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PubMed2002

Risk factors for hepatotoxicity associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection: experience from three public health tuberculosis clinics.

SETTING: Three municipal tuberculosis (TB) clinics. OBJECTIVES: Reports of liver injury in patients treated with a 2-month regimen of daily rifampin and pyrazinamide (2RZ) for latent TB infection have raised concern about its safety. We aimed to evaluate the safety and tolerability of 2RZ and identify risk factors for hepatotoxicity. METHODS: We reviewed charts of adults started on 2RZ between 1999 and 2001. Cases with grade 3 hepatotoxicity (AST or ALT >5.0-20.0 x upper limit of normal) and grade 4 hepatotoxicity (AST or ALT >20.0 x upper limit of normal) were identified. RESULTS: Of 148 patients prescribed 2RZ, 85 (57.4%) completed therapy. Grade 3 or 4 hepatotoxicity occurred in 14 patients (eight grade 4 cases). In multivariate analysis, hepatotoxicity was associated with female sex (odds ratio [OR] 4.1; 95% confidence interval [CI] 1.2-14.3) and with presumed recent infection (recent tuberculin skin test conversion or contact with a TB case) (OR 14.3; 95%CI 1.8-115), but not with alcohol use, illicit drug use, age, race, or pyrazinamide dose. CONCLUSIONS: Hepatotoxicity occurred in a high proportion of patients prescribed 2RZ, and was more common among females and those with recent infection. Caution is warranted in using 2RZ in populations where its safety has not been established.

Adolescent↗
PubMedDate not supplied

The pharmacokinetic factors and bioavailability of rifampicin, isoniazid and pyrazinamid fixed in one dose capsule.

A study was performed at the National Tuberculosis and Lung Diseases Research Institute (NTLDRI) in Warsaw according to the protocol by the Ethics Committee of the Institute. The main target of the mentioned study was a comparison of the bioavailability of rifampicin. isoniazid and pyrazinamid fixed together in one capsule with the bioavailability of the same doses of these drugs, which were given separately. The absorption of rifampicin, isoniazid and pyrazinamid were tested after oral administration of each drug in free simultaneous combinations and in a fixed-dose combination of three drugs--Trifazid. The study was carried out as an open randomised crossover experiment comprising 16 volunteers. The results have shown that the pattern of absorption, plasma concentrations and pharmacokinetic parameters were found to be very similar after administration of the drugs in free and fixed combinations. The triple combination of antituberculosis drugs could replace the separate drugs in the treatment of tuberculosis.

Adult↗
PubMed2003

Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection--United States, 2003.

CDC has reported previously surveillance data of severe liver injury in patients treated for latent tuberculosis infection (LTBI) with a daily and twice-weekly 2-month regimen of rifampin with pyrazinamide (RZ). On the basis of these initial reports, CDC cautioned clinicians in the use of this therapy with advised additional monitoring. To estimate the incidence of RZ-associated severe liver injury and provide more precise data to guide treatment for LTBI, CDC collected data from cohorts of patients in the United States who received RZ for the treatment of LTBI during January 2000-June 2002 and for whom data were reported to CDC through June 6, 2003. This report summarizes the analysis, which found high rates of hospitalization and death from liver injury associated with the use of RZ. On the basis of these findings, the American Thoracic Society (ATS) and CDC now recommend that this regimen should generally not be offered to persons with LTBI. The revised ATS/CDC recommendations described in this report have been endorsed by the Infectious Diseases Society of America (IDSA). Clinicians are advised to use the recommended alternative regimens for the treatment of LTBI. Rifampin and pyrazinamide (PZA) should continue to be administered in multidrug regimens for the treatment of persons with active tuberculosis (TB) disease.

Antitubercular Agents↗
PubMed1990

Short-course chemotherapy for pulmonary tuberculosis with a rifampicin-isoniazid-pyrazinamide combination tablet.

The effectiveness of a tablet containing a combination of rifampicin, isoniazid and pyrazinamide (Rifater; Mer-National) in the treatment of pulmonary tuberculosis was examined by comparing it with a previously evaluated four-drug regimen. Of 150 black goldminers with a first case of pulmonary tuberculosis, 69 were randomly allocated to receive the combination tablet (RHZ), 5 tablets per day on weekdays for 100 treatment-days, and 81 the four-drug regimen (streptomycin, rifampicin, isoniazid and pyrazinamide) (RHZS). Non-compliance was detected in 42% of the RHZ group and in 16% of the RHZS group. Two patients in the RHZ group and 4 in the RHZS group had to have their treatment altered because routine investigations revealed drug-resistant mycobacteria. Treatment was unsuccessful in 10 patients in the RHZ group, with 4 men failing to complete the regimen and being lost to follow-up, 3 cases of failure of conversion of sputum on the regimen, and 3 relapses. The results for the RHZS group were similar, with 4 failures to complete the regimen, 2 treatment failures and 4 relapses. Evaluation of RHZ showed it to be comparable with a previously evaluated, successful short-course regimen (RHZS). The high incidence of non-compliance probably reflects reduced supervision of this wholly oral regimen.

