Pyrazinamide dosing

PYRAZINAMIDE Patients should have baseline liver functions tests to use as a comparison when monitoring liver function during pyrazinamide therapy. The nurse should monitor the patient closely for symptoms of a decline in hepatic functioning (ie, yellowing of the skin, malaise, liver tenderness, anorexia, or nausea). The primary health care provider may order periodic liver function tests. Hepatotoxicity appears to be dose related and may appear at any time during therapy. 

Some drugs can cause hyperuricemia and gout, such as thiazide diuretics, niacin, pyrazinamide, cyclosporine, and occasionally, low-dose aspirin. 

Some drugs can cause hyperuricemia and gout, such as thiazide diuretics, niacin, pyrazinamide, cyclosporine, and occasionally, low-dose aspirin. In most cases, these drugs block uric acid secretion in the kidney. Long-term consequences of gout and hyperuricemia include joint destruction, tophi, and nephrolithiasis. 

Because they are hepatically cleared, isoniazid and rifampin do not require dose modification in renal failure.31,36,39 Pyrazinamide and ethambutol typically are reduced to three times weekly to avoid accumulation of the parent drug (ethambutol) or metabolites (pyrazinamide).28,31 Renally cleared TB drugs include the aminoglycosides (e.g., amikacin, kanamycin, and streptomycin), capreomycin, ethambutol, cycloserine, and lev-ofloxacin.28,31,33,39 Dosing intervals need to be extended for... 

Concurrent administration of rifampin is recommended at doses of 10 to 20 mg/kg/day (maximum 600 mg/day) for children and 600 mg/day for adults. The addition ofpyrazinamide (children and adults, 15 to 30 mg/kg/ day maximum in both, 2 g/day) to the regimen of isoniazid and rifampin is now recommended. The duration of concomitant pyrazinamide therapy should be limited to 2 months to avoid hepatotoxicity. 

Table 49-4 lists options for treatment of culture-positive pulmonary TB caused by drug-susceptible organisms. Doses of antituberculosis drugs are given in Table 49-5. The standard TB treatment regimen INH, RIF, pyrazinamide, and ethambutol for 2 months followed by INH and RIF for 4 months. 

In nearly all patients, INH and RIF do not require dose modifications in renal failure. Pyrazinamide and ethambutol typically require a reduction in dosing frequency from daily to three times weekly (Table 49-6). 

Pyrazinamide Yes 25-35 mj kg per dose three times per week (not daily)... 

Rifater Tuberculostatic Tab Rifampin 120 mg, isoniazid 50 mg, pyrazinamide 6 tabs once daily. Reduce dose to 5 tabs if <54 300 mg kg, and to 4 tabs if <441 ... 

HIV - The initial phase of a 6-month tuberculosis regimen consists of isoniazid, rifabutin, pyrazinamide, and ethambutol for patients receiving therapy with protease inhibitors or nonnucleoside reverse transcriptase inhibitors. These drugs are administered a) daily for at least the first 2 weeks, followed by twice weekly dosing for 6 weeks or b) daily for 8 weeks to complete the 2-month induction phase. The second phase of treatment consists of rifabutin and isoniazid administered twice weekly or daily for 4 months. 

Alternative dosing Alternatively, a twice weekly dosing regimen (50 to 70 mg/kg twice weekly based on lean body weight) has been developed to promote patient compliance on an outpatient basis. In studies evaluating the twice weekly regimen, doses of pyrazinamide in excess of 3 g twice weekly have been administered without an increased incidence of adverse reactions. 

Approximately 70% of an oral dose is excreted in urine, mainly by glomerular filtration, within 24 hours. Pyrazinamide is significantly dialyzed and should be dosed after hemodialysis. 

Tuberculosis The standard regimen for the treatment of drug-susceptible tuberculosis has been 2 months of INH, rifampin, and pyrazinamide followed by 4 months of INH and rifampin (patients with concomitant infection with tuberculosis and HIV may require treatment for a longer period). When streptomycin is added to this regimen because of suspected or proven drug resistance, the recommended dosing for streptomycin is as follows ... 

Most drugs act by reducing active transport rather than by enhancing it. Thus, drugs that promote uric acid loss (uricosuric agents, such as probenecid and sulfinpyrazone) probably inhibit active urate reabsorption, while pyrazinamide, which reduces urate excretion, may block the active tubular secretion of uric acid. A complicating observation is that a drug may primarily inhibit active reabsorption at one dose and active secretion at another, frequently lower, dose. For example, small amounts of salicylate will decrease total urate ex-... 

Fixed dose combination of pyrazinamide with other antitubercular drugs except combination of pyrazinamide with rifampicin and INH as per recommended daily dose given below ... 

Directly observed therapy must be used with twice-weekly dosing For persons who are contacts of patients with isoniazid-resistant, rifampin-susceptible tuberculosis who cannot tolerate pyrazinamide... 

An unsupervised regimen of daily dosing comprising isoniazid and rifampicin for 6 months, plus pyrazinamide for the first 2 months. 

Adverse effects include hyperuricaemia and arthralgia, which is relatively frequent with daily but less so with intermittent dosing and, unlike gout, affects both large and small joints. Pyrazinoic acid, the principal metabolite of pyrazinamide, inhibits renal tubular secretion of urate. Symptomatic treatment with an NSAID is usually sufficient and it is rarely necessary to discontinue pyrazinamide because of arthralgia. Hepatitis, which was particularly associated with high doses, is not a problem with modern short-course schedules. Sideroblastic anaemia and urticaria also occur. 

A1 Sarraf, K.AA., Michielsen, P.P., Hanben, E.I., Lefebure, A., Ramon, A.M., van March, E.A., Pelckmans, P.A. Hepatotoxicity after a short course of low-dose pyrazinamide. Acta Gastro-Enterol. Belg. 1996 59 251-253... 

There is a lack of consensus on the best re-treatment protocol for patients who develop hepatotoxicity during treatment with standard antituberculosis agents. Investigators from Turkey have reported a high risk of recurrence of hepatitis (in six of 25 patients) on re-introduction of all drugs in full doses after recovery from hepatitis (31). This risk was less when rifampicin and isonia-zid were re-introduced sequentially in increasing doses and when pyrazinamide was replaced by streptomycin. 

Pyrazinamide is distributed throughout the body. Peak plasma concentrations are reached 2 hours after oral administration. Excretion is primarily by glomerular filtration. Serum concentrations are generally 30-50 gg/ml with daily doses of 20-25 mg/kg. The maximum daily dose should not exceed 3 g, regardless of weight. At a pH of 5.5, the minimal inhibitory concentration of pyrazinamide for Mycobacterium tuberculosis is 20 pg/ml (1). 

Data are not available for dosing the TB drugs in patients with morbid obesity." Relatively hydrophilic drugs (isoniazid, pyrazinamide, the aminoglycosides, capreomycin, ethambutol, p-aminosalicylic acid, and cycloserine) can be dosed initially based on ideal body weight... 

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