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PubMed1986

Long-term follow-up of a clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis. Singapore Tuberculosis Service/British Medical Research Council.

In a study in Singapore, patients of Chinese, Malay, or Indian ethnic origin with sputum-smear-positive pulmonary tuberculosis received 2 months of daily treatment with streptomycin, isoniazid, rifampin, and pyrazinamide followed by daily isoniazid and rifampin, either with or without pyrazinamide, allocated at random. Both regimens were given for a total duration of either 6 or 4 months by random allocation. As previously reported, all 330 patients with drug-susceptible strains of tubercle bacilli pretreatment had a favorable bacteriologic response during chemotherapy, and only 2 (1%) of 158 in the 6-month series, compared with 15 (10%) of 156 in the 4-month series, relapsed bacteriologically during the 30 months after the start of chemotherapy. A long-term follow-up assessment has been conducted 5 to 8 yr after admission to the study. The excellent results in the 6-month series were maintained; only 1 of the 138 patients assessed relapsed after 30 months, compared with 5 of the 131 in the 4-month series. Of 33 patients with bacilli resistant to isoniazid, streptomycin, or both drugs pretreatment, 1 had an unfavorable response during treatment, and none of 9 in the 6-month series and 2 of 22 in the 4-month series relapsed bacteriologically by 30 months, but none of the nine 6-month and eighteen 4-month patients assessed relapsed subsequently.

Adolescent↗
PubMed1987

Diabetic renal hypouricemia.

In diabetes, the serum uric acid level is low due to increased urate clearance; however, its mechanism remains unknown. We examined seven maturity-onset diabetic patients with rarely reported hypouricemia due to renal tubular abnormality to better understand the renal handling of urate by the diabetic kidney. The results of studies indicate that the increase in urate clearance was entirely accounted for by increased pyrazinamide-suppressible urate clearance. The maximal uricosuric response to probenecid administration was exaggerated. The effects of drugs on urate clearance were similar to those we have previously reported in the syndrome of inappropriate secretion of antidiuretic hormone. In four patients, the family survey did not reveal anyone with hypouricemia. These observations suggest that hypouricemia due to hyperuricosuria, which responds markedly to pyrazinamide and probenecid, is actually an indicator of renal tubular abnormality in diabetics.

Adult↗
PubMed1985

[Controlled study comparing 3 daily chemotherapy regimens for six months in pulmonary tuberculosis in routine practice in Algiers. Results at 30 months].

Three anti-tuberculous regimens were compared in Algiers. The three regimens use Isoniazid and Rifampicin every day for six months; two of them used a third drug, Ethambutol or Pyrazinamide for the first three months. The results at 12 months after cessation of chemotherapy have already been reported. At 30 months (or 24 months after the end of treatment) the results were analysed for 513 cases: in 27 cases (5%) there was a relapse or therapy failed. Of 21 relapses 13 occurred in the first six months of follow up, four during the next six months, three during the third and one in the final six months. No further relapse was seen between the thirtieth and forty second months. All the cases of failure or relapse had received an additive chemotherapy. Two patients were on chemotherapy again for a relapse noted in under six months; the other 25 patients had a satisfactory outcome after receiving a regime of six to 12 months containing Rifampicin in 21 cases or a regime 12 months without Rifampicin in four cases. There was no statistically significant difference between the three therapeutic series for those cases with tubercle bacilli initially sensitive to the antituberculous drugs. On the other hand, for primary Isoniazid resistance a third drug is essential during the initial treatment. In the overall analysis pyrazinamide was as effective as Ethambutol in avoiding failure due to primary drug resistance and relapses up to 30 months.

Antitubercular Agents↗
PubMed1984

A controlled trial of 6 months' chemotherapy in pulmonary tuberculosis. Final report: results during the 36 months after the end of chemotherapy and beyond. British Thoracic Society.

Two 6-month regimens of isoniazid and rifampicin supplemented for the first 2 months by streptomycin and pyrazinamide (SHRZ6 regimen), or by ethambutol and pyrazinamide (EHRZ6 regimen), were compared with a 9-month regimen of isoniazid and rifampicin supplemented for the first 2 months by ethambutol (EHR9 regimen). All 444 patients who completed chemotherapy had negative sputum cultures by the end of treatment. Of these, 373 have been followed for a minimum duration of 36 months after the end of chemotherapy. Relapses have occurred in two of 119 SHRZ6 patients, four of 127 EHRZ6 patients and two of 127 EHR9 patients. These results demonstrate that the two 6-month regimens are as effective as the currently recommended 9-month regimen. They are equally well tolerated and have the advantages of being shorter and cheaper. The Research Committee of the British Thoracic Society now recommends the use of either of the two 6-month regimens as an alternative to the currently recommended 9-month regimen.

Antitubercular Agents↗
PubMed1984

[Pharmacokinetics of antitubercular agents in man].

The good results gotten employing short-term (6 months) medication regimes with rifampin, isoniazid and an initial supplement (2 months) of streptomycin and pyrazinamide, gave an impulse to pharmacodynamic research. Some recent studies divided bacterial population into four groups, according to bacterial growth time and they showed that rifampin, isoniazid and streptomycin act on mycobacterial groups continuously or intermittently growing. This fact confirms the validity of employed therapeutic regimens. An other paper considered the trend of hematic levels of streptomycin, isoniazid, rifampin and pyrazinamide. The results of this study showed that the variations observed in hematic peaks were independent from the administered doses and from the administration way. These researches help in solving the most important problems of present tubercular chemotherapy, such the use of a single drug or the therapy interruption.

Absorption↗
PubMed1995

Xylitol-induced increase in the concentration of oxypurines and its mechanism.

We investigated the effect of xylitol on the plasma concentration and the urinary excretion of purine bases, 5-hydroxypyrazinamide and 5-hydroxypyrazinoic acid in subjects who had ingested pyrazinamide (60 mg/kg weight). One liter of 10% xylitol was infused intravenously over 2 hours to 5 subjects to whom pyrazinamide had been administered 10 hours before. Xylitol increased the plasma concentration of uric acid, hypoxanthine and xanthine, the urinary excretion of hypoxanthine and a ratio of lactic acid/pyruvic acid in blood, while it decreased the plasma concentration and the urinary excretion of inorganic phosphate, 5-hydroxypyrazinamide and 5-hydroxypyrazinoic acid. These results suggested that in addition to an increase in purine degradation by xylitol, xylitol-induced increase in the cytosolic NADH inhibited xanthine dehydrogenase activity in the liver and the small intestine.

Administration, Oral↗
PubMed1994

[Effects of antibacterial preparations on growth of Mycobacterium tuberculosis in a model of primary tuberculous infection in tissue culture].

Bactericidal activity of isoniazid, rifampicin and pyrazinamide in different regimens was studied on 120 mouse lung explants infected with H37Rv M. Tuberculosis. An increase in isoniazid concentration and duration of the exposure entails enhancement of its bactericidal activity. A direct correlation exists between the concentration and the exposure. Rifampicin is active mainly within first 30 minutes of its contact with the infected tissue without further augmentation of bactericidal activity with increasing concentrations and exposure. Pyrazinamide bactericidal activity is not high. Its enhancement depends rather on increasing concentrations than on duration of the exposure.

Animals↗
PubMed1994

Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society.

1. A 6-mo regimen consisting of isoniazid, rifampin, and pyrazinamide given for 2 mo followed by isoniazid and rifampin for 4 mo is the preferred treatment for patients with fully susceptible organisms who adhere to treatment. Ethambutol (or streptomycin in children too young to be monitored for visual acuity) should be included in the initial regimen until the results of drug susceptibility studies are available, unless there is little possibility of drug resistance (i.e., there is less than 4% primary resistance to isoniazid in the community, and the patient has had no previous treatment with antituberculosis medications, is not from a country with a high prevalence of drug resistance, and has no known exposure to a drug-resistant case). This four-drug, 6-mo regimen is effective even when the infecting organism is resistant to INH. This recommendation applies to both HIV-infected and uninfected persons. However, in the presence of HIV infection it is critically important to assess the clinical and bacteriologic response. If there is evidence of a slow or suboptimal response, therapy should be prolonged as judged on a case by case basis. 2. Alternatively, a 9-mo regimen of isoniazid and rifampin is acceptable for persons who cannot or should not take pyrazinamide. Ethambutol (or streptomycin in children too young to be monitored for visual acuity) should also be included until the results of drug susceptibility studies are available, unless there is little possibility of drug resistance (see Section 1 above). If INH resistance is demonstrated, rifampin and ethambutol should be continued for a minimum of 12 mo. 3. Consideration should be given to treating all patients with directly observed therapy (DOT). 4. Multiple-drug-resistant tuberculosis (i.e., resistance to at least isoniazid and rifampin) presents difficult treatment problems. Treatment must be individualized and based on susceptibility studies. In such cases, consultation with an expert in tuberculosis is recommended. 5. Children should be managed in essentially the same ways as adults using appropriately adjusted doses of the drugs. This document addresses specific important differences between the management of adults and children. 6. Extrapulmonary tuberculosis should be managed according to the principles and with the drug regimens outlined for pulmonary tuberculosis, except for children who have miliary tuberculosis, bone/joint tuberculosis, or tuberculous meningitis who should receive a minimum of 12 mo of therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

AIDS-Related Opportunistic Infections↗
PubMed1993

[Hepatic toxicity of antitubercular agents. Role of different drugs. 199 cases].

One hundred and ninety-nine cases of hepatic injury related to antituberculous treatment were analysed in order to assess the role played by each drug and to look for predisposing factors. This is a retrospective study of 169 cases reported in the literature and 30 cases reported to the regional pharmacovigilance centre of Paris Saint-Antoine. The mortality rate was related to the dose of isoniazid: it was 43 percent with a daily dose higher than 300 mg, and 9 percent with a daily dose of 300 mg or less (P < 0.001). Hepatic injury appeared significantly earlier in the case of rifampicin combination: 11 weeks without rifampicin and 2 weeks with rifampicin (P < 0.01). The role of pyrazinamide was difficult to determine because isoniazid and pyrazinamide were always used in combination. The influence of a preexisting liver disease could not be evaluated because of the small number of cases reported (8 cases). Alcoholism did not increase the mortality rate. Our results confirm the dose-dependent toxicity of isoniazid. Because of the short time elapsed before the apparent onset of hepatitis observed with the rifampicin combination, a close supervision of the patients should be exerted during the first weeks of treatment.

Adolescent↗
PubMed1995

Pyrazinoic acid decreases peritoneal transfer rates.

It was shown elsewhere that in a peritoneally dialyzed woman with pulmonary tuberculosis, oral treatment with rifampicin and pyrazinamide (11 and 25 mg/kg/day, respectively) caused a decrease in the peritoneal transport of sodium, potassium, urea, uric acid, protein, and ultrafiltration rate by 48% to 75% compared to the pretreatment values. Pyrazinoic acid (PA), a metabolite of pyrazinamide, may account for these changes, because rifampicin was also previously used in this patient without peritoneal function impairment. Thus in the present study the influence of PA on the human peritoneum is examined using the modified Ussing-type chamber. PA (1 mg/dL) was introduced into the medium on the interstitial side of the membrane. After the introduction of PA, uric acid transfer from the interstitial to the mesothelial side decreased by about 50%. There were no significant changes in the urea and albumin transfer rates. In conclusion, PA induces changes in uric acid transfer acting directly on mesothelial cells, whereas a decrease in the peritoneal transfer of other solutes may be caused by a decrease in convective transfer rates due to impaired ultrafiltration.

Albumins↗
PubMed1996

Outpatient management of tuberculosis.

