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  Table of Contents  
Year : 2012  |  Volume : 30  |  Issue : 3  |  Page : 261-263

Tuberculosis chemotherapy : Present situation, possible solutions, and progress towards a TB-free world

1 Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2 Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine; Department of International Health, Johns Hopkins Bloomberg, School of Public Health, Baltimore, MD, USA

Date of Submission11-Jun-2012
Date of Acceptance15-Jun-2012
Date of Web Publication8-Aug-2012

Correspondence Address:
Petros C Karakousis
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine; Department of International Health, Johns Hopkins Bloomberg, School of Public Health, Baltimore, MD
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0255-0857.99481

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How to cite this article:
Dutta NK, Karakousis PC. Tuberculosis chemotherapy : Present situation, possible solutions, and progress towards a TB-free world. Indian J Med Microbiol 2012;30:261-3

How to cite this URL:
Dutta NK, Karakousis PC. Tuberculosis chemotherapy : Present situation, possible solutions, and progress towards a TB-free world. Indian J Med Microbiol [serial online] 2012 [cited 2020 Jun 4];30:261-3. Available from:

Tuberculosis (TB) is a leading infectious disease responsible for nearly 1.5 million deaths annually. The emergence of multi- and extensively drug-resistant (MDR and XDR) strains of Mycobacterium tuberculosis, in combination with the AIDS pandemic, poses formidable obstacles for global TB control efforts.

Active TB in humans comprises a heterogeneous population of bacilli, including those that are rapidly multiplying and susceptible to the cell wall-agent isoniazid, and sporadically replicating or nonreplicating organisms. The latter population of bacilli, termed 'persisters', [1],[2] are difficult to eradicate with bactericidal drugs and account for the lengthy treatment required to prevent clinical relapse. The synergistic activity of the sterilizing drugs rifampin and pyrazinamide has allowed shortening of treatment duration to the current 6-month DOTS (directly observed treatment, "short-course") regimen, which consists of an initial 2-month "intensive phase" of daily rifampin-isoniazid-pyrazinamide-ethumbutol, followed by a 4-month "continuation phase" of intermittent rifampin and isoniazid. Proper implementation of the 'DOTS' strategy can achieve very high cure rates, while limiting the development of drug resistance, which is considered a "man-made phenomenon" resulting from inappropriate prescribing practices, poor drug quality, erratic drug supply, and poor patient adherence to treatment. [3] Strategies involving new drugs and drug combinations, as well as new uses of existing drugs, are urgently needed to reduce the time required to cure patients with drug-susceptible TB. In addition to improving treatment completion rates and reducing the emergence of drug resistance, shortening treatment duration is expected to have several other beneficial effects, including reducing: i) transmission in the community; ii) potentially unfavorable interactions with antiretroviral drugs in HIV-co-infected persons; and iii) public health care costs. It has been suggested that optimized dosing of rifampin may shorten treatment duration without losing effectiveness. [4] Furthermore, several new or repurposed drugs, including fluoroquinolones (moxifloxacin, gatifloxacin), a diarylquinoline (TMC207/bedaquiline), nitroimidazoles (PA-824, OPC-67683), an ethylene diamine (SQ-109), a pyrrole (LL-3858) and oxazolidinones (Linezolid, PNU-100480/sutezolid, AZD5847), are currently being evaluated in clinical trials to determine if they can shorten the duration of treatment for MDR-TB from the current 18-24 months with less toxicity relative to currently available second-line drugs. [5] Clofazimine is also being re-investigated as a potential drug for MDR/XDR-TB, as a result of recent insights into novel targets and mechanisms of its antimicrobial and anti-inflammatory activities coupled with the acquisition of innovative drug delivery technologies. [6] In addition, thioridazine has been shown to have activity in vitro and ex vivo against MDR/XDR-TB, as well as in mice infected with MDR-TB, and in patients with XDR-TB. [7],[8]

Many of the above drugs have shown some potential to shorten the duration of treatment of drug-resistant TB in preclinical studies and even in clinical trials when combined with existing anti-TB drugs. After four months of treatment, an MDR-TB-type regimen comprising TMC207, PA-824, and moxifloxacin cured half of mice, whereas all mice receiving the first-line regimen rifampin/isoniazid/pyrazinamide remained lung culture-positive. [9] Attesting to the sterilizing activity of TMC207 against clinical MDR-TB, addition of this diarylquinoline to a standard five-drug, second-line antituberculosis regimen showed reduced time to sputum culture conversion and increased the proportion of patients with conversion of sputum culture relative to placebo. [10]

A paradigm shift from "drug development" to "regimen development", wherein the regimen, not an individual drug, is the unit of development, seems a more feasible approach to deliver sufficiently novel combinations more rapidly. [5] A recent study found that a 4-drug combination of TMC207, PA-824, PNU-100480, and clofazimine, had greater activity against acute TB in the murine model than the standard first-line regimen. [11] Since this experimental regimen lacks any current first- or second-line TB drugs, it is highly promising for the treatment of XDR-TB.

Historically, the standard mouse model has accurately represented the clinical activity of TB drugs. However, significant differences in histopathology between mice and humans have raised concerns about the sole use of mouse models in preclinical anti-TB drug screening. Human TB is characterized histologically by the presence of necrotic granulomas harboring extracellular persistent bacilli. On the other hand, mice infected with M. tuberculosis develop highly cellular lesions lacking central necrosis, in which the bacilli are localized almost exclusively to the intracellular compartment. [2],[12],[13] The guinea pig model of TB, which is characterized by a predominantly extracellular population of bacilli residing within necrotic lung granulomas histologically resembling their human counterparts, is useful in discriminating between purely bactericidal drugs and those with more potent sterilizing activity. Thus, while the bactericidal drugs isoniazid and streptomycin showed potent killing of bacilli during the early phase of treatment, their activity was dramatically reduced against persistent bacilli. [14],[15] In contrast, the uniquely sterilizing drug pyrazinamide was shown to have dose-dependent activity against chronic TB infection in guinea pigs and to exhibit synergy with rifampin, as in humans. [13],[16] A recent study has found that substitution of rifapentine for rifampin in the standard antitubercular regimen did not reduce the time to cure in guinea pigs chronically infected with M. tuberculosis. [17] These results may be quite important, as they contradict similar studies in mice. [18] Preliminary findings from clinical trials investigating the substitution of daily rifapentine for rifampin in the first-line regimen for the treatment of drug-susceptible TB appear to corroborate the findings in the guinea pig model. [19] Although larger animal models, including rabbits and nonhuman primates, [20] form necrotic TB granulomas and cavitary lesions similar to human disease, these are expensive for routine preclinical drug studies and require substantial quantities of drug to achieve therapeutic levels. A novel mouse strain (C3HeB/FeJ) deficient in the intracellular pathogen resistance 1 (Ipr1) gene, which develop highly organized encapsulated necrotic lesions following M. tuberculosis infection but share common drug metabolism properties with BALB/c mice, could assist in further determining the role of lung histology on the potency of each combination regimen. [18]

The emergence of MDR- and XDR-TB further accentuates the need to understand the molecular mechanisms underlying this phenomenon, with the ultimate goal of developing new tools for the rapid detection of drug resistance and identification of new drug targets, including the possibility of host-directed therapies to target non-replicating, persistent bacilli. [2],[3],[7],[19],[21] Novel pharmacogenomics-based approaches have exploited the availability of full genome sequences, computer-aided analysis, and high throughput screening to identify potential anti-TB drug targets. [2],[3],[6],[19],[21]

In conclusion, health policy makers, clinicians, the research community, and patients must all work together towards supporting the development of new, highly-active, universally accessible short-course regimens for the treatment of drug-susceptible and drug-resistant TB. In the meantime, we must ensure a high level of implementation of 'DOTS', especially in high-burden, resource-limited areas in order to achieve our ultimate goal of a TB-free world.

