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Therapeutics

Oral trimethoprim-sulfamethoxazole and trimethoprim-dapsone were equally effective in PCP, but fewer adverse reactions occurred with trimethoprim-dapsone

ACP J Club. 1991 Jan-Feb;114:5. doi:10.7326/ACPJC-1991-114-1-005


Source Citation

Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med. 1990 Sep 20;323:776-82.


Abstract

Objective

To determine the effectiveness and safety of oral trimethoprim-dapsone compared with trimethoprim-sulfamethoxazole in the treatment of first episodes of Pneumocystis carinii pneumonia (PCP) in patients with AIDS.

Design

Randomized, double-blind, controlled trial of 21 days' duration.

Setting

The medical service of San Francisco General Hospital in the United States.

Patients

All patients aged ≥ 18 years with AIDS and a histologically confirmed first episode of PCP between March 1986 and January 1987 were evaluated for study participation. Of 79 patients with a first episode of PCP, 60 met the study criteria.

Intervention

Patients were prescribed either trimethoprim (20 mg/kg/d in 4 divided doses) and dapsone (single dose of 100 mg/d) (n = 30), or trimethoprim (dose as above) and sulfamethoxazole (100 mg/kg/d in 4 divided doses) (n = 30). No subjects received zidovudine during therapy.

Main outcome measures

Failure to respond was defined as profound deterioration within the first 4 days of therapy or lack of improvement after 1 week of therapy, as assessed by the attending physician and verified by 2 other study physicians.

Main results

Of the 60 patients randomized, 5 (2 receiving trimethoprim-dapsone and 3 receiving trimethoprim-sulfamethoxazole) were changed to treatment with intravenous pentamidine at day 4 because of severe and progressive pulmonary deterioration. Dyspnea scores, frequency of cough, respiratory rates, and body temperatures did not differ significantly between the 2 treatment groups. The power to detect a specified difference was not reported. Major adverse reactions, causing treatment withdrawal, were more common in the trimethoprim-sulfamethoxazole group than in the trimethoprimdapsone group (57% vs 30%, P < 0.025). {This absolute risk reduction of 27% means that 4 patients would need to be treated with trimethoprim-dapsone (rather than trimethoprim-sulfamethoxazole) to prevent 1 additional major adverse reaction, 95% CI 2 to 63; the relative risk reduction was 47%, CI 4% to 72%.}* Hepatitis and neutropenia accounted for most of the adverse effects in those receiving trimethoprim-sulfamethoxazole.

Conclusion

Treatment of first episodes of Pneumocystis carinii pneumonia in patients with AIDS was equally effective with oral trimethoprim-dapsone or trimethoprim-sulfamethoxazole, but there were significantly fewer major adverse reactions that required the discontinuation of therapy with trimethoprim-dapsone than with trimethorpim-sulfamethoxazole.

Sources of funding: The Food and Drug Administration; State of California Universitywide Task Force on AIDS; AIDS Clinical Study Center of the University of California.

Address for article reprint: Dr. C. B. Wofsy, Ward 95, Building. 90, San Francisco General Hospital, 995 Potrero Avenue, San Francisco, CA 94110, USA.

*Numbers calculated from data in article.


Commentary

Pneumocystis carinii pneumonia affects most persons presenting with AIDS. The principal finding that combination therapy with trimethoprim-dapsone caused significantly fewer major adverse reactions than trimethoprim-sulfamethoxazole has already been reported from this trial (1, 2). Both combinations appeared equally effective, but given the small sample size, some caution is warranted. In addition, the long-term follow-up data from this trial may already be outdated because relatively few patients in the study received subsequent antiretroviral therapy.

The development of safe and effective outpatient management of mild-to-moderate P. carinii pneumonia has been an important step in treating AIDS, but it has been limited by the problem of adverse reactions; use of trimethoprim-dapsone appears to reduce these reactions by 50% more than trimethoprim-sulfamethoxazole. For this reason, trimethoprim-dapsone has already become the initial therapy of choice in many centers for persons with mild-to-moderate P. carinii pneumonia. Even with the latter combination, however, major adverse reactions continue to pose a significant problem, and patients must be followed closely. Moreover, the search for optimal doses and better therapies must continue.

Martin T. Schechter, MD, Msc, PhD
University of British ColumbiaVancouver, British Columbia, Canada


References

1. Lee BL, Medina I, Benowitz NL, et al. Dapsone-trimethoprim interaction in AIDS patients with pneumocystosis [Abstract 7281]. Presented at the IVth International Conference on AIDS, Stockholm, 12-16 June 1988.

2. Lee BL, Medina I, Benowitz NL, et al. Dapsone, trimethoprim, and sulfamethoxazole plasma levels during treatment of pneumocystis pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). Evidence of drug interactions. Ann Intern Med. 1989;110:606-11.