All patients with a positive reaction to the tuberculin skin test should be evaluated for weight loss, night sweats, fever, chronic cough and other signs of active tuberculosis. Chest radiographs should also be obtained in these patients. All converters receiving isoniazid should be examined monthly for signs of hepatitis and neurotoxicity. Liver function tests should be obtained at initiation of isoniazid therapy and again during the first two to four months in patients age 35 or older or with a history of alcoholism, liver disease or intravenous drug use. All cases of active tuberculosis should be reported to the local public health department. Most patients with active tuberculosis should receive isoniazid, rifampin, ethambutol and pyrazinamide daily for two weeks, followed by directly observed administration twice weekly for six additional weeks. If sputum cultures show no resistance after two months of therapy, pyrazinamide and ethambutol may be discontinued, with isoniazid and rifampin taken for an additional 16 weeks. Patients with human immunodeficiency virus infection or acquired immunodeficiency syndrome should receive the initial treatment for at least nine to 12 months, and isoniazid and rifampin for at least six months after culture conversion has occurred.

Algorithms↗
PubMed1997

[Liver injury under tuberculostatic treatment].

We report the case of a patient with nausea, loss of appetite and increase of the aminotransferase levels to eight times the upper normal limit occurring two weeks after she was started on isoniazide, rifampicine and pyrazinamide for treatment of tuberculosis. Isoniazide is the most likely cause of liver injury occurring during combined antituberculosis therapy, whereas pyrazinamide or rifampicine are only rarely responsible. The case presented is used to review and compare the different recommendations concerning the monitoring of patients receiving antituberculous therapy and the clinical management of patients developing liver injury.

Aged↗
PubMed1997

[A case of multiple intracranial tuberculoma diagnosed by open brain biopsy].

To provide histological diagnoses of brain diseases, CT-guided stereotactic brain biopsy (CT-SBB) has been widely used because of its less invasive technique compared with open brain biopsy (OBB). However, CT-SBB is not always diagnostic. We report a case of multiple intracranial tuberculoma whose diagnosis was not made by CT-SBB but by OBB. The patient is a 46-year-old man with insulin-dependent diabetes mellitus who had been receiving immunosuppressive agents (azathioprine, cyclosporin, and prednisolone) after renal transplantation for diabetic renal failure for 9 years. He gradually developed febrile, headache and unsteady gait. Brain MRI demonstrated multiple intracranial lesions involving left fronto-temporal and right parietal lobes, left cerebellar hemisphere, and the fourth ventricle. Although the MRI findings were consistent with those of previously reported cases of intracranial tuberculoma, other conditions, such as malignant lymphoma and toxoplasmosis, were not ruled out. Therefore, CT-SBB targeting the left temporal lobe lesion was done for definitive diagnosis, but it revealed only mild perivascular infiltration of mononuclear cells and hemorrhage. He was transferred to our clinic for further evaluation. On examination, mild truncal and limb ataxia on the left were noted in addition to the neurological findings corresponding to diabetic retinopathy and neuropathy. Despite vigorous laboratory examinations, including repeated bacterial cultures and PCR of cerebrospinal fluid, no evidence of tuberculous infection was obtained. A tentative diagnosis of multiple intracranial tuberculoma was made, and anti-tuberculous drugs (isoniazid 400 mg, ethambutol 750 mg, and pyrazinamide 1.5 g) were administered. Since his symptoms deteriorated because of ventricular dilatation resulting from the enlarged lesion in the fourth ventricle after a temporary clinical improvement, VP-shunting and OBB from the left temporal lobe lesion were done. The excised lesion was firmly encapsulated and the histological examination revealed typical pathology of tuberculoma. Ziehl-Neelsen staining and PCR for Mycobacterium tuberculosis of the biopsied specimen were also positive. Further administration of increased doses of anti-tuberculous drugs (isoniazid 600 mg, ethambutol 500 mg, pyrazinamide 2.0 g and intramuscular injection of streptomycin 0.3 g twice a week) eventually ameliorated the symptoms and shrank the lesions. In case of intracranial tuberculoma, the needle of CT-SBB may not penetrate the firm capsule of tuberculoma and only the surrounding brain tissue may be obtained as in the present case. Therefore, it is recommended to consider OBB from the beginning for definitive diagnosis of intracranial tuberculoma. Paradoxical worsening of the clinical and laboratory findings of tuberculosis in spite of appropriate anti-tuberculous therapy as seen in the present case has been described in both pulmonary and extra-pulmonary tuberculosis. The phenomenon, called transient worsening, could happen and we have to keep it in mind during the treatment of intracerebral tuberculoma.

