rifampicin, pyrazinamide and streptomycin), visual hallucinosis and a headache appeared. The symptoms disappeared when Isoniazid was stopped and an anxiolytic drug prescribed. These findings suggest that these effects were due to isoniazid. DISCUSSION: Two mechanisms may explain these psychiatric manifestations: vitamin B6 deficiency or interference between isoniazid and bioamine metabolism.

Adult↗

[Medical-surgical treatment of pulmonary infection with Mycobacterium malmoense].

CASE REPORT: We report the case of a patient with chronic obstructive pulmonary disease in whom pulmonary infection due to mycobacterium malmoense was discovered unexpectedly. A diagnostic and therapeutic surgical resection was performed. CONCLUSION: The non-tuberculous mycobacterium was identified by culture of the specimen. Surgery was followed by empirical antibiotic treatment with rifampicin and pyrazinamide for two and a half months. Isoniazid was withdrawn rapidly on account of hepatitis and the treatment was supplemented later with clarithromycin, leading to a total duration of treatment of seven and a half months. This case is unusual because of its medico-surgical management that led to assessment and appropriate treatment of this infection.

Anti-Bacterial Agents↗

An assessment of a multiplex PCR assay for differentiating clinically important mycobacteria based on pncA gene variation.

The pncA genes in mycobacteria are responsible for the production of pyrazinamidase (PZase). In Mycobacterium tuberculosis, PZase hydrolyses pyrazinamide (PZA) to pyrazonic acid, a compound that possesses bactericidal activity against tubercle bacilli. Nucleotide sequences of pncA genes found within mycobacteria where aligned in an effort to ascertain the significance of any variability in sequence. Three sets of primers (one degenerate and five consensus sequences) were designed and employed in a multiplex PCR assay to amplify the pncA region in seven clinically common mycobacteria. The banding patterns generated from each species in conjunction with PZase activity tests demonstrated that the mycobacterial species examined could be clearly identified and differentiated from one another. Although not yet tested with clinical isolates, the combination of these two assays has provided a promising discriminatory tool for the identification of commonly encountered clinical mycobacteria species.

Amidohydrolases↗

[Treatment of tuberculosis in children].

The treatment of tuberculosis in children has evolved towards a short course regimen based on 6 months therapy with isoniazid and rifampin supplemented during the first 2 months with pyrazinamide in the case of pulmonary tuberculosis due to susceptible organisms. In the presence of adult type tuberculosis (upper lobe infiltration and cavitation) or in case of increased risk of drug - resistant organisms, a fourth drug is added initially. Extra pulmonary tuberculosis is generally treated similarly to pulmonary disease, except disseminated disease and meningitis, which are treated during 9 to 12 months. The treatment of children co-infected by HIV is more complex due to increased risk of drug resistant organisms and by interaction between rifampin and anti-retroviral agents. Concerning latent tuberculosis infection, the association of isoniazid and rifampin for 3 months is recommended. The drug treatment of tuberculosis should be integrated in a global approach comprising the detection of new cases, organisation of the treatment and follow up of the child to ensure the completion of treatment.

Antibiotics, Antitubercular↗

Spectrum of drugs against atypical mycobacteria: how valid is the current practice of drug susceptibility testing and the choice of drugs?

The in vitro activity of 13 drugs against 552 clinical isolates of atypical mycobacteria representing 12 species was performed in 7H11 agar medium at the National Reference Laboratory for Mycobacteria, using the 1% proportion method. All the species tested were resistant to isoniazid and pyrazinamide. In general, clofazimine and D-cycloserine showed the widest spectrum of activity except in the case of Mycobactrium fortuitum and M. chelonei which were resistant to both drugs, and the M. szulgai and M. terrae complex which was resistant to D-cycloserine. The next broad-spectrum drug was ethionamide, followed by ansamycin, rifampin, capreomycin, kanamycin, streptomycin and ethambutol. Among the fluoroquinolones, both ciprofloxacin and ofloxacin were active against M. xenopi, M. gordonae and M. fortuitum whereas M. kansasii and M. gastri were sensitive to ofloxacin only. When the species were listed in respect of the number of drugs to which they were susceptible (less than 10% of resistant strains), they were classified as follows; 7/13 drugs for M. kansasii, M. gastri and M. xenopi; 6/13 for M. gordonae; 5/13 for M. marinum; 3/13 for M. szulgai; 2/13 for M. fortuitum; 1/13 for the M. avium, M. scrofulaceum, M. simiae, and M. terrae complex, and none of the 13 in the case of M. chelonei. These results are discussed in relation to the multiple drug resistance of atypical mycobacteria. We conclude that the critical concentrations of drugs established for M. tuberculosis are not appropriate for atypical mycobacteria.

