New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development

Abstract

2One-third of the world population is infected with Mycobacterium tuberculosis (MTB) and hence at risk of developing active tuberculosis (TB). Each year, 8.8 million patients are newly diagnosed with active TB and 1.6 million patients die of TB. The rapid spread of the human immunodeficiency virus (HIV) has fueled the TB epidemic, especially in sub-Saharan Africa, where 28% of TB patients are HIV positive (176). The current first-line treatment for TB is a multidrug regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE). It must be taken for at least 6 months to achieve high cure rates (more than 95% in experimental settings). PROBLEMS WITH CURRENT TUBERCULOSIS TREATMENTThere are several major problems associated with the currently available TB treatment. First, the duration and complexity of treatment result in nonadherence to treatment. This leads to suboptimal response (failure and relapse), the emergence of resistance, and continuous spread of the disease (168). Second, adverse events in response to anti-TB drugs are common and contribute to the problem of nonadherence (19,168). Third, the increasing incidence of multidrug-resistant (MDR; resistance to at least rifampin and isoniazid) and extensively drug-resistant (XDR; MDR resistance plus resistance to a fluoroquinolone and an aminoglycoside) TB is a serious concern. Resistant TB occurs in the presence of partially suppressive drug concentrations that enable replication of bacteria, the formation of mutants, and overgrowth of wild-type strains by mutants (selective pressure) (175). The prevalence of MDR TB in new TB cases ranged from 0% in some Western European countries to more than 22% in Azerbaijan (2002 to 2007 survey); 14 of 72 participating countries reported an MDR TB prevalence of more than 5% (177). Second-line drugs for drug-resistant TB are not available everywhere and are less effective, more toxic, and require longer use than first-line drugs (61). Fourth, coinfection of TB and HIV is a problem by itself. Combined treatment of TB and HIV involves a high pill count with associated adherence problems, overlapping toxicity profiles of the antiretroviral and anti-TB drugs, drug interactions between rifampin and the antiretroviral protease inhibitors, and the risk of immune reconstitution syndrome (104). Fifth, prophylactic therapy of latent TB (TB infection without symptoms) with isoniazid is also associated with problems of nonadherence (180). Attempts to shorten treatment with alternative drugs resulted in severe adverse events (64,150,155).The World Health Organization (WHO) has developed the directly observed therapy short course (DOTS) strategy to optimize response and adherence to TB treatment. However, DOTS is labor-intensive and expensive. It causes a high burden on public health programs, especially in developing countries with limited human resources (49). In addition, TB diagnosis in the DOTS strategy is based on sputum microscopy, rather than sputum culture (173). Only advanced pulmonary TB is detected by sputum...

Challenges of Antibacterial Discovery

“…Indeed, since the standard of care for M. tuberculosis and HIV is treatment with combinations, the resistance potential of new single-targeted agents for treatment of those pathogens is not as problematic as it might be for more-standard pathogens. In contrast to the case with standard pathogens, a number of interesting new anti-M. tuberculosis agents are in various stages of development (229,374). Is combination therapy a feasible path for development of new single-targeted agents?…”

Development of New Anti-tuberculosis Drug Candidates

“…The early bactericidal activity of 400 mg OPC-67683 in patients with pulmonary TB was low during the first 4 days. However, from day 4 onwards, a significant decrease in CFU was seen (Van den Boogaard et al 2009;Kaiser Family Foundation 2009). OPC-67683 in multiple doses up to 400 mg was tolerated well by healthy volunteers, and no serious adverse events were reported.…”

“…In February 2008, Bayer distributed a "Dear Doctor" letter warning physicians about rare but severe hepatological and dermatological adverse events associated with moxifloxacin. Therefore, the adverse events associated with moxifloxacin require extended evaluation (Van den Boogaard et al 2009). …”

An Impact of Biofield Treatment: Antimycobacterial Susceptibility Potential Using BACTEC 460/MGIT-TB System

“…Apart from first and second generations antitubercular drugs fluoroquinolones also possess antitubercular activity and it is well accepted by the scientific community. Due to its wide distribution pattern, can easily invade to an intracellular compartment of Mycobacterium and produce strong effects like macrophages without cross-resistance to antitubercular drugs [26][27][28]. Among them, moxifloxacin resistance to MDR-TB is very low [29] and highly effective to isoniazide and rifampicin resistance cases.…”