© 2004 American Thoracic Society
Number of Drugs to Treat Multidrug-resistant TuberculosisTo the Editor:We read the comments by Drs. Caminero and de March and the response by Dr. Iseman (1) with great interest. Although Caminero and de March correctly note that the optimal number of drugs used in a retreatment regimen for multidrug-resistant tuberculosis (MDR-TB) has never been studied in a clinical trial, we agree with Dr. Iseman's opinion that a successful retreatment regimen should include four to six drugs, and not less, as Caminero and de March argue. Our experience is with approximately 2,000 patients with MDR-TB in Peru over the last 8 years, which constitutes the largest MDR-TB patient cohort to date. In reviewing treatment histories, we have found that the most common mistake in the medical management of these patients has been the prescription of weak retreatment regimens: most patients were referred to us after failing to respond to regimens that added one, two, or three second-line drugs to a failing first-line regimen. A similar finding was reported at the chief MDR-TB referral center in the United States by Mahmoudi and Iseman (2), who classified undertreatment as a physician error. Caminero and de March are correct that the use of four, six, or more drugs will lead to greater toxicity, but our experience has shown that adverse reactions can be controlled, as Iseman suggests, even in resource-poor settings (3). Although physicians with less experience in the treatment of drug-resistant TB may be reluctant to prescribe four to six drugs because of fears of drug toxicity, it is patients and their families who are, in the end, the most adversely affected by the use of inadequate treatment regimens. When treating patients with MDR-TB, we recommend using at least the number of drugs used for treating drug-sensitive TB (four in the World Health Organization–recommended Category 1 regimen). In addition, directly observed therapy, aggressive management of adverse effects, rigorous drug susceptibility testing, adjuvant resective surgery, and any other treatment options that are available to the patient should be considered, because retreatment regimens are often the only hope for cure of this disease (4). Experience in Peru, Haiti, and Russia has taught us deep respect for Mycobacterium tuberculosis and its ability to survive and evolve in the face of even the best-laid therapeutic plans. Caminero and de March cite studies from the National Jewish Hospital in the 1960s, where researchers reported relapse rates as high as 20.5% after culture conversion with a three-drug regimen (5). We suspect our distinguished predecessors were not satisfied with these outcomes and hope that others engaged in responding to MDR-TB feel similarly chastened.
Partners In Health and Harvard Medical School Boston, Massachusetts FOOTNOTES Conflict of Interest Statement: K.J.S., K.J., R.H., M.R., S.S., J.F., F.L., J.M., and P.F. do not have a financial relationship with a commercial entity that has an interest in the subject of this letter. REFERENCES
From the Authors: Seung and colleagues write in relation to their experience in Peru, but control of tuberculosis in Peru was chaotic in the 1980s. For this reason, Peru currently has one of the worst multidrug-resistant tuberculosis (MDR-TB) situations in the world. But this is not the general situation. A lot of patients with MDR-TB in many countries have only received first-line drugs and/or quinolones. Most of these patients can be cured if three good, previously unused drugs are selected. I could accept the administration of four drugs in the initial phase of this retreatment, to standardize management, but six or more drugs are too many, even for patients who have received many second-line drugs in the past. The problem is more a question of selection of drugs than the number of drugs. A detailed history of drugs taken in the past is pivotal in the correct selection of drugs to be used in current treatment. The problem of giving an excessive number of drugs is not only the difficult and expensive management of the side effects (Peru has the technical and economical support of Partners in Health), but the probable higher tendency to abandon the treatment when patients improve, a topic never addressed in these studies. Seung and colleagues have found that the most common mistake in the treatment of patients who do not respond to regimens is the addition of one, two, or three second-line drugs. However, they must perform in-depth analyses of these data, as all the doctors working with MDR-TB recognize the hidden monotherapy as the most important mistake. This statement could be certain even if only two weak drugs are added; but it does not hold true with the addition of three new drugs (1–4) or two effective drugs (5). The administration of three new drugs could never be considered a physician error, because in that case the professors who wrote the 1965 (1), 1966 (1), and 1994 (2) American Thoracic Society recommendations, the 1990 British Thoracic Society guidelines (3), and the 1988 International Union against Tuberculosis and Lung Disease recommendations (4) also made this important error, and they cannot be considered inexperienced physicians. Even among the 1960s National Jewish Hospital publications, a relapse rate of 4% was reported (6), which is very close to other reports from the United Kingdom, Africa, Spain, Poland, and Czechoslovakia, all of which used only three drugs and are reviewed in our letter (1).
University Hospital "Dr. Negrín" Las Palmas de Gran Canaria, Spain FOOTNOTES Conflict of Interest Statement: J.A.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter. REFERENCES
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