PZA—The Most Likely Culprit

Abstract & Commentary

Synopsis: Pyrazinamide was the most frequent cause of drug-related adverse events, especially hepatitis, among patients with tuberculosis receiving first-line drugs.

Source: Yee D, et al. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med. 2003;167: 1472-1477.

Yee and colleagues in Montreal reviewed the incidence of drug-related adverse events in 430 patients who received treatment for pulmonary tuberculosis between 1990 and 1999. Liver transaminases were measured after 1 month of therapy and thereafter only if symptoms occurred. A major side effect was defined as any adverse reaction resulting in discontinuation of one or more drugs and/or directly resulted in hospitalization.

The incidence of major side effects per 100 person-months of exposure was 1.48 for pyrazinamide (PZA), 0.49 for isoniazid, 0.43 for rifampin, and 0.07 for ethambutol. The occurrence of any major side effect was associated with female sex, age older than 60 years, and birthplace in Asia. The most common serious side effect was rash and/or drug fever. Twelve patients, all of whom had normal pretreatment transaminase levels, developed drug-induced hepatitis. There were no deaths due to drug therapy.

Comment by Stan Deresinski, MD, FACP

Although its mechanism of action remains uncertain, PZA has been demonstrated in clinical trials to act synergistically with rifampin and to be an important contributor to sterilization in tuberculosis.1 While widely used for many years, its potential toxicity seems to only now be coming into clear focus. The combination of pyrazinamide with either rifampin or levofloxacin in the treatment of latent tuberculosis has recently been associated with high frequencies of hepatotoxicity.2,3 Now, this retrospective analysis indicates that adverse events occur significantly more frequently with PZA than with either isoniazid, rifampin, or ethambutol. In fact, ethambutol at 15 mg/kg/d was remarkably well tolerated; a single case of ocular toxicity was detected.

Despite the relatively frequent toxicity detected, it is likely that the incidence of significant hepatitis was underestimated in this study since routine follow-up liver enzyme tests were not performed. The recently published tuberculosis treatment guidelines, developed jointly by the American Thoracic Society, the CDC, and the Infectious Disease Society of America, recommend routine laboratory monitoring of hepatic function only in patients at increased risk of hepatitis (see Table).

PZA therapy is associated with a variety of side effects in addition to hepatitis. These include anorexia and nausea, nongouty polyarthralgia (in up to 40% of patients receiving daily therapy), asymptomatic hyperuricemia, acute gouty arthritis (rare in the absence of preexisting gout), rash, and photosensitivity.

References

1. Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: A review. Int J Tuberc Lung Dis. 2003;7:6-21.

2. McNeill L, et al. Pyrazinamide and rifampin vs isoniazid for the treatment of latent tuberculosis: Improved completion rates but more hepatotoxicity. Chest. 2003;123:102-106.

3. Papastavros T, et al. Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis. CMAJ. 2002;167:131-136.

Dr. Derenski is Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center.

Table

Selected, Relevant Topics from Treatment of Tuberculosis Guidelines

Laboratory Monitoring

Routine measurements of hepatic and renal function and platelet count are not necessary during treatment unless patients have baseline abnormalities or are at increased risk of hepatotoxicity (eg, hepatitis B or C virus infection, alcohol abuse). At each monthly visit, patients taking EMB should be questioned regarding possible visual disturbances including blurred vision or scotomata; monthly testing of visual acuity and color discrimination is recommended for patients taking doses that on a milligram per kilogram basis are greater than [approximately 20 mg/kg/d in patients receiving daily therapy—higher doses for intermittent therapy] and for patients receiving the drug for longer than 2 months. For patients receiving PZA, serum uric acid measurements are not recommended as a routine but may serve as a surrogate marker for compliance.

Management of Drug-Induced Hepatitis

Drug-induced hepatitis, the most serious common adverse effect, is defined as a serum AST level more than 3 times the upper limit of normal in the presence of symptoms, or more than 5 times the upper limit of normal in the absence of symptoms. If hepatitis occurs, INH, RIF, and PZA, all potential causes of hepatic injury, should be stopped immediately. Serologic testing for hepatitis viruses A, B, and C (if not done at baseline) should be performed and the patient questioned carefully regarding exposure to other possible hepatotoxins, especially alcohol. Two or more antituberculosis medications without hepatotoxicity, such as EMB, SM, amikacin/kanamycin, capreomycin, or a fluoroquinolone (levofloxacin, moxifloxacin, or gatifloxacin), may be used until the cause of the hepatitis is identified. Once the AST level decreases to less than 2 times the upper limit of normal and symptoms have significantly improved, the first-line medications should be restarted in sequential fashion. Close monitoring, with repeat measurements of serum AST and bilirubin and symptom review, is essential in managing these patients.

Antituberculous Therapy in Patients with Preexisting Liver Disease

In all patients with preexisting liver disease, frequent clinical and laboratory monitoring should be performed to detect drug-induced hepatic injury. INH, RIF, and PZA all can cause hepatitis that may result in additional liver damage in patients with preexisting liver disease. However, because of the effectiveness of these drugs (particularly INH and RIF), they should be used if at all possible, even in the presence of preexisting liver disease. If serum AST is more than 3 times normal before the initiation of treatment (and the abnormalities are not thought to be caused by tuberculosis), several treatment options exist. One option is to treat with RIF, EMB, and PZA for 6 months, avoiding INH. A second option is to treat with INH and RIF for 9 months, supplemented by EMB until INH and RIF susceptibility are demonstrated, thereby avoiding PZA. For patients with severe liver disease, a regimen with only 1 hepatotoxic agent, generally RIF plus EMB, could be given for 12 months, preferably with another agent, such as a fluoroquinolone, for the first 2 months; however, there are no data to support this recommendation.

Source: CDC. MMWR. Morb Mortal Wkly Rep. Recommendations and Reports. Treatment of Tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America. 2003;52(RR11):1-77. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm.