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PubMed1999

[Infection by resistant Mycobacterium tuberculosis in a hospital population. A longitudinal study of incidental cases at the Fundación Jiménez Díaz].

OBJECTIVE: Evaluation of epidemiologic, clinical and prognostic characteristics in cases of resistant tuberculosis (MRTB). METHODS: Retrospective longitudinal and observational study of resistant cases of tuberculosis at Fundación Jiménez Díaz (1991-1997). Statistical analysis of conventional tests and significance level at p < 0.05. RESULTS: Twenty patients out of 558 with recovery of Mycobacterium tuberculosis showed resistance to some drugs (isoniazid, rifampicin, ethambutol, streptomycin or pyrazinamide). Information was gathered from 19 patients: eight (42%) HIV-positive patients; eight (42%) with the antecedent of tuberculosis (2 abandoned treatment). There were eleven cases (58%) of secondary resistance and eight of primary resistance but only five (25%) with multi-resistance criteria (1 primary and 4 secondary); five cases showed primary resistance to isoniazid. The number of resistances and HIV seropositivity or antecedent of prophylaxis was not statistically significant. In contrast, the higher number of resistances and tuberculosis antecedent were indeed statistically significant. CONCLUSIONS: There was a low resistance rate at our institution. All multi-resistant cases had antecedents of therapy or prophylaxis abandon or previous tuberculosis. Only one case was MRTB. The relevance of complying with a proper therapy is emphasized (consider therapies directly monitored if there is risk of abandon). In patients with epidemiologic risk factors susceptibility studies should be performed and also start therapy with four drugs. The objective is to decrease the percentages of resistance and morbi-mortality.

AIDS-Related Opportunistic Infections↗
PubMed1999

Tuberculous pleurisy with effusion.

To assess the clinical features of Taiwanese patients with tuberculous pleurisy and their response to treatment, we analyzed the records of patients treated for this condition from December 1990 through November 1995, at a regional 100-bed referral center for tuberculosis care. Diagnosis of tuberculous pleurisy was based on histologic evidence of caseating granulomatous inflammation in the pleural biopsy specimen, or evidence of mycobacteria in pleural fluid. Patients were also stratified on the basis of parenchymal involvement. Ninety-seven patients (79 men, 18 women) with a mean age of 47.5 (range, 15-90) years were included in the analysis. The two major symptoms were cough (69%) and shortness of breath (57%). Chest roentgenographs showed that the pleural effusion was unilateral in 88 (91%) patients, and small to moderate in amount in 74 (76%). Laboratory analysis of the pleural fluid showed moderate levels of glucose (4.6 mmol/L), with no significant difference between patients with and without parenchymal involvement. The levels of lactate dehydrogenase and triglycerides were significantly higher in patients with parenchymal involvement (172 vs 240.5 IU and 0.36 vs 0.45 mmol/L, respectively). In 85 of 93 patients (91%) with available data, lymphocytes were predominant in the differential count. All patients had received short-course chemotherapy for at least 6 months. After excluding the defaulters and patients receiving subsequent management in other hospitals, the overall rate of successful treatment was 97% (72/74). There was no significant difference in the treatment outcome between patients with parenchymal involvement and those without. None of the successfully treated patients had a relapse within a mean follow-up period of 31.7 +/- 18.4 months. We conclude that current patients with tuberculous pleurisy in Taiwan are not young, and short-course chemotherapy with isoniazid, ethambutol, rifampicin, and pyrazinamide is an effective treatment. The presence of parenchymal tuberculous lesions does not appear to influence the treatment outcome.

Adolescent↗
PubMed1999

Unassisted conception with a normal pregnancy outcome in a woman with active Mycobacterium tuberculosis infection of the endometrium. A case report.