Antitubercular Agents↗

In vitro antimycobacterial activities of Physalis angulata L.

The HIV-tuberculosis co-infection has caused an impact on tuberculosis epidemiology all over the world and the efficacies of the therapeutic schemes traditionally prescribed in the treatment of tuberculosis, such as isoniazid, rifampicin and pyrazinamide, have decreased due to the appearance of multidrug-resistant M. tuberculosis strains (MDR). This work is part of research on natural antimicrobial agents from plant extracts through bioassay-guided fractionation, by in vitro determination of the minimum inhibitory concentration (MIC) using the microdilution method with Alamar blue oxidation-reduction dye. Crude CHCl3 Physalis angulata extracts and physalin-containing fractions displayed antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium malmoense and Mycobacterium intracellulare.

Humans↗

A pilot study of antituberculosis combinations comparing rifabutin with rifampicin in the treatment of HIV-1 associated tuberculosis. A single-blind randomized evaluation in Ugandan patients with HIV-1 infection and pulmonary tuberculosis.

SETTING: This pilot study was conducted at the Joint Clinical Research Centre (JCRC) in Kampala, Uganda, where tuberculosis (TB) is an epidemic health problem aggravated by the HIV-1 pandemic. OBJECTIVE: To evaluate the feasibility of a larger phase III trial utilizing rifabutin as a substitute for rifampicin in short-course therapy for pulmonary TB. DESIGN: Single-blind randomized trial in 50 patients with new onset smear- and culture-positive pulmonary tuberculosis and HIV-1 infection. Comparison of daily, intermittently supervised 6-month treatment regimens of rifabutin versus rifampicin, together with isoniazid, ethambutol and pyrazinamide. RESULTS: Rifabutin- and rifampicin-containing regimens had comparable efficiency. However, rifabutin-treated patients had significantly more rapid clearance of acid-fast bacilli from sputum at 2 months (P < 0.05, Fisher exact test) and over the entire study period (P < 0.05, logrank test) than rifampicin-treated patients. The presence of cavitary disease was associated with a longer sputum conversion time for patients treated with either regimen. No major adverse events requiring dosage reduction or withdrawal of any study medication were seen in either treatment group. Mean absolute peripheral blood CD4 T lymphocyte counts increased by 28% from week 0 to week 12 in all subjects (334-427/microliters, respectively). An unexpected finding was the isolation of Mycobacterium africanum from 49% of the sputum cultures. This is the first report indicating a high prevalence of M. africanum in human TB in Uganda. CONCLUSION: Short-course antituberculosis regimens containing rifabutin or rifampicin are both safe and efficacious in the treatment of HIV-1 associated tuberculosis. Rifabutin-containing regimens were associated with earlier sputum smear and culture conversion.

AIDS-Related Opportunistic Infections↗

Rapid changes in thyroid function tests upon treatment of tuberculosis.

SETTING: Inpatient service and tuberculosis (TB) clinic of a public hospital. OBJECTIVES: (1) To test the hypothesis that an hepatic effect of antituberculosis drugs increases serum thyroxine-binding globulin (TBG); (2) to resolve conflicting reports on thyroid function in TB. DESIGN: Measurement of serum thyroid hormones, thyroid hormone binding (T3RU) and binding proteins (TBG, transthyretin [TTR] and albumin) in 38 patients with active TB and in 29 healthy tuberculin-positive controls, before and about 10 days into therapy. RESULTS: With therapy of TB (with isoniazid [INH], rifampin [RIF], ethambutol and/or pyrazinamide), TBG increased above control values and T3RU decreased (P < 0.001). These changes were weakly correlated with liver enzyme activities but did not predict clinical hepatitis, which developed in only 1 patient. T3 was initially subnormal in 61% of 38 TB patients, while T4, thyrotropin (TSH) and TBG were normal. T3, TTR and albumin, all negative acute phase reactants, increased towards normal by day 10 (P < 0.001). Thyroid function remained unaltered in 14 control patients taking INH, whereas T3RU decreased (binding increased) and T3 increased in 15 taking INH and RIF (P < 0.001). CONCLUSIONS: TB patients manifest the expected low T3 of non-thyroid illness, but, unlike most sick patients, usually have normal or increased serum binding of thyroid hormones. Chemotherapy further increases binding by increasing TBG, an effect probably due to RIF.

