Sandbox/mdr
Treatment of Drug-Resistant Tuberculosis
WHO has recommended the following for the susceptibility and response monitoring of MDR-TB Treatment:
- Rapid drug susceptibility testing (DST) of isoniazid and rifampicin or of rifampicin alone is recommended over conventional testing or no testing at the time of diagnosis of TB(subject to available resources
- The use of sputum smear microscopy and culture rather than sputum smear microscopy alone is recommended for the monitoring of patients with MDR-TB during treatment
General principles for Designing MDR-TB Treatment Regimens
|
Drugs Groups for Treatment of MDR-TB
- Anti-TB drugs are grouped according to efficacy, experience of use and drug class.
- All the first-line anti-TB drugs are in (Group 1), except streptomycin, which is classified with the other injectable agents in (Group 2).
- All the drugs in Groups 2–5 (except streptomycin) are second-line, or reserve, drugs.
- The features of the cross-resistance means that resistance mutations (in M. tuberculosis bacteria) to one anti-TB drug may confer resistance to some or all of the members of the drug family of the same group and less commonly to other members of different drug groups (1).
|
Drugs Groups for Treatment of MDR-TB
- Anti-TB drugs are grouped according to efficacy, experience of use and drug class.
- All the first-line anti-TB drugs are in (Group 1), except streptomycin, which is classified with the other injectable agents in (Group 2).
- All the drugs in Groups 2–5 (except streptomycin) are second-line, or reserve, drugs.
- The features of the cross-resistance means that resistance mutations (in M. tuberculosis bacteria) to one anti-TB drug may confer resistance to some or all of the members of the drug family of the same group and less commonly to other members of different drug groups (1).
|
WHO Guidelines for second-line Anti-TB Regimens for MDR
- In the treatment of patients with MDR-TB, a Fluoroquinolone should be used (strong recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, a Ethionamide (or prothionamide) should be used (strong recommendation, very low quality evidence).
- In the treatment of patients with MDR-TB, a later-generation fluoroquinolone rather than an earlier-generation fluoroquinolone should be used (conditional recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, four second-line antituberculosis drugs likely to be effective (including a parenteral agent), as well as pyrazinamide, should be included in the intensive phase3 (conditional recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, regimens should include at least pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide), and either cycloserine or PAS (p-aminosalicylic acid) if cycloserine cannot be used (conditional recommendation,very low quality evidence).
Major changes in recommendation for second-line Anti-TB Regimens for MDR:
- Include at least four second-line Anti-TB drugs likely to be effective as well as pyrazinamide during the intensive phase of treatment.
- No evidence found to support the use of more than four second-line anti-tuberculosis drugs in patients with extensive disease. Increasing the number of second-line drugs in a regimen is permissible if the effectiveness of some of the drugs is uncertain.
- Ethambutol may be used but is not included among the drugs making up the standard regimen.
- Group 5 drugs may be used but are not included among the drugs making up the standard regimen.
Treatment in Special Situations
Culture-Negative Pulmonary Tuberculosis and Radiographic Evidence of Prior Pulmonary Tuberculosis
Failure to isolate M. tuberculosis from persons suspected of having pulmonary tuberculosis on the basis of clinical features and chest radiographic examination does not exclude a diagnosis of active tuberculosis. Alternative diagnoses should be considered carefully and further appropriate diagnostic studies undertaken in persons with apparent culture-negative tuberculosis. The general approach to management is shown in Figure 2. A diagnosis of tuberculosis can be strongly inferred by the clinical and radiographic response to antituberculosis treatment. Careful reevaluation should be performed after 2 months of therapy to determine whether there has been a response attributable to antituberculosis treatment. If either clinical or radiographic improvement is noted and no other etiology is identified, treatment should be continued for active tuberculosis. Treatment regimens in this circumstance include one of the standard 6-month chemotherapy regimens or INH, RIF, PZA, and EMB for 2 months followed by INH and RIF for an additional 2 months (4 months total). However, HIV-infected patients with culture-negative pulmonary tuberculosis should be treated for a minimum of 6 months.