BACKGROUND: Tuberculosis of the endometrium is usually associated with infertility. Once a patient is diagnosed with endometrial tuberculosis, she is almost certain to experience infertility; in vitro fertilization and embryo transfer offer the only realistic treatment for tuberculous infertility. We describe one case of unassisted conception with a normal pregnancy outcome in a patient with Mycobacterium tuberculosis infection of the endometrium. CASE: A 34-year-old woman who suffered from 10 years of infertility was investigated in the authors' unit. She gave no significant past medical or surgical history, and initial examinations and investigations were normal. Her husband was 34 years old, and his semen analysis was normal. The patient underwent diagnostic laparoscopy, chromohydrotubation and endometrial biopsy, which showed patency of both fallopian tubes and normal pelvic organs, with no evidence of endometriosis or previous pelvic inflammatory disease. Histologic examination of the biopsied endometrium showed no granulomas; however, culture of the endometrium yielded Mycobacterium tuberculosis. When the patient was called back for antituberculosis chemotherapy, we found that she had become pregnant within one month of the endometrial biopsy. Antituberculosis chemotherapy was commenced at 14 weeks' gestation with rifampicin, isoniazid, pyrazinamide and pyridoxine. The pregnancy remained uneventful, and the patient delivered a normal female infant, 3,380 g at term. Pathologic examination of the placenta was performed, but there were no granulomas or features of chronic inflammation. CONCLUSION: Despite the successful fertility outcome in our patient, we do not think that this case was a challenge to previous concepts of endometrial tuberculosis. In vitro fertilization and embryo transfer are usually the most suitable options for these patients.

Adult↗
PubMed1999

Estimate of the global market for rifampicin-containing fixed-dose combination tablets.

SETTING: Despite WHO and IUATLD recommendations to use fixed-dose combination (FDC) tablets for treatment of tuberculosis, more than 75% of all rifampicin used in the public sector globally is administered as single drug tablets. OBJECTIVE: To estimate the potential global market for rifampicin-containing FDCs in the public and private sectors. DESIGN: The public sector market for FDCs was calculated from the number of tuberculosis cases notified to WHO for 1996 and from information on treatment regimens currently used in each country. The private sector market was calculated from the estimated number of treated tuberculosis cases and the treatment regimens presumed to be used in the private sector. RESULTS: The potential global market for the four-drug FDC tablet (rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg and ethambutol 275 mg) is 305 (90%CI 145-505) million tablets per year, 105 (90%CI 50-160) and 200 (90%CI 95-345) million of which would be distributed in the public and private sectors, respectively. The uncertainty of the estimate remains considerable, as shown by the 90% confidence intervals. CONCLUSION: The study demonstrated a large potential global market for FDCs that should encourage pharmaceutical manufacturers to produce WHO-recommended dosages of FDCs at affordable prices.

Antibiotics, Antitubercular↗
PubMed1999

The WHO simplified study protocol in practice: investigation of combined formulations supplied by the WHO.

SETTING: The benefits of fixed-dose combination (FDC) formulations of rifampicin, isoniazid and pyrazinamide over individual formulations are well recognised. OBJECTIVES: To evaluate the comparative bioavailability of antituberculosis drugs in FDC formulations and the same doses in separate formulations of antituberculosis drugs, using a simplified protocol developed by the World Health Organization (WHO). METHODS: Twenty healthy volunteers were included in the study and evaluated for bioequivalence of rifampicin in a cross-over experimental design. After administration of drugs the plasma concentration of rifampicin and desacetyl-rifampicin was measured repeatedly up to 8 hours in both plasma and urine. Various pharmacokinetic parameters of rifampicin, such as Cmax, Tmax, elimination rate constant, area under the curve (AUC) up to 8 hours and absorption efficiency were calculated. RESULTS: No significant differences were observed between the FDCs and separate formulations when Cmax, Tmax, AUC and absorption efficiencies were compared by parametric test and Hauschke's analysis. CONCLUSION: The WHO simplified protocol is suitable for evaluating bioequivalence of antituberculosis drugs.

Adolescent↗
PubMed1999

Detection of substandard fixed-dose combination tuberculosis drugs using thin-layer chromatography.

