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Statements of ATS, CDC, and IDSA on Treatment of Tuberculosis

With regard to the "Treatment of Tuberculosis" document of the American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America (ATS/CDC/IDSA) published in your journal (1), we would like to make some comments concerning the management of tuberculosis caused by drug-resistant organisms. This document states, "Do not limit the regimen to three agents if other previously unused drugs that are likely to be active are available. In patients with multidrug-resistant (MDR) organisms in whom there is resistance to first-line agents in addition to INH and RIF, regimens employing four to six medications appear to be associated with better results" (p. 657). To support this statement, the document cites three references. However, none of them (References 24–26 of the ATS Document) support the affirmation made in the text. Reference 24 corresponds to the work of Goble and colleagues (2), who report the results of treating 171 patients whose organisms were resistant to isoniazid (INH) and rifampin (RIF) and were resistant, on average, to six drugs. Of the 134 patients in whom adequate follow-up was possible, 65% responded to the prescribed treatment, whereas 35% did not. In their univariate analysis a nonfavorable response was associated with four factors (prior administration of a higher number of drugs, treatment patterns with fewer drugs not previously used, resistance in vitro to a higher number of drugs, and male sex), although in the multivariate analysis only the first and fourth of these factors achieved statistical significance. Reference 25 corresponds to the article by Park and colleagues (3) on the results of treatment of 107 patients in Korea whose organisms had resistance to INH and RIF and were resistant to an average of four drugs. Of the 63 patients with sufficient follow-up data, 52 (82.5%) responded to treatment and 11 (17.5%) did not. They only reported the univariate analysis of those with nonfavorable responses and concluded that there was only an association with a higher number of drugs resistant in vitro, which is also the only factor that remained in a multiple-logistic regression model. Finally, Reference 26 corresponds to the article by Geerligs and colleagues (4) on treatment performed in The Netherlands of 44 patients with resistance to INH and RIF, whose organisms were resistant to a mean of five drugs. The patients were treated with an average of six drugs, including INH in 36 patients, despite the organisms' proven resistance. In the end it was considered that 33 patients (75%) had been cured, 6 died (14%; although only 1 died of tuberculosis [TB]), and the rest were still under observation. In this article there was no statistical analysis that tried to relate good or poor response with particular factors.

Consequently, none of the cited articles (2–4) conclude that using four to six drugs is associated with better results (1). The only thing that can be concluded is that in these three articles acceptable results have been obtained using more than four drugs, with favorable responses varying between 65% (2) and 85.5% (3). However, it should be remembered that during the 1960s, when RIF did not exist, several publications in Europe (5–9) and the United States (10–12) established the rules or guidelines for re-treatment of tuberculosis cases resistant to first-line drugs (13, 14). These prestigious reports (5–12) concluded that it was necessary to combine, just as in the initial treatment, two or three effective drugs, whether empirically by administering agents they had not received before, or alternatively by waiting for a drug with proven susceptibility to become available. This rule (13, 14) remains unchanged, although it has benefited from the discovery of new antituberculosis drugs.

These ATS recommendations of 1965 and 1966 (13, 14) changed slightly in the official document of 1994 (15), in which the recommendation was for at least three new drugs, although no bibliographic reference to justify this change was provided.

Administration of four, six, or more drugs, apart from being bacteriologically unjustified, ensures a high probability of intolerance by the patient who will default from treatment or will refuse to take it when faced with the appearance of severe side effects. It is not insignificant that in the article by Goble and colleagues (2) 30% of patients experienced side effects that obliged them to discontinue one or two drugs, and this percentage increases to 54.5% in the article by Geerligs and colleagues (4).

The number of drugs needed to constitute a good re-treatment regimen in the patients with MDR-TB is one of the most controversial topics debated in the Green Light Committee of the World Health Organization, and the conclusion is that clinical trials, comparing different number and type of drugs, are necessary to develop the evidence base for the most appropriate treatment of MDR-TB. However, while these clinical trials are being developed, it is necessary to state that, to date, the best evidence in the treatment of these patients support the use of only three and not more drugs.

