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TB Drugs – First line, second line & new TB drugs

There are more than twenty drugs that are currently used for the treatment of TB and almost all of them were developed some years ago. The drugs are used in differing combinations in different circumstances. For example some TB drugs are only used for the treatment of new patients who are very unlikely to have resistance to any of the TB drugs. There are other TB drugs that are only used for the treatment of drug resistant TB.1“Treatment of Tuberculosis guidelines”, WHO, Geneva, 2010, 85 www.who.int/tb/en/

TB drugs – the basic drugs

The five basic or “first line” TB drugs are:2“Treatment of Tuberculosis Guidelines”, WHO, Geneva, 2010, 30 www.who.int/tb/

  • Isoniazid
  • Rifampicin
  • Pyrazinamide
  • Ethambutol
  • and Streptomycin

These are the TB drugs that generally have the greatest activity against TB bacteria and they are core to any TB drug treatment program. These TB drugs are particularly used for someone with active TB disease who has not had TB drug treatment before.

All the other TB drugs are generally referred to as “second line” or reserve TB drugs.

TB drug treatment for new patients

New patients are those who have either not had any TB treatment before, or they have had less than one month of anti TB drugs. New patients are presumed to have drug susceptible TB (i.e. TB which is not resistant to any of the drugs) unless there is a high level of isoniazid resistance in new patients in the area, or the patient has developed active TB disease after they have had contact with a patient who is known to have drug resistant TB.

For these patients the World Health Organisation (WHO) recommends that they should have six months of TB drug treatment. This should consist of a two month “intensive” treatment phase followed by a four month “continuation” phase.

For the two month “intensive” TB drug treatment phase they should receive:

  • Isoniazid
  • with rifampicin
  • and pyrazinamide
  • and ethambutol

followed by

  • Isoniazid
  • with rifampicin

for the “continuation” TB drug treatment phase.

It is essential to take several TB drugs together. If only one TB drug is taken on its own, then the patient will very quickly become resistant to that drug.

TB drugs © WHO

TB drugs © WHO

It is recommended that patients take the TB drugs every day for the six months, although taking them three times a week is possible in some circumstances. It is extremely important that all the recommended TB drugs are taken for the entire time.

If only one or two of the TB drugs are taken, or the treatment is interrupted or stopped early, then the treatment probably won’t work. This is because the TB bacteria that a patient has develops resistance to the TB drugs. Not only is the patient then still ill, but to be cured they then have to take drugs for the treatment of drug resistant TB. These drugs are more expensive, have more side effects, and have to be taken for longer.

TB drugs for the treatment of drug resistant TB

For the treatment of drug resistant TB, the current TB drugs are grouped according their effectiveness, experience of use, and drug class, as shown below.

All the first line TB drugs are in Group or class 1, apart from streptomycin which is with the other injectable agents in Group 2. All the drugs in Groups 2 to 5, apart from streptomycin, are referred to as “second line” or reserve TB drugs.3“Treatment of Tuberculosis Guidelines”, WHO, Geneva, 2010, 84 www.who.int/tb/

The first four groups of TB drugs listed below, are those that are mainly used for the treatment of drug resistant TB. The fifth group of TB drugs are some drugs that are unknown in how effective they are in the treatment of TB, but they can be tried when there is no other option. An example is using them in the treatment of totally drug resistant TB.

TB drugs used to treat drug resistant TB according to group (class)

Group 1 TB drugs : First Line Oral Agents
pyrazinamide
ethambutol
rifabutin
Group 2 TB drugs : Injectable Agents
kanamycin
amikacin
capreomycin
streptomycin
Group 3 TB drugs : Fluoroquinolones
levofloxacin
moxifloxacin
ofloxacin
Group 4 TB drugs : Oral Bacteriostatic Second Line Agents
para–aminosalicylic acid
cycloserine
terizidone
thionamide
protionamide
Group 5 TB drugs: Agents with an unclear role in the treatment of drug resistant TB
clofazimine
linezolid
amoxicillin/clavulanate
thioacetazone
imipenem/cilastatin
high dose isoniazid
clarithromycin

Very few actual trials have been carried out of the drugs in Group 5 to see how effective they actually are in the treatment of drug resistant TB. For example, the drug linezolid is an antibiotic usually used to treat severe bacterial infections. The first trial has just been carried out of this drug looking at the use of it in treating XDR-TB. It was a small trial but it did show that the drug was effective when added to patients current treatments, although most of the patients experienced side effects.4Steenhuysen, J. “Drug showed promise in clearing drug-resistant tuberculosis”, Reuters, 17 October 2012 www.reuters.com/article/2012/

Further information about how the anti TB drugs are used to treat drug resistant TB, and about the role of drug susceptibility testing, can be found on the treatment of drug resistant TB page.