Persons with a positive tuberculin skin test who have radiographic evidence of prior tuberculosis (e.g., upper lobe fibronodular infiltrations) but who have not received adequate therapy are at increased risk for the subsequent development of tuberculosis. Unless previous radiographs are available showing that the abnormality is stable, it is recommended that sputum examination (using sputum induction if necessary) be performed to assess the possibility of active tuberculosis being present. Also, if the patient has symptoms of tuberculosis related to an extrapulmonary site, an appropriate evaluation should be undertaken. Once active tuberculosis has been excluded (i.e., by negative cultures and a stable chest radiograph), the treatment regimens are those used for latent tuberculosis infection: INH for 9 months, RIF (with or without INH) for 4 months, or RIF and PZA for 2 months (for patients who are unlikely to complete a longer course and who can be monitored closely).
Pregnancy and Breastfeeding
Because of the risk of tuberculosis to the fetus, treatment of tuberculosis in pregnant women should be initiated whenever the probability of maternal disease is moderate to high. The initial treatment regimen should consist of INH, RIF, and EMB. Although all of these drugs cross the placenta, they do not appear to have teratogenic effects. Streptomycin is the only antituberculosis drug documented to have harmful effects on the human fetus (congenital deafness) and should not be used. Although detailed teratogenicity data are not available, PZA can probably be used safely during pregnancy and is recommended by the World Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD). If PZA is not included in the initial treatment regimen, the minimum duration of therapy is 9 months.
Breastfeeding should not be discouraged for women being treated with the first-line antituberculosis agents because the small concentrations of these drugs in breast milk do not produce toxicity in the nursing newborn. Conversely, drugs in breast milk should not be considered to serve as effective treatment for tuberculosis or for latent tuberculosis infection in a nursing infant. Pyridoxine supplementation (25 mg/day) is recommended for all women taking INH who are either pregnant or breastfeeding. The amount of pyridoxine in multivitamins is variable but generally less than the needed amount.
Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and Guidelines from the IUATLD
The rise in HIV infections and the neglect of TB control programs have enabled a resurgence of tuberculosis.[1] The emergence of drug-resistant strains has also contributed to this new epidemic with, from 2000 to 2004, 20% of TB cases being resistant to standard treatments and 2% resistant to second-line drugs.[2] TB incidence varies widely, even in neighboring countries, apparently because of differences in health care systems.[3] The World Health Organization declared TB a global health emergency in 1993, and the Stop TB Partnership developed a Global Plan to Stop Tuberculosis aiming to save 14 million lives between 2006 and 2015.[4]
To place the current guidelines in an international context it is necessary to have an understanding of the approaches to treatment of tuberculosis in high-incidence, low-income countries. It is important to recognize that the American Thoracic Society/CDC/Infectious Diseases Society of America (ATS/CDC/IDSA) recommendations cannot be assumed to be applicable under all epidemiologic and economic circumstances. The incidence of tuberculosis and the resources with which to confront the disease to an important extent determine the approaches used. Given the increasing proportion of patients in low-incidence countries who were born in high-incidence countries, it is also important for persons managing these cases to be familiar with the approaches used in the countries of origin.
The major international recommendations and guidelines for treating tuberculosis are those of the WHO and of the IUATLD. The WHO document was developed by an expert committee whereas the IUATLD document is a distillation of IUATLD practice, validated in the field.
The WHO and IUATLD documents target, in general, countries in which mycobacterial culture, drug susceptibility testing, radiographic facilities, and second-line drugs are not widely available as a routine. A number of differences exist between these new ATS/CDC/IDSA recommendations, and the current tuberculosis treatment recommendations of the WHO and guidelines of the IUATLD. Both international sets of recommendations are built around a national case management strategy called "DOTS", the acronym for "Directly Observed Therapy, Short course", in which direct observation of therapy (DOT) is only one of five key elements. The five components of DOTS are 1) government commitment to sustained tuberculosis control activities, 2) case detection by sputum smear microscopy among symptomatic patients self-reporting to health services, 3) a standardized treatment regimen of 6-8 months for at least all confirmed sputum smear-positive cases, with DOT for at least the initial 2 months, 4) a regular, uninterrupted supply of all essential antituberculosis drugs, and 5) a standardized recording and reporting system that enables assessment of treatment results for each patient and of the tuberculosis control program overall.
A Number of Other Differences Exist as Well
The WHO and the IUATLD recommend diagnosis and classification of tuberculosis cases and assessment of response based on sputum AFB smears. Culture and susceptibility testing for new patients is not recommended because of cost, limited applicability, and lack of facilities. Chest radiography is recommended by both the WHO and IUATLD only for patients with negative sputum smears and is not recommended at all for follow-up. Both 6- and 8-month treatment regimens are recommended by the WHO. The IUATLD recommends an 8-month regimen with thioacetazone in the continuation phase for HIV-negative patients. For patients suspected of having or known to have HIV infection, ethambutol is substituted for thioacetazone The WHO and the IUATLD recommend a standardized 8-month regimen for patients who have relapsed, had interrupted treatment, or have failed treatment. Patients who have failed supervised retreatment are considered "chronic" cases and are highly likely to have tuberculosis caused by MDR organisms. Susceptibility testing and a tailored regimen using second-line drugs based on the test results are recommended by the WHO, if testing and second-line drugs are available. The IUATLD recommendations do not address the issue. Neither baseline nor follow-up biochemical testing is recommended by the WHO and the IUATLD. It is recommended that patients be taught to recognize the symptoms associated with drug toxicity and to report them promptly.
New Advances in Pharmacotherapy
A new drug, called Bedalaquine, was recently approved by the FDA in December 2012, to treat multi-drug resistant tuberculosis[5]. About 12 million people worldwide had tuberculosis in 2011, and about 630,000 had multidrug-resistant forms of tuberculosis. Bedaquiline affects theproton pump for ATP synthase, which is unlike the quinolones, whose target is DNA gyrase [6]. It was formally approved for use by the U.S. Food and Drug Administration (FDA) for use intuberculosis (TB) treatment- but it is to be used normally only in cases of multi-drug-resistant tuberculosis, and in an even more resistant category, extensively drug resistant tuberculosis. Multi-drug resistant tuberculosis is defined as tuberculosis cases that do not respond to at least two of the four primary (first-line) antibiotics, developed mostly in the 1950s and 1960s, that are used to treat tuberculosis. The drug has been given a black-box warning for arrhythmias which may cause cardiac arrest [7].
In addition, a novel, 3-drug, anti-TB regimen (PaMZ) consisting of the chemical entity, nitroimidazooxazine, PA-824 (Pa), the fluoroquinolone, moxifloxacin (M), and the first-line TB drug, pyrazinamide (Z), has shown recent promise in the treatment of tuberculosis. The results of a recent phase II clinical trial published in the Lancet, showed that the three drug regimen killed more than 99% of TB bacteria within 2 weeks of treatment.
A Research Agenda for Tuberculosis Treatment
New antituberculosis drugs are needed for three main reasons: 1) to shorten or otherwise simplify treatment of tuberculosis caused by drug-susceptible organisms, 2) to improve treatment of drug-resistant tuberculosis, and 3) to provide more efficient and effective treatment of latent tuberculosis infection. No truly novel compounds that are likely to have a significant impact on tuberculosis treatment are close to clinical trials. However, further work to optimize the effectiveness of once-a-week rifapentine regimens using higher doses of the drug and using rifapentine in combination with moxifloxacin is warranted, on the basis of experimental data.
New categories of drugs that have shown promise for use in treating tuberculosis include the nitroimidazopyrans and the oxazolidinones. Experimental data also suggest that a drug to inhibit an enzyme, isocitrate lyase, thought to be necessary for maintaining the latent state, might be useful for treatment of latent tuberculosis infection.
A number of other interventions that might lead to improved treatment outcome have been suggested, although none has undergone rigorous clinical testing. These include various drug delivery systems, cytokine inhibitors, administration of protective cytokines such as interferon-g and interleukin-2, and nutritional supplements, especially vitamin A and zinc.
Research is also needed to identify factors that are predictive of a greater or lesser risk of relapse to determine optimal length of treatment. Identification of such factors would enable more efficient targeting of resources to supervise treatment. In addition, identification of behavioral factors that identify patients at greater or lesser likelihood of being adherent to therapy would also enable more efficient use of DOT.
Drugs Groups for Treatment of MDR-TB
- Anti-TB drugs are grouped according to efficacy, experience of use and drug class.
- All the first-line anti-TB drugs are in (Group 1), except streptomycin, which is classified with the other injectable agents in (Group 2).
- All the drugs in Groups 2–5 (except streptomycin) are second-line, or reserve, drugs.
