Isoniazid, rifampin, and streptomycin for 6 months plus pyrazinamide for 2 months increased culture negativity in pulmonary tuberculosis
ACP J Club. 1991 Sep-Oct;115:36. doi:10.7326/ACPJC-1991-115-2-036
Hong Kong Chest Service/British Medical Research Council. Controlled trial of 2, 4, and 6 months of pyrazinamide in 6-month, three-times-weekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin, and pyrazinamide. Am Rev Respir Dis. 1991 April; 143:700-6.
To determine the efficacy of 6-month treatment regimens including 2, 4, or 6 months of pyrazinamide with and without streptomycin for the treatment of sputum smear-positive pulmonary tuberculosis.
Randomized controlled trial.
Hong Kong Chest Service.
1386 patients met the inclusion criteria of age ≥ 15 years old, pulmonary tuberculosis with sputum positive for acid-fast bacilli, and ≥ one third of 1 lung field, and 33% had cavitation.
Patients were allocated to 1 of 4 treatment regimens given 3 times/wk for 6 months, all containing isoniazid (600 to 1000 mg/dose) and rifampin (500 to 700 mg/dose). 3 regimens included streptomycin (1 g/dose) for 4 months and pyrazinamide (1875 to 3000 mg/dose) for the first 2, 4, or 6 months. The fourth regimen included 6 months of pyrazinamide and no streptomycin. Doses were based on body weight and formulation composition. Randomization to combined or separate formulations began part way through the study, making 8 treatment groups. Sputum samples were taken each month to 24 months.
Main outcome measure
Negative sputum culture for tuberculosis.
After 3 months 97% to 100% of 892 patients with fully drug-susceptible bacilli were culture negative across the 8 treatment arms. Culture negativity was achieved more quickly with streptomycin-containing regimens than the regimen without streptomycin (P = 0.03 for the difference at 1 month). Bacteriologic failure during chemotherapy occurred in 4 patients and was associated with acquired drug resistance. Bacteriologic relapse rates during 30 months of follow-up (34 of 832 patients, 4% overall) were not influenced by use of streptomycin, duration of pyrazinamide treatment, or formulation used. Among 137 patients resistant to isoniazid, streptomycin, or both, 4 (3%) experienced bacteriologic failure during chemotherapy and 7% relapsed during 30 months of follow-up. Rates of adverse reactions were similar for all treatment groups and for both formulations.
A 6-months, a treatment regimen administered 3 times per week consisting of isoniazid, rifampin, and streptomycin, with pyrazinamide given for the first 2 months, was effective for the treatment of pulmonary tuberculosis.
Source of funding: Not stated.
Address for article reprint: Dr. D.J. Girling, MRC Cardiothoracic Epidemiology Group, Brompton Hospital, Fulham Road, London SW3 6HP, England, UK.
These 2 studies are part of an ongoing research program of the Medical Research Council Cardiothoracic Epidemiology Group (British) evaluating effectiveness of short-course, multiple-drug combination chemotherapy in active pulmonary tuberculosis. An additional aim of these studies was to assess patient acceptance of a combined formulation of isoniazid, rifampin, and pyrazinamide compared with the individual drugs taken separately. The settings for the studies were Hong Kong and Singapore. Patient demographics were similar for the 2 studies. As would be expected from studies coordinated by a single group, the general design and methods were also similar.
In the Hong Kong study, all mycobacteriologic studies were done in London, England. In Singapore, entry laboratory studies for tuberculosis were done by both the London laboratory and by a facility in Singapore. After chemotherapy, any sputum smear or culture whose result was positive in Singapore was repeated by the London laboratory. It would have been illustrative for the authors to have given the interlaboratory agreement between London and Singapore and to have described how discrepancies were dealt with. If the agreement was not 100%, how confident were the authors in the bacteriologically defined relapse rate (especially if the Singapore laboratory produced false-negative results)? It is also not clear from either article how patients with postive sputum smears who did not subsequently have a positive culture for Mycobacterium tuberculosis (either on entry or during follow-up) were handled in the analysis. This information would be important for the specimens that were transported from Hong Kong to London, because the organism may have died in transit, yet still be seen on staining of the sputum smear but not be recoverable on culture. The last point concerning the laboratory component of both studies is the definition of bacteriologic relapse after chemotherapy "...as a culture growing 10 or more colonies in 2 different months during any consecutive 3 months up to 24 months or 6 months thereafter (Hong Kong) or to 18 months or 4 months thereafter (Singapore)." The authors did not comment on this breakpoint of colonies and time frame with respect to the clinical significance of any positive Mycobacterium tuberculosis culture after chemotherapy. The distribution of all the quantified positive cultures would be an interesting feature in the effectiveness analysis of these studies.
Although these laboratory points may affect the magnitude of the observed effectiveness, they would be unlikely to affect the intertreatment group comparisons because the laboratory effects should be evenly distributed. Hence, these studies, and presumably the studies to follow from this group, add to the overall knowledge base for the treatment of active pulmonary tuberculosis in southeast Asia and elsewhere, including North America, where the combined issues of drug cost and availability, compliance and tolerance with prescribed therapy, and clinical follow-up must be balanced with treatment efficacy, emergence of bacterial resistance to single and multiple agents, and the public health issues related to spread of tuberculosis.
The results related to the 2 combined formulations of isoniazid, rifampin, and pyrazinamide used in these studies (Rifater 2 in Singapore and Rifater 3 in Hong Kong) are encouraging in that they were subjectively well accepted by the patients. It is unfortunate that the former product appeared to be less effective than the agents used individually because the latter agent is reported by the authors to be no longer available.
Douglas MacPherson, MD
McMaster UniversityHamilton, Ontario, Canada