Adult↗
PubMed1990

Pharmacokinetics of pyrazinamide and its metabolites in patients with hepatic cirrhotic insufficiency.

The pharmacokinetics of pyrazinamide (Pirilène) and its metabolites are evaluated in ten subjects with hepatic insufficiency, after an oral dose of 19.3 +/- 0.6 mg.kg-1 and the results are compared to those of a group of nine healthy subjects (control group). The results exhibit a marked reduction of the pyrazinamide total clearance (0.48 vs 0.84 ml.min-1.kg-1) and an increase in half-life from 9.19 h to 15.07 h in the patients group. The area under the curve of pyrazinoic acid (the main metabolite) is increased from 97 to 280 mg.h.l-1 with a half-life twice as much as that of the control group. The hepatic insufficiency entails a marked reduction of the common posology as well as a closer survey of the biologic hepatic parameters and of uric acid the renal elimination of which is inhibited by pyrazinoic acid.

Adult↗
PubMed1989

[Therapeutic trial of a combination of isoniazid, rifampicin and pyrazinamide in the first 2 months of treatment of pulmonary tuberculosis].

250 patients suffering from smear positive pulmonary tuberculosis who had never been treated before, received a six-month regimen combining isoniazid and rifampicin every day with a supplement of pyrazinamide for the first eight weeks of treatment. The three drugs given during the initial phase of therapy were administered in two different forms: either as separate tablets or in a form combining all three drugs in fixed proportions (each tablet contained 50 mg of isoniazid, 120 mg of rifampicin and 300 mg of pyrazinamide). The patients were randomised into two groups of 125 receiving one or other combination of medications with the dose adapted for their weight. An analysis of the results at the end of the second month of treatment was carried out on 240 cases who could be analysed for tolerance and acceptability and in 193 cases who were analysed for the efficacy of therapy as judged by negative cultures. The treatment results were excellent in both groups, as was patient acceptability. The level of side effects was significantly lower in the group receiving combined medication (p less than 0.02). Both groups gave a similar proportion of negative cultures at the end of two months. The combined medicaments studied are thus well tolerated and at least as effective as individual drugs. They may thus replace them.

Adolescent↗
PubMed1989

[Short-term therapy of lung tuberculosis using a fixed combination of isoniazid, rifampicin and pyrazinamide. Results after 2 years].

Treatment of tuberculosis should be as short and as simple as possible in order to improve patient compliance; and combinations of at least three drugs should be used in order to kill the different populations of mycobacteria and to avoid development of drug resistance.--In a controlled multicentre study two regimens were compared in 93 patients with newly-diagnosed pulmonary tuberculosis: 1) Six-month therapy (47 cases): Daily rifampicin and isoniazid, supplemented with pyrazinamide for the first 2 months. A tablet with a fixed combination of 120 mg rifampicin, 50 mg isoniazid and 300 mg pyrazinamide (Rifater) was used. 2) Present Swiss standard therapy (46 cases): Daily rifampicin, isoniazid and ethambutol for 2 months followed by rifampicin and isoniazid for 7 months.--The time-course of culture negativation and the frequency of adverse events were similar in the two groups. During a follow-up period of at least two years only one relapse was observed in the six-month regimen, 3 months after completion of treatment. This was one of three patients with pretreatment resistance to isoniazid. Nevertheless, two of them were cured with the six-month regimen containing Rifater.--Patient compliance, assessed during outpatient treatment by detecting isoniazid metabolites in the urine, was very good (93% of tests were positive in each group).--These results with a follow-up of more than 2 years, indicate that short-course therapy of 6 months duration with the fixed combination tablet may be recommended as treatment of choice in pulmonary tuberculosis except in cases of isoniazid resistance and other special situations (i.e. large cavitations, large number of viable bacilli).

Adult↗
PubMedDate not supplied

[Pharmacokinetic study of pyrazinamide and pyrazinoic acid in subjects with normal renal function and patients with renal failure].