SETTING: A convenience sample of 13 fixed-dose combination (FDC) tuberculosis (TB) drugs from 'The Fixed Dose Combination Project' was analysed in laboratories at the University of Botswana and the US Food and Drug Administration (FDA). OBJECTIVE: To determine actual versus stated content of drugs in these FDCs. DESIGN: Chemical analysis was performed using thin-layer chromatography (TLC) as a screening method, and ultraviolet (UV) spectrophotometry or liquid chromatography (LC) as confirmation. FDCs with content outside of 85-115% of stated concentration were defined as substandard. RESULTS: All 13 FDCs contained the stated drugs. However, four (31%) were substandard, including two (15%) with low rifampicin content, one (8%) with excessive rifampicin, and one (8%) with excessive pyrazinamide. Both FDCs with low rifampicin contained four drugs and failed TLC screening. The FDC with excessive rifampicin was not detected by TLC screening. Using UV as the gold standard, the sensitivity of TLC for low rifampicin was 2/2 (100%), and the specificity was 9/10 (90%). CONCLUSION: This study found that 31% of the FDCs in 'The Fixed Dose Combination Project' had substandard content, irrespective of bioavailability. Low rifampicin content, which can be reliably detected by TLC screening, was identified in both four-drug FDC products and is particularly worrisome. TB drugs should be screened for quality using TLC to optimise treatment outcomes and to prevent increases in acquired drug resistance.

Antitubercular Agents↗
PubMed1999

Proposed minimum registration requirements for fixed-dose combination anti-tuberculosis drugs.

Registration requirements for combined pharmaceutical preparations have been published before, but not specifically for fixed-dose combination (FDC) anti-tuberculosis preparations. With tuberculosis being a high priority disease world-wide and concerns being raised over substandard FDC anti-tuberculosis preparations being marketed on a wide scale, specific guidelines for industry seem to be indicated. This is predominantly necessitated by the fact that rifampicin bioavailability can be adversely affected when put in combination with isoniazid and pyrazinamide, and by the need for standardisation of the formulations to only a few essential combinations in order to better control quality. This paper proposes certain minimum requirements to be met when standardising dose in the combinations and when ensuring bioavailability of the preparations. Nine rifampicin-containing combinations are listed as essential. Furthermore, bioavailability testing of the rifampicin component only by a restricted assay protocol of six sample times over 8 hours is advocated, whilst in vitro procedures for other actives in the combination would suffice for registration purposes.

Adult↗
PubMed1999

Structures required, roles and responsibilities in maintaining laboratories for quality assurance of anti-tuberculosis fixed-dose combinations in accordance with the IUATLD/WHO statement.

Combining rifampicin in the same tablet with isoniazid, with or without pyrazinamide, is known to affect the bioavailability of the drug. It is also known that many fixed-dose combination (FDC) preparations exist in the market which are of inferior quality, but are unknowingly used extensively in tuberculosis treatment programmes in low-income countries with high tuberculosis caseloads. This has led to joint statements by the International Union Against Tuberculosis and Lung Disease and the World Health Organization (WHO) pointing out that anti-tuberculosis FDCs should only be used in National Tuberculosis Programmes if the bioavailability of at least the rifampicin component has been demonstrated. Through the FDC Quality Assurance Project launched by the WHO in 1997, a strategy was proposed which aimed to provide specific guidance to ensure the improved quality of such preparations, and in particular the bioavailability of the rifampicin component. A crucial component of drug quality assurance is to ensure that the infrastructure and logistics required to carry out the operational aspects of quality assurance are adequate and sustainable. This paper describes the structures and management responsibilities required to meet this objective, based on general WHO guidelines for the quality assurance of pharmaceuticals.

Antibiotics, Antitubercular↗
PubMed1999

[Commemorative lecture of receiving Imamura Memorial Prize. Studies on prevention and treatment of childhood tuberculosis].