José A. Caminero^a and Pere de March^b

^a Pneumology Department University Hospital "Dr. Negrín" Las Palmas de Gran Canaria, Spain International Union Against Tuberculosis and Lung Disease Paris, France
^b Thoracic Diseases Service Tuberculosis Investigation Unit Barcelona, Spain

FOOTNOTES

Conflict of Interest Statement: J.A.C. and P.D.M. have no declared conflict of interest.

REFERENCES

1. American Thoracic Society Documents. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603–662.[Free Full Text]
2. Goble M, Iseman MD, Madsen LA, Waite D, Ackerson L, Horsburgh R. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993;328:527–532.[Abstract/Free Full Text]
3. Park SK, Kim CT, Song SD. Outcome of chemotherapy in 107 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. Int J Tuberc Lung Dis 1998;2:877–884.[Medline]
4. Geerligs WA, Altena R, de Lange WCM, van Soolingen D, van der Werf TS. Multidrug-resistant tuberculosis: long-term treatment outcome in the Netherlands. Int J Tuberc Lung Dis 2000;4:758–764.[Medline]
5. A Report from the Research Committee of the British Tuberculosis Association. Ethionamide, Pyrazinamide and Cicloserine in the treatment of drug-resistant pulmonary tuberculosis. Tubercle 1963;44:195–214.
6. Janc'ik E, Zelenka M, Tousek J, M'akov'a M. Chemotherapy for patients with cultures resistant to streptmomycin, isoniazid and PAS. Tubercle 1963;44:443–445.[Medline]
7. de March P, Turell J. Resultados obtenidos mediante regimenes de asociacion con dos o tres drogas secundarias en el retratamiento del tuberculoso pulmonar cronico. Rev Clin Esp 1968;109:119–126.
8. Tousek J, Jancik E, Zelenca M, Jancikova-Makova M. The results of treatment in patients with cultures resistant to streptomycin, isoniazid and PAS: a five-year follow-up. Tubercle 1967;48:27–31.[Medline]
9. Zierski M, Zachara A. Late results in re-treatment of patients with pulmonary tuberculosis. Tubercle 1970;51:172–177.[Medline]
10. Fischer DA, Lester W, Dye WE, Moulding TS. Retreatment of patients with isoniazid-resistant tuberculosis: analysis and follow-up of 146 cases. Am Rev Respir Dis 1968;97:390–398.
11. Kass I. Chemotherapy regimens used in retreament of pulmonary tuberculosis. I: observations on the efficacy of combinations of Kanamycin, Ethionamide and either Cycloserine or Pyrazinamide. Tubercle 1965;46:151–165.[Medline]
12. Kass I. Chemotherapy regimens used in retreatment of pulmonary tuberculosis. Part II: observations on the efficacy of combinations of Ethambutol, Capreomycin and companion drugs, incluing 4–4 Diisoamyloxythiosemicarbanilide. Tubercle 1965;46:166–177.[Medline]
13. American Thoracic Society. Chemotherapy of pulmonary tuberculosis in adults: the choice of drugs in relation to drug susceptibility. Am Rev Respir Dis 1965;92:508–512.[Medline]
14. American Thoracic Society. Treatment of drug-resistant tuberculosis. Am Rev Respir Dis 1966;94:125–127.
15. American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994;149:1359–1374.[Abstract]

From the Authors:

As one of the committee members who helped develop the section on the management of patients with multidrug-resistant tuberculosis (MDR-TB) in the 2003 American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of American (ATS/CDC/IDSA) guidelines, I have been asked to reply to the comments on this document (1) by Drs. Caminero and de March. There are several very important issues imbedded in the debate over optimal treatment of such cases:

1. Ideal number of medications: Caminero and de March point out that in none of the studies cited in the guidelines was there a controlled trial comparing three drug with four or more drug regimens; and, in none of the studies did the use of more drugs reach statistical significance in terms of favorable outcome. Indeed, we recognized the inherent uncertainty afforded by the data and, hence, used the cautious claim that, "regimens employing four to six medications appear to be associated with better results." Although the use of more drugs was not itself proven to be a favorable factor, the obverse is readily apparent in all reports of MDR-TB treatment: the prognosis worsens with resistance to more drugs. We infer from this that extensive patterns of drug resistance compromise outcomes by limiting the number of active drugs that can be used. Thus, we reasoned that willingly limiting the number of drugs to three would be an inappropriate simulation of more extensive patterns of resistance.
   