Antitubercular Agents↗

Immune activation, allergic drug toxicity and mortality in HIV-positive tuberculosis.

SETTING: Tuberculosis Treatment Center, Kampala, Uganda. OBJECTIVE: HIV-1 affects outcome in pulmonary tuberculosis (TB). Immune mechanisms triggered by Mycobacterium tuberculosis may lead to increased HIV expression and accelerated disease progression. This study was conducted to correlate serum levels of markers of immune activation with mortality and drug toxicity in HIV + TB. DESIGN: Substudy of a randomized clinical trial of streptomycin-thiacetazone-isoniazid (STH) vs. rifampin-isoniazid-pyrazinamide (RHZ) in HIV + TB. RESULTS: Neopterin > or = 14 ng/ml, TNF-alpha receptors > or = 6.5 ng/ml, and negative skin test were independently associated with increased mortality (P < 0.01). Among STH-treated subjects, dermatologic toxicity and mortality were respectively 13- and 6.3-fold more likely to occur in subjects with elevated neopterin (P < 0.05), although these two adverse events occurred independently. Activation markers increased from baseline after 2 months of therapy with the less rapidly bactericidal STH regimen, whereas they declined in those treated with RHZ, suggesting a relationship with continued mycobacterial replication. CONCLUSIONS: Immune activation in HIV + TB is associated with shortened survival and increased risk of drug toxicity. HIV + TB patients with elevated serum neopterin should be treated with a rapidly-bactericidal drug regimen which does not include thiacetazone.

AIDS-Related Opportunistic Infections↗

Genetic diversity and evidence for acquired antimicrobial resistance in Mycobacterium tuberculosis at a large hospital in South India.

OBJECTIVE: To assess genetic diversity and drug resistance of Mycobacterium tuberculosis isolates collected at Christian Medical College Hospital (CMCH), Vellore, India, between July 1995 and May 1996. MATERIALS AND METHODS: Isolates were subjected to IS6110-based restriction fragment length polymorphism (RFLP) analysis and tested for resistance to isoniazid, rifampin, ethambutol, streptomycin, and pyrazinamide, and DNA from selected strains was sequenced in regions associated with drug resistance. RESULTS: One hundred and one M. tuberculosis isolates were collected from 87 patients with pulmonary tuberculosis. Charts of 69 patients were reviewed for history of tuberculosis illness and treatment. DNA from 29 strains was sequenced in katG, rpoB, and gyrA, and sometimes pncA regions. Analysis by RFLP revealed a high degree of genetic diversity, with no identifiable clusters of infection. Of the strains tested, 51% were resistant to at least one antibiotic, and 43% were resistant to more than one drug. There was a high rate of resistance observed in patients whose charts indicated a history of improperly administered tuberculosis treatment, whereas little drug resistance was observed in patients never previously treated for tuberculosis. Sequencing of genes associated with drug resistance revealed several previously unreported mutations in resistant strains. CONCLUSIONS: This analysis suggests that the cases of tuberculosis in the sample are largely reactivation of long-standing infections and that the drug resistance among patients in CMCH is largely acquired or secondary rather than attributable to the spread of drug-resistant strains.

Antitubercular Agents↗

Preliminary results of an operational field study to compare side-effects, complaints and treatment results of a single-drug short-course regimen with a four-drug fixed-dose combination (4FDC) regimen in South Sulawesi, Republic of Indonesia.

SETTING: Health centres in the South Sulawesi Province, Republic of Indonesia. OBJECTIVES: To compare complaints, side-effects and treatment outcome in new smear-positive patients treated with a single-drug short-course (National TB Programme (NTP)) regimen with those treated with a four-drug fixed-dose combination (4FDC) regimen. DESIGN: A prospective study in which patients are randomly allocated to the NTP or the 4FDC regimen. RESULTS: Preliminary results of the first 360 patients (162 treated with the NTP regimen and 198 with the 4FDC regimen) show that two patients, treated with the NTP regimen, developed jaundice. During the intensive phase of treatment, gastro-intestinal and muscle-joint complaints of any duration and gastro-intestinal complaints lasting for 2 consecutive weeks or more were more frequent in patients treated with the NTP regimen. Sputum conversion was 89% in patients treated with the NTP regimen and 94% in those treated with the 4FDC regimen. Nine-five per cent of patients, both regimens, were cured. CONCLUSION: The results so far show that complaints during the intensive phase of treatment are less frequent among patients treated with the 4FDC regimen. The lower dose of pyrazinamide might be the reason. Treatment results are excellent for both regimens.

Antitubercular Agents↗