We performed a retrospective analysis of 394 patients who were treated for active tuberculosis (TB) at our hospital from 1976 to 1997. We had started early BCG vaccination campaign in Osaka Prefecture from 1995 and the coverage of BCG vaccination in infants rose up to about 90%. From that experience, we studied the current situations and measures on prevention and treatment of childhood tuberculosis. Pulmonary TB in children is successfully treated with 6-month standard short-course chemotherapy using isoniazid, rifampin, and pyrazinamide daily for 2 months, followed by isoniazid and rifampin daily for 4 months. Prognosis of childhood tuberculous meningitis (TBM) is poor, early diagnosis and prevention of TBM is important. In order to promote TB control and eliminate childhood TB, especially in infants, the following is necessary; 1) early detection and treatment of adult TB patients, source of infection, 2) prompt and appropriate contact examination and chemoprophylaxis, 3) BCG vaccination during early infancy, 4) protection from MDR-TB are most important.

Adult↗
PubMed1999

[Phantom thoracic opacity].

The etiology of the respiratory distress syndrome is dominated by pulmonary edema and the septic shock. We report a rare etiology of a respiratory distress secondary to a rupture of a well treated tuberculous latero-tracheal adenopathy. A 24-year-old woman was treated a year ago for a peripheral and mediastinal lymph node tuberculosis confirmed by the biopsy of a left supra clavicular adenopathy, by two months of isoniazid-rifampicin-pyrazinamide-ethambutol and seven months of isoniazid-rifampicin. The patient completed 9 month treatment with a good clinical and radiology course. Two months after stopping the antibacillary treatment, the patient was admitted to an intensive care unit with a respiratory distress syndrome requiring both intubation and artificial ventilation. The bronchial aspiration brought back plain pus. The telethorax from admission was normal and the retrospective history suggested the diagnostic of a ganglio-bronchial fistula which was confirmed by bronchial fibroscopy demonstrating right latero-tracheal fistula. The course was good with recovery of consciousness on the seventh day. Direct bacilloscopies and culture were negative. The digestive fibroscopy was normal. Finally, fistulization of a tuberculous adenopathy must be considered among the etiologies of respiratory distress even in a patient appropriately treated for mediastinal lymph node tuberculosis.

Acute Disease↗
PubMed1999

[Phlyctenular keratoconjunctivitis and lymph node tuberculosis].

It is presented 28 cases of tuberculous keratoconjunctivitis from which 13 cases appears between 4-13 years at children with primary tuberculosis. All patients have a positive tuberculin skin test, a family or personal history of tuberculosis. Many of them have perihilar or cervical adenopathy and radiological evidence of a healed pulmonary tuberculous lesion. We report a case of tuberculous adenopathy with histopathological examine and tuberculous adenopathy with histopathological examine and tuberculous keratoconjunctivitis. Anti-tuberculous treatment was with isoniazid, pyrazinamide, rifampicin in cases with primary tuberculosis. The rest of patients was treated with topical medicine.

Adolescent↗
PubMed2000

Molecular determinants of drug resistance in tuberculosis.

Rapid detection of drug-resistant tuberculosis (TB) has become increasingly important in the era of pandemic human immunodeficiency virus infection and antibiotic resistance. The identification of the molecular correlates of antibiotic resistance in Mycobacterium tuberculosis have engendered the development of DNA-based assays for the identification of drug-resistant TB. This review summarizes the recent discoveries concerning resistance to isoniazid, rifampin, pyrazinamide, ethambutol, streptomycin, amikacin, kanamycin and the quinolones.

Antitubercular Agents↗
PubMed2000

Using treatment failure under effective directly observed short-course chemotherapy programs to identify patients with multidrug-resistant tuberculosis.