The main pharmacokinetic parameters of pyrazinamide and pyrazinoïc acid (its major metabolite) were determined after oral administration of 1,500 mg/d in 10 patients with normal renal function and of 1,000 mg/d in 10 patients with impaired renal function (renal insufficiency). This study shows that, with these dosage regimens, almost all the pharmacokinetic parameters are identical for pyrazinamide and pyrazinoic acid in patients with normal renal function and patients with impaired renal function. Comparison of results between patients allows us to propose a dosage regimen of 1,000 mg/d as maintenance in patients with renal insufficiency.

Humans↗
PubMed1989

Hypouricemia due to familial isolated renal tubular uricosuria. Evaluation with the combined pyrazinamide-probenecid test.

A Jewish Iraqi woman with familial isolated renal tubular uricosuria, urate clearance of 60.5 +/- 5.7 ml/min and hypouricemia of 1.0 +/- 0.2 mg/dl is described. The combined pyrazinamide-probenecid test suggested a presecretory defect in urate reabsorption. Four offspring were moderately affected. This family represents the sixth Jewish Iraqi family with familial isolated presecretory uricosuria, and emphasizes the marked prevalence of this disease among the Iraqi Jewish population. Since the inheritance of the presecretory defect is autosomal recessive, we suggest that this family is an example of pseudodominant transmission. The combined pyrazinamide-probenecid test may cause a reduction in glomerular filtration rate and filtered load of urate and thereby affect urinary excretion rate of urate in patients with urate wasting.

Creatinine↗
PubMed1988

Pyrazinamide and rifampicin regimens for patients on maintenance dialysis.

We measured pyrazinamide and rifampicin plasma concentrations in five patients with pulmonary tuberculosis and end stage renal failure treated by haemodialysis or continuous ambulatory peritoneal dialysis. Using conventional daily doses of oral pyrazinamide and rifampicin, we found that the drugs were removed efficiently by both dialysis methods, so that plasma levels were sub-optimal for maximal bactericidal action. These findings suggest that in patients with tuberculosis on maintenance dialysis, treatment should be either with higher doses of these two drugs, or with additional replacement doses given after each dialysis. Further detailed pharmacokinetic studies on larger numbers of patients are indicated.

Adolescent↗
PubMed1987

Clinical pharmacokinetics and metabolism of pyrazinamide in healthy volunteers.

Eight healthy volunteers were treated with a single dose of pyrazinamide 35 mg/kg. The aim of the study was to evaluate the pharmacokinetic profile of the product and of its metabolites. Urine and blood samples were collected till the 60th h. The kinetics of pyrazinamide could be characterized as follows: CPmax = 50.1 micrograms/ml, tmax less than 1 h, t1/2 alpha = 3.2 h, t1/2 beta = 23 h, U(0-60 h) = 1.6% of the dose administered. The kinetics of the main metabolite, the pyrazinoic acid, gave the following values: CPmax = 66.6 micrograms/ml, tmax = 4 h, t1/2 beta = 12.3 h, U(0-60 h) = 37.5%, of the administered dose.

Adult↗
PubMed1968

Toxicity of pyrazinamide, administered once weekly in high dosage, in tuberculous patients.

The success of a twice-weekly regimen of streptomycin plus isoniazid, reported earlier from the Tuberculosis Chemotherapy Centre, Madras, prompted an investigation at the Centre of various once-weekly regimens of chemotherapy. In this context, a pilot study was undertaken in 19 patients to assess the toxicity of high-dosage pyrazinamide (70 mg/kg of body-weight), when administered once weekly, together with isoniazid (14 mg/kg of body-weight) and streptomycin (1 g), for at least 6 months. Serial estimations of SGOT and SGPT activity, urine tests for urobilin and bilirubin and haematological investigations were undertaken at frequent intervals. None of the patients showed any clinical evidence of hepatotoxicity; however, there was a slight and transient elevation in aminotransferase activity, probably of a non-specific nature, at 2 weeks. These findings are encouraging for the use of high-dosage pyrazinamide in once-weekly regimens of chemotherapy.

Adult↗
PubMed1980

[Toxicity of pyrazinamide in antituberculous treatments (author's transl)].

Pyrazinamide, an antituberculous drug discovered in 1952, was first considered as a toxic drug. As it appeared as a bactericidal drug for the organisms inside macrophages, its usefulness has been re-appraised. In combination with other bactericidal drugs, it contributes to speed up the sterilization of tuberculous lesions. A review of the more recent clinical trials allows to assess the real toxicity of Pyrazinamide. Prescribed at a daily dosage of 30 to 35 mg/kg (1,5 to 2 g daily), it gives no major side effects.

Chemical and Drug Induced Liver Injury↗
PubMedDate not supplied

Hepatotoxicity after a short course of low-dose pyrazinamide.

We report on a patient who developed extensive centrolobular liver necrosis after a treatment with low-dose (25 mg/kg/d) pyrazinamide for only 4 weeks, combined with rifampicin, 600 mg/d). In the past, the patient already developed severe aminotransferase elevations under isoniazid treatment. After prompt withdrawal of the drugs, a gradual decline of the aminotransferases was observed. No signs of hepatic failure developed. Pyrazinamide has to be used with caution, even in low-dose, especially when combined with rifampicin.

Adult↗
PubMedDate not supplied

[Hepatic functional changes induced by the combined use of isoniazid, pyrazinamide and rifampicin in the treatment of pulmonary tuberculosis].

Antituberculosis therapy commonly used for pulmonary tuberculosis in Brazil include isoniazid (440 mg), rifampicin (600 mg) both for six months plus pyrazinamide (2 g) together in the first two months. Such therapy may induce acute or chronic liver damage in some individuals. The purpose of this study is to evaluate 1096 patients treated with antituberculous drugs, being 773 males and 323 females. Clinical and laboratory signs of hepatic cell injury was present in 66 patients. Serum bilirubin and transaminase levels were evaluated in 21 (31.81%) and 45 (68.19%) respectively, with a female preponderance. Early return to normal values occurred more frequently among alcoholic drinkers and non-cigarette smokers. Liver injury was characterized as being mild and moderate and the type of injury associated was represented by pure cholestasis and hepatocanalicular lesions. Probably, rifampicin is the drug responsible for this kind of evolution aggravating the hepatotoxicity induces by isoniazid and pyrazinamide.

Adult↗
PubMed1998

Bioavailability of rifampicin, isoniazid and pyrazinamide from fixed-dose combination capsules.

SETTING: The absorption of rifampicin, isoniazid and pyrazinamide was tested after administration of each drug in free combinations and in a fixed-dose combination of the three drugs, known as Trifazid. OBJECTIVE: To examine the relative bioavailability of rifampicin, isoniazid and pyrazinamide after oral administration of the drugs given alone in comparison to that of the same drugs after administration of Trifazid. DESIGN: An open, randomized, cross-over study comprising 16 healthy volunteers. RESULTS: The pattern of absorption, plasma concentrations and pharmacokinetic parameters were very similar after administration of the drugs in free and fixed combinations. CONCLUSION: The triple combination of antituberculosis drugs could replace the separate drugs in the treatment of tuberculosis.

Administration, Oral↗
PubMed2001

Serial counts of Mycobacterium tuberculosis in sputum as surrogate markers of the sterilising activity of rifampicin and pyrazinamide in treating pulmonary tuberculosis.

BACKGROUND: Since the sterilising activity of new antituberculosis drugs is difficult to assess by conventional phase III studies, surrogate methods related to eventual relapse rates are required. METHODS: A suitable method is suggested by a retrospective analysis of viable counts of Mycobacterium tuberculosis in 12-hr sputum collections from 122 newly diagnosed patients with pulmonary tuberculosis in Nairobi, done pretreatment and at 2, 7, 14 and 28 days. Treatment was with isoniazid and streptomycin, supplemented with either thiacetazone (SHT) or rifampicin + pyrazinamide (SHRZ). RESULTS: During days 0-2, a large kill due to isoniazid occurred, unrelated to treatment or HIV status; thereafter it decreased exponentially. SHRZ appeared to have greater sterilising activity than SHT during days 2-7 (p = 0.044), due to rifampicin, and during days 14-28, probably due mainly to pyrazinamide. The greatest discrimination between SHRZ and SHT treatments was found between regression estimates of kill over days 2-28 (p = 0.0005) in patients who remained positive up to 28 days with homogeneous kill rates. No associations were found between regression estimates and the age, sex, and extent of disease or cavitation. An increased kill in HIV seropositive patients, unrelated to the treatment effect, was evident during days 2-28 (p = 0.007), mainly during days 2-7. CONCLUSIONS: Surrogate marker studies should either be in small groups treated with monotherapy during days 2 to about 7 or as add-ons or replacements in isoniazid-containing standard regimens from days 2 to 28 in large groups.

Journal Article↗