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Side effects of antituberculous treatment
  1. A DE MARIA,
  1. Department of Internal Medicine
  2. University of Genoa
  3. Genoa 16132, Italy
  4. de-maria{at}

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Combined antimycobacterial chemotherapy has been shown to be very effective in the treatment of Mycobacterium tuberculosis hominis (MTH) pulmonary infections with a cure rate of >85% for short term (6 month) courses.1 Recent WHO initiatives have been launched and are aimed at eradicating pulmonary tuberculosis by intensive adoption of directly observed treatment (DOT) strategies in countries in which the incidence is high.

A new drug formulation has recently been produced which provides the three main first line drugs in the same tablet in a fixed ratio (rifampin (RIF) 120 mg, isoniazid (INH) 50 mg, and pyrazinamide (PZM) 300 mg).2 This formulation is likely to be extremely useful, particularly in developing countries where it can provide reliable simultaneous administration of all the drugs needed on bi-weekly or tri-weekly DOT programmes.3 However, it is not intended to substitute any (or all) of the single components in countries where they are already available and marketed.

In a recent WHO report, of all the industrialised European countries, Italy reported the highest prevalence of multidrug resistance among previously treated cases of tuberculosis (33.9%, 95% CI 25.7 to 42.7), with any drug resistance accounting for up to 60.6% of the strains.4 In addition, there was a high prevalence of resistance in new cases of tuberculosis with 12.3% resistance to any drug.4

In Italy the distribution and marketing of PZM ceased as a single drug formulation between 15 June 2000 and early 2001. This abrupt policy change temporarily introduced a new and interesting challenge to the treatment of MTH, and possibly increased risks of toxicity and decreased treatment efficiency for some patients.

Over the last 2 years we have treated 26 patients with pulmonary tuberculosis using the standard four drug regimens administered as single drugs and have recorded a relatively high rate of hepatotoxicity (35%) compared with previous North American and European analyses (11%).1 ,5 In eight of the nine patients with hepatotoxicity the substitution of INH led to normalisation of liver function. This incidence of side effects approaches the cumulative incidence of side effects (26%) reported in a European study of similar design on 519 patients of similar mean age.

In our 26 patients we estimated that, if a fixed dose formulation had been used to maintain the dose of RIF at 10 mg/kg/day, a significantly increased dose of PZM (not correlated to the one that was actually given) would have been administered. Thus, it is reasonable to suggest that the already high rate of toxicity could increase in incidence and severity when PZM is administered daily as a fixed dose formulation. When considered in the context of the unavailability of PZM single drug formulations, two additional considerations are warranted.

Firstly, there is a limited choice of first line regimens which exclude INH for patients with INH related hepatotoxicity (for example, RIF+STM+EMB but not RIF+PZM+STM). Side effects in hospital treated patients usually lead to withdrawal of one of the basic drugs and replacement by other drugs such as ethambutol or streptomycin. This may lead to more prolonged treatment and to decreased adherence.5 However, these negative consequences would be considerably enhanced if single drug formulations of PZM are not available since withdrawal of at least two first line drugs would be needed (PZM + INH).

Secondly, the treatment of patients with chronic tuberculosis who are infected with the most frequent INH or RIF resistant MTH (43.3% and 44.9%, respectively)4 or with multidrug resistant MTH could lead to the drug being acquired from abroad at high cost, and sometimes to interruptions in the supply with dangerous consequences for the patient's health. In fact, most tuberculosis units in our area acquired PZM as a single drug formulation from neighbouring countries during the time when it was not available.

Thus, available data do not support the use of fixed dose formulations as the only treatment choice in developed countries. This could be particularly dangerous where there is a high prevalence of multiple drug resistant MTH, including developing countries.