SETTING: Public ambulatory care centers in three districts of northern metropolitan Lima, Peru. OBJECTIVE: To document drug resistance patterns of isolates of Mycobacterium tuberculosis from patients identified as treatment failures under a model tuberculosis (TB) control program based on directly observed, short-course chemotherapy (DOT-SCC). DESIGN: Case series. RESULTS: In a referred, consecutive sample of 173 patients identified as treatment failures on DOT-SCC, 160 (92.5%) had culture-positive TB. Of those 160, 150 (93.8%) had active, pulmonary multidrug-resistant TB (MDR-TB, resistance to at least isoniazid [INH] and rifampicin [RIF]). Sixty of the 150 (40.0%) had isolates resistant to at least INH, RIF, ethambutol (EMB) and pyrazinamide (PZA), the initial first-line empiric treatment regimen used locally. Forty-four (29.3%) had isolates resistant to at least INH, RIF, EMB, PZA and streptomycin (SM), the first retreatment regimen. This series of patients had isolates resistant to a mean of 4.5 of the ten drugs tested. The local profile of multidrug resistance is very different from that obtained from national data from Peru. CONCLUSION: In this setting, treatment failure on DOT-SCC is strongly predictive of active MDR-TB. Because of existing local drug resistance patterns in northern Lima, 89.3% of MDR-TB patients identified as treatment failures will receive ineffective therapy with two or fewer secondary TB drugs if they are given the five-drug empiric retreatment regimen endorsed by the World Health Organization. Further short-course chemotherapy for these patients would only serve to amplify ominous existing drug resistance patterns.

Antitubercular Agents↗
PubMed2000

Rifapentine and isoniazid in the continuation phase of a 6-month regimen. Interim report: no activity of isoniazid in the continuation phase.

SETTING: Clinical trial amongst 762 patients with newly diagnosed pulmonary tuberculosis in Hong Kong. After an initial 2 months of a four-drug intensive phase consisting of streptomycin, isoniazid, rifampicin and pyrazinamide (SHRZ), a random allocation in continuation to once-weekly rifapentine + isoniazid (HRp1), HRp1 given in 2 of every 3 weeks (HRp1.2/3), or to three times weekly isoniazid + rifampicin (HR3). OBJECTIVE: Interim report evaluating progress of study and the role of isoniazid in the continuation phase. METHODS: Kaplan-Meier analysis and response of patients related to susceptibility of pretreatment organisms to isoniazid and to rate of isoniazid acetylation determined by NAT2 genotyping. RESULTS: In the 30-month follow-up, rates for adverse treatment events (failure and relapse) were 4.2% in the HR3, 10.2% in the HRp1 and 11.2% in the HRp1.2/3 series (P = 0.02 for HR3 vs HRp1 and P = 0.01 for HR3 vs HRp1.2/3). Occurrence of adverse events was not related to initial susceptibility to isoniazid nor to the rate of acetylation of isoniazid. CONCLUSIONS: The two rifapentine regimens had similar final rates of adverse events which were unsatisfactory. Isoniazid had little or no activity in the continuation phase, indicating that no improvement of the continuation regimen is likely to be obtained by alteration of the isoniazid dosage.

Acetylation↗
PubMed1999

Serum pharmacokinetics of antimycobacterial drugs in patients with multidrug-resistant tuberculosis during therapy.

Serum samples of 13 patients with multidrug-resistant tuberculosis were taken 0, 1, 2, 4, 8 h after administration of antimycobacterial drugs for assay of levels in order to gain further insight into their basic pharmacokinetics. The drugs assessed were amikacin, kanamycin, ofloxacin, levofloxacin, para-aminosalicylic acid, prothionamide, cycloserine, pyrazinamide and ethambutol. Techniques used for assay were reversephase high-performance liquid chromatography, gas liquid chromatography and fluorescent polarization immunoassay. The results from 12 patients were evaluated. These provided new pharmacokinetic data on high-dose levofloxacin, cycloserine and prothionamide given once daily, and could be useful in guiding the scheduling of drugs. The data obtained might also lead to insights into the development of therapeutic drug monitoring in multidrug-resistant tuberculosis.

Adult↗
PubMed2000

The impact of HIV infection on recurrence of tuberculosis in South African gold miners.