Antitubercular Agents↗
PubMed1998

Does AIDS impair the absorption of antituberculosis agents?

SETTING: Case reports of low serum concentrations of antituberculosis drugs, with resultant treatment failure and emergence of drug-resistant organisms in patients with the acquired immune-deficiency syndrome (AIDS), have prompted suggestions that therapeutic drug monitoring (TDM) may be indicated in patients co-infected with the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. OBJECTIVE: To test whether the bioavailability of antituberculosis drugs is altered in HIV-infected patients with tuberculosis. METHOD: Twenty-seven hospitalized tuberculosis patients (13 with AIDS, 14 HIV-negative) were entered into a pharmacokinetic trial. Following the supervised administration of standardized doses of isoniazid, rifampicin and pyrazinamide, the plasma concentrations of the drugs were measured repeatedly over 12 hours and the following parameters were derived for each agent: maximum measured drug concentration (Cmax), time-to-maximum measured drug concentration (Tmax) and area-under-the-concentration-time curve to 12 hours (AUC). RESULTS: No significant differences emerged between the two groups in Cmax, Tmax, and AUC for isoniazid and pyrazinamide. For rifampicin the AIDS patients showed a greater AUC (P < 0.01) than the controls, but there were no significant differences in Cmax and Tmax. CONCLUSION: There was no evidence that HIV infection reduced the plasma concentrations of antituberculosis drugs.

Absorption↗
PubMed1992

Influence of cyclosporin A (CyA) on renal handling of urate.

Hyperuricaemia is a frequent side-effect of cyclosporin A (CyA) therapy in renal transplant patients, and gout arthritis is the cause of considerable morbidity among these patients. However, neither the potential predisposing factors nor the mechanisms of hyperuricaemia have been clearly elucidated. It has been reported that hyperuricaemia in patients on CyA is associated with a lowered glomerular filtration rate, or with a reduced urate clearance, due to an increase in the net tubular urate reabsorption or to a decrease in secretion. These conclusions are mostly supported by measurements of the basal clearance rate and fractional excretion of urate, but more precise studies of renal handling of urate by the renal tubule have seldom been performed. The purpose of our study was to investigate the prevalence of hyperuricaemia in our population of renal transplant patients, as well as the risk factors involved. Furthermore, we have evaluated the mechanism of hyperuricaemia by a combined pyrazinamide and probenecid test allowing a better evaluation of urate transport processes than pyrazinamide alone.

Adult↗
PubMedDate not supplied

Neurological manifestations and toxicities of the antituberculosis drugs. A review.

The neurological manifestations and toxicities of 12 antituberculosis drugs [isoniazid, rifampicin (rifampin), ethambutol, p-aminosalicylic acid, pyrazinamide, streptomycin, kanamycin, ethionamide, cycloserine, capreomycin, viomycin and thiacetazone] are reviewed. Their effects upon the central nervous system, cranial nerves, peripheral nerves and the neuromuscular junction are examined, and drug interactions of neurological concern are briefly discussed. Isoniazid is well known to increase the concentrations of gamma-aminobutyric acid in neural tissues. Although conflicting data have been published, isoniazid may play a limited future role in reducing the degree of adventitious movements noted in certain neurological diseases such as multiple sclerosis, spasmodic torticollis, and other segmental dystonic syndromes. With rifampicin neurological complications have been observed infrequently. Rifampicin penetrates into the CSF and has been shown to have useful activity against various micro-organisms in the CSF, including certain viruses; however, contrary to earlier suggestions, it appears to have no role in the treatment of subacute sclerosing panencephalitis. A number of studies have indicated that isoniazid is associated with a large number of accidental and intentional poisonings. The highest incidence has been observed with Southwestern American Indians in which this agent was involved in 7% of all suicide attempts and 19% of the suicide deaths. Degeneration of the optic chiasma and nerve is a well-known adverse effect of ethambutol; toxicity is manifested by impairment of visual acuity, marked loss of colour discrimination, constricted visual fields, and central and peripheral scotoma. Ototoxicity is a well known problem caused by streptomycin, kanamycin, capreomycin and viomycin. The use of streptomycin in pregnant mothers is associated with congenital deafness in newborns in certain cases. The aminoglycoside antibiotics are also associated with flaccid paralysis following neuromuscular blockade. Adverse reactions to cycloserine are mainly dose-related with neurological and psychiatric syndromes noted in up to 50% of patients. Recent data indicate that isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, kanamycin, ethionamide, and cycloserine appear in measurable quantities in the cerebrospinal fluid. Five of these compounds (isoniazid, rifampicin, ethambutol, kanamycin, cycloserine) pass to some degree through non-inflamed meninges. Other than discontinuation of the therapeutic regimen and general supportive measures, very few methods are described in the literature for treatment of acute intoxications with antituberculosis drugs.

Antitubercular Agents↗
PubMed2002

Tuberculous Meningitis in Children.

Initial empiric treatment for central nervous system (CNS) tuberculosis should include four antituberculous drugs until results of cultures and sensitivities are available. Treatment should include isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. Total treatment should extend for 12 months. Daily therapy should be used for the first 2 months, followed by either twice a week treatment or continued with daily therapy for the duration with directly observed therapy (DOT). Pyrazinamide should be included in all treatment regimes for the first 2 months of therapy. Corticosteroids should be used in the management of children with tuberculous meningitis. Corticosteroids have been shown to decrease mortality, long-term neurologic complications, and permanent sequelae. Prednisone is often used at a dosage of 1 to 2 mg/kg per day. Steroids should be used for 4 to 6 weeks, and then tapered over the next 2 to 3 weeks. Cerebrospinal fluid (CSF) cultures and other infected sites must be aggressively pursued in order to obtain an organism for identification and sensitivities testing. Cranial CT scans with contrast should be included in the early diagnostic work-up of a child with suspected CNS tuberculosis infection. Hydrocephalus is often an early finding and may be helpful in establishing the diagnosis of CNS tuberculosis. Treatment of CNS tuberculosis should be for 12 months. All children with CNS tuberculosis should be promptly reported to the local public health department. Public health will facilitate the case-contact study and assist with follow-up and DOT after discharge. Directly observed therapy should be given for the entire treatment course. This is best accomplished with the collaboration of local public health services. Children with tuberculous meningitis should be evaluated in follow-up monthly. Monitoring should include determining adherence to drug treatment, an interval history for signs and symptoms of disease progression, careful physical examinations and evaluation for adverse effects of drugs. Liver function tests should be obtained at baseline, 2-, 4-, 6-, and 8 weeks, and then monthly for the first several months of treatment. Children with tuberculous meningitis should be tested for HIV infection, including pre- and post-test counseling.

Journal Article↗
PubMedDate not supplied

The impact of human immunodeficiency virus on mortality of patients treated for tuberculosis in a cohort study in Zambia.

We have examined the impact of human immunodeficiency virus (HIV) on mortality of patients treated for tuberculosis in a prospective study in Lusaka, Zambia. Patients with sputum smear-positive, miliary, or meningeal tuberculosis were prescribed 2 months' daily streptomycin, thiacetazone, isoniazid, rifampicin, and pyrazinamide followed by 6 months thiacetazone and isoniazid; others, 2 months streptomycin, thiacetazone and isoniazid followed by 10 months thiacetazone and isoniazid. 239 patients (65 HIV-negative and 174 HIV-positive) were followed to 2 years from start of treatment. The crude mortality rate ratio for HIV-positive compared with HIV-negative patients over 2 years was 5.00 (95% confidence interval 2.30-10.86). Median survival for HIV-positive patients from the start of treatment was 22 months. At least 34% of HIV-positive patients for whom cause of death was known died from tuberculosis, three-quarters of these during the first month of treatment. Risk factors for death in HIV-positive patients included multi-site tuberculosis, history of prolonged diarrhoea or fever, oral thrush, splenomegaly, anergy to tuberculin, low weight, anaemia or lymphopenia, and poor compliance with regimens containing rifampicin and pyrazinamide. Tuberculosis, even treated, was a major cause of death in patients with HIV infection.

AIDS-Related Opportunistic Infections↗