Back to the Future: Where Now for Antituberculosis Drugs?

Abstract

Muniz outbreak was larger – while the US-based outbreaks involved seven hospitals and approximately 250 patients, the Muniz outbreak, in a single hospital, involved at least 731 patients. Finally, the human and financial resources available for the implementation of measures to interrupt transmission were different not only in quantity, but also in matters of policy, epidemiology, and health care. Nonetheless, the numerous control measures implemented within a few months for all US hospitals were later adapted effectively in Argentina. The MDRTB “hot spots” in both North and South America were controlled by a combination of factors that included reduction of the population at risk by very high mortality, introduction of effective anti-HIV treatment, improved infection control, and earlier diagnosis and treatment for TB and MDRTB. However, cure rates are low (60-75%) when the current second-line drugs are used to treat patients with MDRTB. Both drug toxicities and nonadherence to the necessarily lengthy regimens contribute to high rates of treatment failures and thus, promote continued transmission of MDRTB. In the domain of drugs, we can again learn from the past. The presently recommended treatment regimen (the combined use of the drugs isoniazid [discovered in 1952], rifampicin [1963], pyrazinamide [1954], and ethambutol [1962]) addresses three separate properties of the tubercle bacillus to provide an effective cure: active replication, spontaneous mutation to drug resistance, and persistence5. However, the basic science behind these medicines is half a century old. Treatment regimens for MDRTB lack an adequate replacement for rifampin, whose ability to affect nonreplicating persistent bacilli6 is the mainstay of current short-course (6 month) regimens. Second-line drugs are almost all far more toxic, far less active, far slower to act (requiring longer therapy), and far more costly (about 100 times more) compared to the existing first-line anti-tuberculosis drugs7. On the other hand, significant advances in TB and pharmaceutical science – such as sequencing of the M. tuberculosis genome, new technologies for drug development (including combinatorial chemistry, high throughput screening, and rational drug design based on knowledge of molecular structures), and improved understanding of the biology of the tubercle bacillus – provide hope that we may soon achieve our goal of shorter and more active therapies for both drug-susceptible and drug-resistant TB5. Several antibiotics are currently being evaluated for use as TB drugs. Both moxifloxacin and linezolid have been used successfully in the treatment of MDRTB. Moxifloxacin is a broad-spectrum fluoroquinolone. In several murine studies, moxifloxacin was shown to have dose-dependent bactericidal activity against M. tuberculosis8,9. A review of the current portfolio of anti-tuberculosis drug candidates beckons us not only to look towards the future and the hope of a new era of tuberculosis (TB) therapy, when promising new drugs are incorporated into shorter, simpler, and less toxic treatment regimens, but also to consider the past for the lessons to be learned from what has gone before. The development of TB drug therapy was a landmark in the fight against TB. Groups such as the British Medical Research Council1 and the US Public Health Service2 have studied tuberculosis medications since the discovery of streptomycin in 1944. Since then, the necessary duration of TB treatment has been reduced almost fourfold: from more than 24 months to only 6 months. The roles of multidrug therapy and of adherence to the treatment regimen in the prevention of acquired drug resistance have been elucidated. Worldwide, TB treatment for most patients is now affordable and intermittent (or simplified through fixed-dose combinations), and no longer requires hospitalization. On the other hand, challenges remain: the current standard anti-tuberculosis regimen must still be taken for 6 to 9 months, TB is still a leading infectious disease (with 10 million new cases per year), and the continued spread of multidrug-resistant tuberculosis (MDRTB) endangers the control of TB globally. In this issue of Enfermedades Infecciosas y Microbiologia Clinica, Waisman et al3 add to the body of reports that have evaluated interventions for the control of nosocomial outbreaks of MDRTB, defined as TB due to strains of Mycobacterium tuberculosis resistant to at least isoniazid and rifampin. Like the MDRTB nosocomial outbreaks reported previously in the United States, the outbreak in Hospital Muniz (Buenos Aires) primarily involved patients with advanced human immunodeficiency virus (HIV) infection (the median CD4+ cell count was below 40/ l among the Argentinean patients studied). Like the US outbreaks, the Hospital Muniz outbreak was initially characterized by delays in diagnosis and delays in institution of effective therapy. And just as in the US, serious deficiencies in infection control led to broad transmission to susceptible persons (including both patients and health care workers) of an individual MDR isolate4. However, important differences exist between the two settings. The US-based outbreaks occurred between 1990 and 1992, while the Muniz outbreak occurred during 1994-2002. The