UNLABELLED: DESIGN AND OBJECTIVES: Potential risk factors for recurrence of tuberculosis (TB) were investigated in a retrospective cohort study of 305 human immunodeficiency virus (HIV) positive and 984 HIV-negative South African gold miners treated for TB with directly-observed, rifampicin-based regimens. Standard treatment changed from rifampicin, isoniazid and pyrazinamide (RHZ) to RHZ plus ethambutol (RHZE) during the study period. RESULTS: Recurrence occurred in 37 HIV-positive and 46 HIV-negative men. HIV infection was associated with a significantly higher recurrence rate (8.2 vs 2.2 per 100 person-years; multivariate-adjusted incidence rate ratio [IRR] 4.9, 95% confidence interval [CI] 3.0-8.1), as were post-tuberculous scarring (multivariate-adjusted IRR 1.6 for one or two scarred lung zones, 4.0 for three or more zones; test for trend P < 0.001) and drug resistance (multivariate-adjusted IRR 2.7, 95%CI 1.01-7.4). The recurrence rate was significantly higher following treatment with RHZ than RHZE (multivariate-adjusted IRR 2.1, 95%CI 1.1-4.0). The difference between regimens needs to be interpreted with caution, however, as allocation was not randomised. CONCLUSION: The high recurrence rate among HIV-positive men requires further investigation to distinguish relapse from re-infection as the predominant cause, leading to consideration of further intensification of the initial regimen or use of secondary prophylaxis.

AIDS-Related Opportunistic Infections↗
PubMed2000

[Fulminant liver failure caused by antitubercular drugs. Report of a clinical case].

The incidence of tuberculosis has grown seriously in the last ten years and so have the risks due to drug toxicity of Ethambutol, Isoniazid, Pyrazinamide, Rifampicin. One of the questions is whether a careful monitoring of liver function during anti-tubercular chemotherapy could be useful, given that once severe organ toxicity initiates the survival rate remains under 10% if organ transplant is not available. International literature shows a clear prevalence of this event in Asiatic populations which are now well represented in Italy owing to incoming migrations. A case of fulminant hepatitis in a young Chinese man under treatment for TBC arrived at our ICU with a drug-induced acute hepatitis is reported.

Adult↗
PubMed2000

[Tuberculosis management unit: 7-year experience].

Between January 1992 and December 1998 we collected clinical, epidemiological and treatment data on all patients diagnosed of tuberculosis in our specialized unit. Five hundred sixty-seven patients (70% male and 30% female) were studied prospectively. The rate of new cases increased until 1995 and decreased during the last three years of study. Mean patient age was 38.8 years, with nearly 64% of patients under 45 years of age. Predisposing disease, mainly chronic alcoholism, was present in 36%. Fifteen percent belonged to a high-risk social group (6.5% were drug addicts and 6.3% lived inside secure institutions). The mean time elapsing from the appearance of symptoms until referral to our service was 80.4 days and the most common clinical picture at presentation was general unwellness with cough and expectoration (46%) followed by hemoptysis (18%). Cavitation was visible in 48.5% of x-rays, while alveolar infiltrates were seen in 33%, pleural effusion in 12% and lymph node involvement in 10%. Adult tuberculosis was diagnosed in 80% of cases, 10% were reactivations and 9% were primary. Bacteriological diagnosis was available for 85%. Therapy usually involved six months with hydrazide, rifampicin and pyrazinamide (81%). Therapy was generally well-tolerated, although analyses revealed some anomalies, such as transaminase alteration (18%) and hyperuricemia (19%). Therapy was changed because of toxicity in only 2.6%. Follow-up after therapy was strict and the rate of successful cure was 97.5%. We conclude that diagnosis was not prompt enough and believe that knowledge of epidemiological, clinical and evolutionary data, as well as monitoring of real rates of cure of treated patients justifies the existence of specialized centers for managing tuberculosis.

Adult↗