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Clin Chest Med 26 (2005) 273 – 282

Treatment of Active Tuberculosis: Challenges and Prospects
Behzad Sahbazian, DOa, Stephen E. Weis, DOb,*
a

John Peter Smith Hospital, Viola Pitts/Como Community Health Clinic, 4701 Bryant Irvin Road, Fort Worth, TX 76107, USA b Department of Medicine, University of North Texas Science Center, Texas College of Osteopathic Medicine, 3500 Camp BowieBoulevard, Fort Worth, TX 76107, USA

In the past 5 years, the Tuberculosis Trials Consortium (TBTC) of the Centers for Disease Control and Prevention has completed several large studies that have improved the understanding of pharmacotherapy of tuberculosis. Insights gained from these studies have resulted in major changes in drug therapy of tuberculosis in HIV-infected and noninfected individuals [1– 5]. These advances require that tuberculosis drug therapy now be individualized. Recommended treatment regimens are based on a patient’s risk profile that is determined by a combination of hematologic, microbiologic, clinical, and radiographic findings [6]. These studies have resulted in substantial changes in the treatment guidelines. Although they are more complicated than the previousguidelines, they allow treatment to be refined so that it can be extended in patients at high risk for treatment failure and allow shorter, more convenient treatment regimens in patients who can be identified as being at very low risk for failure [2]. This article reviews the basic principles of drug treatment of tuberculosis, individual pharmacologic agents, current treatment recommendations, and severalspecial situations that clinicians are likely to encounter in medical practice.

Axioms of chemotherapy of tuberculosis Effective tuberculosis drug therapy requires not one but at least two effective drugs. This axiom

* Corresponding author. E-mail address: sweis@hsc.unt.edu (S.E. Weis).

emerged from the first studies of drug therapy of tuberculosis initiated in the late 1940s. Thesestudies evaluated monotherapy with streptomycin and subsequently para-aminosalicylic acid (PAS) [7 – 9]. They demonstrated that drug resistance developed frequently in persons treated with monotherapy. During 3 months of monotherapy with streptomycin, 92% of persons who remained culture-positive developed streptomycin resistance [3]. Resistance also developed commonly during monotherapy with PAS andwas found in approximately one third of patients during 4 months of treatment [9]. It was also observed that resistance was much less common in persons treated with the combination of streptomycin and PAS, and that many more patients treated with the two-drug regimen became bacteriologically negative with 4 months of therapy [9]. Ten percent or less of persons treated simultaneously withstreptomycin and PAS developed streptomycin resistance [7,8]. It also was observed that development of resistance was associated with a worse prognosis and with more severe disease [3]. From these early observations came the principle that tuberculosis treatment must include simultaneous treatment with at least two effective drugs. The microbiologic basis for these early observations was not identified untilthe early 1960s and remains as important today to understand the design of current treatment regimens [10]. Persons with cavitary disease are estimated to have bacterial populations of approximately 108 organisms in each cavity [10,11]. During division, Mycobacterium tuberculosis bacilli mutate from drug-susceptible to drugresistant status spontaneously, randomly, and at a predictable rate [12].The proportion of naturally oc-

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.02.011

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curring organisms that are resistant to antituberculosis drugs is variable, approximately 10À5 for ethambutol, 10À6 for isoniazid and streptomycin, and 10À8 for rifampin [8]. The probability...