- The features of the cross-resistance means that resistance mutations (in M. tuberculosis bacteria) to one anti-TB drug may confer resistance to some or all of the members of the drug family of the same group and less commonly to other members of different drug groups (1).
|
WHO Guidelines for second-line Anti-TB Regimens for MDR
- In the treatment of patients with MDR-TB, a Fluoroquinolone should be used (strong recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, a Ethionamide (or prothionamide) should be used (strong recommendation, very low quality evidence).
- In the treatment of patients with MDR-TB, a later-generation fluoroquinolone rather than an earlier-generation fluoroquinolone should be used (conditional recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, four second-line antituberculosis drugs likely to be effective (including a parenteral agent), as well as pyrazinamide, should be included in the intensive phase3 (conditional recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, regimens should include at least pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide), and either cycloserine or PAS (p-aminosalicylic acid) if cycloserine cannot be used (conditional recommendation,very low quality evidence).
Major changes in recommendation for second-line Anti-TB Regimens for MDR:
- Include at least four second-line Anti-TB drugs likely to be effective as well as pyrazinamide during the intensive phase of treatment.
- No evidence found to support the use of more than four second-line anti-tuberculosis drugs in patients with extensive disease. Increasing the number of second-line drugs in a regimen is permissible if the effectiveness of some of the drugs is uncertain.
- Ethambutol may be used but is not included among the drugs making up the standard regimen.
- Group 5 drugs may be used but are not included among the drugs making up the standard regimen.
Treatment in Special Situations
Culture-Negative Pulmonary Tuberculosis and Radiographic Evidence of Prior Pulmonary Tuberculosis
Failure to isolate M. tuberculosis from persons suspected of having pulmonary tuberculosis on the basis of clinical features and chest radiographic examination does not exclude a diagnosis of active tuberculosis. Alternative diagnoses should be considered carefully and further appropriate diagnostic studies undertaken in persons with apparent culture-negative tuberculosis. The general approach to management is shown in Figure 2. A diagnosis of tuberculosis can be strongly inferred by the clinical and radiographic response to antituberculosis treatment. Careful reevaluation should be performed after 2 months of therapy to determine whether there has been a response attributable to antituberculosis treatment. If either clinical or radiographic improvement is noted and no other etiology is identified, treatment should be continued for active tuberculosis. Treatment regimens in this circumstance include one of the standard 6-month chemotherapy regimens or INH, RIF, PZA, and EMB for 2 months followed by INH and RIF for an additional 2 months (4 months total). However, HIV-infected patients with culture-negative pulmonary tuberculosis should be treated for a minimum of 6 months.
Persons with a positive tuberculin skin test who have radiographic evidence of prior tuberculosis (e.g., upper lobe fibronodular infiltrations) but who have not received adequate therapy are at increased risk for the subsequent development of tuberculosis. Unless previous radiographs are available showing that the abnormality is stable, it is recommended that sputum examination (using sputum induction if necessary) be performed to assess the possibility of active tuberculosis being present. Also, if the patient has symptoms of tuberculosis related to an extrapulmonary site, an appropriate evaluation should be undertaken. Once active tuberculosis has been excluded (i.e., by negative cultures and a stable chest radiograph), the treatment regimens are those used for latent tuberculosis infection: INH for 9 months, RIF (with or without INH) for 4 months, or RIF and PZA for 2 months (for patients who are unlikely to complete a longer course and who can be monitored closely).
Pregnancy and Breastfeeding
Because of the risk of tuberculosis to the fetus, treatment of tuberculosis in pregnant women should be initiated whenever the probability of maternal disease is moderate to high. The initial treatment regimen should consist of INH, RIF, and EMB. Although all of these drugs cross the placenta, they do not appear to have teratogenic effects. Streptomycin is the only antituberculosis drug documented to have harmful effects on the human fetus (congenital deafness) and should not be used. Although detailed teratogenicity data are not available, PZA can probably be used safely during pregnancy and is recommended by the World Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD). If PZA is not included in the initial treatment regimen, the minimum duration of therapy is 9 months.
Breastfeeding should not be discouraged for women being treated with the first-line antituberculosis agents because the small concentrations of these drugs in breast milk do not produce toxicity in the nursing newborn. Conversely, drugs in breast milk should not be considered to serve as effective treatment for tuberculosis or for latent tuberculosis infection in a nursing infant. Pyridoxine supplementation (25 mg/day) is recommended for all women taking INH who are either pregnant or breastfeeding. The amount of pyridoxine in multivitamins is variable but generally less than the needed amount.
Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and Guidelines from the IUATLD
The rise in HIV infections and the neglect of TB control programs have enabled a resurgence of tuberculosis.[8] The emergence of drug-resistant strains has also contributed to this new epidemic with, from 2000 to 2004, 20% of TB cases being resistant to standard treatments and 2% resistant to second-line drugs.[2] TB incidence varies widely, even in neighboring countries, apparently because of differences in health care systems.[3] The World Health Organization declared TB a global health emergency in 1993, and the Stop TB Partnership developed a Global Plan to Stop Tuberculosis aiming to save 14 million lives between 2006 and 2015.[9]
To place the current guidelines in an international context it is necessary to have an understanding of the approaches to treatment of tuberculosis in high-incidence, low-income countries. It is important to recognize that the American Thoracic Society/CDC/Infectious Diseases Society of America (ATS/CDC/IDSA) recommendations cannot be assumed to be applicable under all epidemiologic and economic circumstances. The incidence of tuberculosis and the resources with which to confront the disease to an important extent determine the approaches used. Given the increasing proportion of patients in low-incidence countries who were born in high-incidence countries, it is also important for persons managing these cases to be familiar with the approaches used in the countries of origin.
The major international recommendations and guidelines for treating tuberculosis are those of the WHO and of the IUATLD. The WHO document was developed by an expert committee whereas the IUATLD document is a distillation of IUATLD practice, validated in the field.
The WHO and IUATLD documents target, in general, countries in which mycobacterial culture, drug susceptibility testing, radiographic facilities, and second-line drugs are not widely available as a routine. A number of differences exist between these new ATS/CDC/IDSA recommendations, and the current tuberculosis treatment recommendations of the WHO and guidelines of the IUATLD. Both international sets of recommendations are built around a national case management strategy called "DOTS", the acronym for "Directly Observed Therapy, Short course", in which direct observation of therapy (DOT) is only one of five key elements. The five components of DOTS are 1) government commitment to sustained tuberculosis control activities, 2) case detection by sputum smear microscopy among symptomatic patients self-reporting to health services, 3) a standardized treatment regimen of 6-8 months for at least all confirmed sputum smear-positive cases, with DOT for at least the initial 2 months, 4) a regular, uninterrupted supply of all essential antituberculosis drugs, and 5) a standardized recording and reporting system that enables assessment of treatment results for each patient and of the tuberculosis control program overall.
A Number of Other Differences Exist as Well
The WHO and the IUATLD recommend diagnosis and classification of tuberculosis cases and assessment of response based on sputum AFB smears. Culture and susceptibility testing for new patients is not recommended because of cost, limited applicability, and lack of facilities. Chest radiography is recommended by both the WHO and IUATLD only for patients with negative sputum smears and is not recommended at all for follow-up. Both 6- and 8-month treatment regimens are recommended by the WHO. The IUATLD recommends an 8-month regimen with thioacetazone in the continuation phase for HIV-negative patients. For patients suspected of having or known to have HIV infection, ethambutol is substituted for thioacetazone The WHO and the IUATLD recommend a standardized 8-month regimen for patients who have relapsed, had interrupted treatment, or have failed treatment. Patients who have failed supervised retreatment are considered "chronic" cases and are highly likely to have tuberculosis caused by MDR organisms. Susceptibility testing and a tailored regimen using second-line drugs based on the test results are recommended by the WHO, if testing and second-line drugs are available. The IUATLD recommendations do not address the issue. Neither baseline nor follow-up biochemical testing is recommended by the WHO and the IUATLD. It is recommended that patients be taught to recognize the symptoms associated with drug toxicity and to report them promptly.
New Advances in Pharmacotherapy
A new drug, called Bedalaquine, was recently approved by the FDA in December 2012, to treat multi-drug resistant tuberculosis[10]. About 12 million people worldwide had tuberculosis in 2011, and about 630,000 had multidrug-resistant forms of tuberculosis. Bedaquiline affects theproton pump for ATP synthase, which is unlike the quinolones, whose target is DNA gyrase [6]. It was formally approved for use by the U.S. Food and Drug Administration (FDA) for use intuberculosis (TB) treatment- but it is to be used normally only in cases of multi-drug-resistant tuberculosis, and in an even more resistant category, extensively drug resistant tuberculosis. Multi-drug resistant tuberculosis is defined as tuberculosis cases that do not respond to at least two of the four primary (first-line) antibiotics, developed mostly in the 1950s and 1960s, that are used to treat tuberculosis. The drug has been given a black-box warning for arrhythmias which may cause cardiac arrest [11].
In addition, a novel, 3-drug, anti-TB regimen (PaMZ) consisting of the chemical entity, nitroimidazooxazine, PA-824 (Pa), the fluoroquinolone, moxifloxacin (M), and the first-line TB drug, pyrazinamide (Z), has shown recent promise in the treatment of tuberculosis. The results of a recent phase II clinical trial published in the Lancet, showed that the three drug regimen killed more than 99% of TB bacteria within 2 weeks of treatment.
A Research Agenda for Tuberculosis Treatment
New antituberculosis drugs are needed for three main reasons: 1) to shorten or otherwise simplify treatment of tuberculosis caused by drug-susceptible organisms, 2) to improve treatment of drug-resistant tuberculosis, and 3) to provide more efficient and effective treatment of latent tuberculosis infection. No truly novel compounds that are likely to have a significant impact on tuberculosis treatment are close to clinical trials. However, further work to optimize the effectiveness of once-a-week rifapentine regimens using higher doses of the drug and using rifapentine in combination with moxifloxacin is warranted, on the basis of experimental data.
New categories of drugs that have shown promise for use in treating tuberculosis include the nitroimidazopyrans and the oxazolidinones. Experimental data also suggest that a drug to inhibit an enzyme, isocitrate lyase, thought to be necessary for maintaining the latent state, might be useful for treatment of latent tuberculosis infection.
A number of other interventions that might lead to improved treatment outcome have been suggested, although none has undergone rigorous clinical testing. These include various drug delivery systems, cytokine inhibitors, administration of protective cytokines such as interferon-g and interleukin-2, and nutritional supplements, especially vitamin A and zinc.
Research is also needed to identify factors that are predictive of a greater or lesser risk of relapse to determine optimal length of treatment. Identification of such factors would enable more efficient targeting of resources to supervise treatment. In addition, identification of behavioral factors that identify patients at greater or lesser likelihood of being adherent to therapy would also enable more efficient use of DOT.
- ↑ Iademarco MF, Castro KG (2003). "Epidemiology of tuberculosis". Seminars in respiratory infections. 18 (4): 225–40. PMID 14679472.
- ↑ 2.0 2.1 "Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs—worldwide, 2000–2004". MMWR Morb Mortal Wkly Rep. 55 (11): 301–5. 2006. PMID 16557213.
- ↑ 3.0 3.1 Sobero R, Peabody J (2006). "Tuberculosis control in Bolivia, Chile, Colombia and Peru: why does incidence vary so much between neighbors?". Int J Tuberc Lung Dis. 10 (11): 1292–5. PMID 17131791.
- ↑ World Health Organization (WHO). Stop TB Partnership. Retrieved on 3 October 2006.
- ↑ Matteelli A, Carvalho AC, Dooley KE, Kritski A (2010). "TMC207: the first compound of a new class of potent anti-tuberculosis drugs". Future Microbiol. 5 (6): 849–58. doi:10.2217/fmb.10.50. PMC 2921705. PMID 20521931. Unknown parameter
|month=ignored (help) - ↑ 6.0 6.1 Kotz J (2005). "Targeting tuberculosis". Nature Chemical Biology. doi:10.1038/nchembio002. Unknown parameter
|month=ignored (help) - ↑ http://news.msn.com/science-technology/fda-approves-1st-new-tuberculosis-drug-in-40-years-1?
- ↑ Iademarco MF, Castro KG (2003). "Epidemiology of tuberculosis". Seminars in respiratory infections. 18 (4): 225–40. PMID 14679472.
- ↑ World Health Organization (WHO). Stop TB Partnership. Retrieved on 3 October 2006.
- ↑ Matteelli A, Carvalho AC, Dooley KE, Kritski A (2010). "TMC207: the first compound of a new class of potent anti-tuberculosis drugs". Future Microbiol. 5 (6): 849–58. doi:10.2217/fmb.10.50. PMC 2921705. PMID 20521931. Unknown parameter
|month=ignored (help) - ↑ http://news.msn.com/science-technology/fda-approves-1st-new-tuberculosis-drug-in-40-years-1?