2. Drug side effects and toxicity: Caminero and de March make the grandiose claim that four, six, or more drugs used is "bacteriologically unjustified" and "ensures a high probability of intolerance by the patient who will default from treatment or will refuse to take it..." If we cannot prove the utility of four to six drug regimens, they certainly cannot disprove it. Their concerns over intolerance are suitable. However, our experience at the National Jewish Medical and Research Center over the past 20 years where we have treated approximately 230 patients with MDR-TB with a median of six drugs indicates that, with clinical experience and palliative measures, patients can and do tolerate these regimens. The observations of the Partners in Health MDR-TB Program in Peru confirm these findings (2). Caminero and de March cite the report by Goble and colleagues (3) of a 1973–1983 cohort from National Jewish where 30% of patients required discontinuation of one or two drugs. What they do not acknowledge is that the most common offending agents were sodium p-aminosalicylic acid (PAS; which has been replaced by an imminently more tolerable agent, Paser granules) and ethionamide (which we use only when there are no alternative agents). The care of patients with MDR-TB is never routine; as we strongly indicated in the guidelines, these patients should be promptly referred to specialized centers or programs where their treatment can be conducted by knowledgeable clinicians.
   
3. To whom were these guidelines directed? Caminero and de March indicate that the Green Light Committee of the World Health Organization is debating the appropriate treatment of MDR-TB cases. We readily acknowledge that caring for MDR-TB in resource-limited regions will inevitably require different approaches than those of the more affluent, industrialized nations. The ATS/CDC/IDSA guidelines were primarily developed for the United States, but should be suitable for other resource-rich countries.
   
4. What should be the nature of "guidelines"? There is a great and understandable clamor for evidence-based recommendations in modern medicine; in our document, we used this approach when adequate data were available. However, as noted earlier, randomized/controlled clinical trials for MDR-TB have not been conducted. In the absence of such information, "expert opinion" is commonly used. Without question, such expertise may be proven wrong. However, on the basis of our interpretation of the available literature, as well as our professional experiences, the committee believed these recommendations to be the best available, contemporary guidance in this era.
   
5. Future studies: Caminero and de March talk about future clinical trials for MDR-TB. Having worked with patients with MDR-TB for the past 21 years at National Jewish, I have pondered often the design of such trials in terms of which drugs? How many drugs? And the use of resectional surgery? Given the extraordinary number of variables in these cases, study design would be most daunting and the number of patients difficult to obtain. Most significant, for me, however, are these critical issues: (a) using an inadequate regimen may lead to treatment failure and additional acquired drug resistance, which would compromise future efforts at treatment; (b) medical treatment failure may be associated with spread to new areas of the lung, thus lessening the likelihood of surgical cure; and (c) treatment failure leaves the patient, at best, socially isolated, and at worst, dead.
   

Although hypothetical questions are potentially misleading, I think it fair to pose to Caminero and de March this scenario: If they or their colleagues developed cavitary TB resistant to isoniazid, rifampin, streptomycin, and ethambutol, would they be content to use a three-drug regimen? If not, I trust they would factor that element into their study design.

Michael D. Iseman

National Jewish Medical and Research Center Denver, Colorado

FOOTNOTES

Conflict of Interest Statement: M.D.I. has no declared conflict of interest.

REFERENCES

1. American Thoracic Society Documents. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603–662.
2. Furin JJ, Mitnick CD, Shin SS, Bayona J, Becerra MC, Singler JM, Alcantara F, Castanieda C, Sanchez E, Acha J, et al. Occurrence of serious adverse effects in patients receiving community-based therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2001;5:648–655.[Medline]
3. Goble M, Iseman MD, Madsen LA, Waite D, Ackerson L, Horsburgh R. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993;328:527–532.

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