 ~ References Top

1.Karakousis PC. Mechanisms of action and resistance of antimycobacterial agents. In: Mayers DL, editor. Antimicrobial drug resistance. Vol. 1. New York: Humana Press; 2009. p. 271-91.  Back to cited text no. 1
2.Karakousis PC, Williams EP, Bishai WR. Altered expression of isoniazid-regulated genes in drug-treated dormant Mycobacterium tuberculosis. J Antimicrob Chemother 2008;61:323-31.  Back to cited text no. 2
3.Kolyva AS, Karakousis PC. Old and new TB drugs: Mechanisms of action and resistance. In : C0 ardona PJ, editor.Understanding tuberculosis - new approaches to fighting against drug resistance. InTech. ISBN: 978-953-307; 2012. p. 948-56.  Back to cited text no. 3
4.Lauzardo M, Peloquin CA. Antituberculosis therapy for 2012 and beyond. Expert Opin Pharmacother 2012;13:511-26.  Back to cited text no. 4
5.Ma Z, Lienhardt C, McIlleron H, Nunn AJ, Wang X. Global tuberculosis drug development pipeline: The need and the reality. Lancet 2010;375:2100-9.  Back to cited text no. 5
6.Cholo MC, Steel HC, Fourie PB, Germishuizen WA, Anderson R. Clofazimine: Current status and future prospects. J Antimicrob Chemother 2012;67:290-8.  Back to cited text no. 6
7.Dutta NK, Mazumdar K, Dastidar SG, Karakousis PC, Amaral L. New patentable use of an old neuroleptic compound thioridazine to combat tuberculosis: A gene regulation perspective. Recent Pat Antiinfect Drug Discov 2011;6:128- 38.  Back to cited text no. 7
8.Abbate E, Vescovo M, Natiello M, Cufré M, García A, Gonzalez Montaner P, et al. Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and thioridazine. J Antimicrob Chemother 2012;67:473-7.  Back to cited text no. 8
9.Tasneen R, Li SY, Peloquin CA, Taylor D, Williams KN, Andries K, et al. Sterilizing activity of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis. Antimicrob Agents Chemother 2011;55:5485-92.  Back to cited text no. 9
10.Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, et al.The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med 2009;360:2397-405.  Back to cited text no. 10
11.Williams K, Minkowski A, Amoabeng O, Peloquin CA, Taylor D, Andries K, et al. Sterilizing activity of novel combinations lacking first- and second-line drugs in a murine model of tuberculosis. Antimicrob Agents Chemother 2012;56:3114-20.  Back to cited text no. 11
12.Roy CJ, Sivasubramani SK, Dutta NK, Mehra S, Golden NA, Killeen S, et al. Aerosolized gentamicin reduces the burden of tuberculosis in a murine model. Antimicrob Agents Chemother 2012;56:883-6.  Back to cited text no. 12
13.Ahmad Z, Fraig MM, Bisson GP, Nuermberger EL, Grosset JH, Karakousis PC. Dose-dependent activity of pyrazinamide in animal models of intracellular and extracellular tuberculosis infections. Antimicrob Agents Chemother 2011;55:1527-32.  Back to cited text no. 13
14.Ahmad Z, Klinkenberg LG, Pinn ML, Fraig MM, Peloquin CA, Bishai WR, et al. Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, Mycobacterium tuberculosis in the guinea pig. J Infect Dis 2009;200:1136-43.  Back to cited text no. 14
15.Ahmad Z, Pinn ML, Nuermberger EL, Peloquin CA, Grosset JH, Karakousis PC. The potent bactericidal activity of streptomycin in the guinea pig model of tuberculosis ceases due to the presence of persisters. J Antimicrob Chemother 2010;65:2172-5.  Back to cited text no. 15
16.Ahmad Z, Nuermberger EL, Tasneen R, Pinn ML, Williams KN, Peloquin CA, et al. Comparison of the 'Denver regimen' against acute tuberculosis in the mouse and guinea pig. J Antimicrob Chemother 2010;65:729-34.  Back to cited text no. 16
17.Dutta NK, Illei PB, Peloquin CA, Pinn ML, MdluliKE, Nuermberger EL, et al. Rifapentine is not more active than rifampin against chronic tuberculosis in guinea pigs. Antimicrob Agents Chemother 2012;56:3726-31.  Back to cited text no. 17
18.Rosenthal IM, Tasneen R,Peloquin CA,Zhang M, Almeida D, Mdluli KE, et al. Dose-ranging comparison of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis. Antimicrob Agents Chemother 2012; 56:4331-40  Back to cited text no. 18
19.Dorman S, Goldberg S,Feng P,Heilig C, Stout JE,Schluger NW ,et al. A phase II study of a rifapentine-containing regimen for intensive phase treatment of pulmonary tuberculosis : p0 reliminary results for tuberculosis trials consortium study 29. Am J Respir Crit Care Med 2011;183 : A0 6413.  Back to cited text no. 19
20.Dutta NK, Mehra S, Didier PJ, Roy CJ, Doyle LA, Alvarez X, et al. Genetic requirements for the survival of tubercle bacilli in primates. J Infect Dis 2010;201:1743-52.  Back to cited text no. 20
21.Dutta NK, Veeramani B, Lamichhane G, Bader J, Karakousis PC. Computational modeling of genetic requirements for Mycobacterium tuberculosis persistence in vivo and experimental validation in murine lungs. Abstract 112 th Gen Meet Am Soc Microbiol. S0 an Francisco, CA: American Society for Microbiology ;0 2012. P. U-2061.  Back to cited text no. 21

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