The cost of TB drugs

The cost of drugs per patient, amounts to less than US$40 in low and middle income countries, and is around US$50 in upper middle income countries. This is the cost of treatment with first line anti TB drugs. The unit cost for second line anti TB drugs, is much greater than for first line drugs.5“Global Tuberculosis Control 2012”, WHO, Geneva, 2012, www.who.int/tb/publications/global_report/

Shortages of TB drugs

In June 2013 it was reported that severe shortages of some TB drugs were occurring in a number of countries, including the U.S. and India.6Anand, Geeta “Shortages of Drugs Threaten TB Fight”, The Wall Street Journal, 6 June 2013 online.wsj.com/article/ Particularly affected were the drugs used for the treatment of TB in children, with adult doses of drugs on occasions being divided up to provide the dosages required for children. In India the drugs rifampicin, streptomycin and kanamycin used for adults were also in short supply.

India apparently solved the problem of the shortage of adult dosages by letting the states buy the drugs themselves from private suppliers and by making emergency purchases. However, this was not possible for the children’s drugs, because private suppliers mainly make the daily dosages of the children’s drugs, whilst under the government’s treatment plan children receive their medication on alternate days.

Why are new TB drugs needed?

New TB drugs are needed because of the complexity and toxicity of the current TB drug regimes and the major problem of TB drug resistance. This together with the problem of the interactions of the current TB drugs with the antiretroviral drugs taken by HIV positive people, means that there is an urgent need for new TB drugs. However, what is required of these new TB drugs is considerable as:

New TB drugs need to provide:7Ginsberg, A. “Drugs in Development for Tuberculosis”, Drugs, 70(17), 3 December 2010, 2201-2214 adisonline.com/drugs/Fulltext/2010/70170/Drugs_in_Development_for_Tuberculosis

  • Shorter and simpler, but still affordable, multi drug regimes for drug sensitive TB
  • Shorter, more effective , less toxic, and less expensive regimes for drug resistant TB
  • Short, simple, easily tolerable and safe regimes for latent TB
  • Drugs with few drug drug interactions, so they can be safely provided to people with HIV

TB drug trials

Before a TB drug is made available for general use it needs to go through a series of clinical trials, to check that amongst other things, that as a TB drug it is effective and doesn’t have too many side effects. The main trials for any drug are referred to as phases 1, 2 and 3. In addition there are now trials referred to as phase 2a and phase 2b.8“Phases of clinical research”, Wikipedia https://en.wikipedia.org/wiki/Phases_of_clinical_research Those drugs going through a phase 3 trial are the closest to being made available for general use, provided of course that the phase 3 trial is successful.9“Understanding Clinical Trials”, U . S. National Institutes of Health clinicaltrials.gov/

Phase three trials for TB drugs take a long time. Such a trial requires a lengthy TB drug treatment period, followed by a one to two year period of patient follow up to determine treatment failure and relapse, in order to then know the effectiveness of the drug.

A drugs “pipeline” in drug development terms, refers to all the drugs at different stages of development, and how the drugs progress down the “pipeline” through the various clinical trial stages etc., until at the point at which they exit the “pipeline” they are available for general use.

The American NIAID is looking at the efficiency of the various stages of TB drug trials, and is trying to improving their design, as well as improving collaboration amongst researchers and companies.10Hafner, R. “NIAID TB Therapeutic Clinical Research Priorities”, Working Group on New TB Drugs 2011 Annual Meeting, 25-26 October 2011 www.newtbdrugs.org/meetings/annual-meeting-2011 However, organisations such as the American Thoracic Society have been calling for innovative collaborative relationships to aid new TB drug development since at least 1998, and there are still no new TB drugs.11O’Brien, R. “New Tuberculosis Drug Development How Can We Do Better?”, Am. J. Respir. Crit. Care Med., 157(6), 1 June 1998, 1705-1707 ajrccm.atsjournals.org/

New TB drugs under clinical development

The pipeline below of new drugs for TB under clinical development is not considered to be a very extensive drugs “pipeline” for such a major disease as TB.12Zhenkun, Ma. “Global tuberculosis drug development pipeline: the need and the reality”, The Lancet, Vol 375(9731), 12 June 2010, 2011-2109 www.thelancet.com/journals/lancet

TB drug clinical development pipeline
Phase 1 Phase 2 Phase 3
Q203-Novel anti-TB agent
Imidazopyridine
Sutezolid (PNU-100480)
Oxazolidinone
Bedaquiline (TMC207)
with OBR for MDR-TB
Diarylquinoline OBR = Optimized Background Regimen
SQ109
Ethylenediamine
Delamanid (OPC-67683)
with OBR for MDR-TB
Nitro-dihydro-imidazooxazole
Rifapentine for DS-TB
Rifamycin
Pretomanid – Moxifloxacin – Pyrazinamide
New chemical entity
Bedaquiline – Pretomanid – Pyrazinamide
Levofloxacin
Fluoroquinolone

The table below is of projects that have been put on hold, or paused or completed.

Projects put on hold, paused or completed
Phase 1 Phase 2 Phase 3
TBA-354

Nitroimidazole

AZD5847

Oxazolidinone

Gatifloxacin

Fluoroquinolone

Moxifloxacin for

Drug-Sensitive TB

©2016 Working Group on New TB Drugs13www.newtbdrugs.org/pipeline.php 14www.newtbdrugs.org/pipeline-hold.php

TB drug bedaquiline

Bedaquiline is the active substance in the new TB drug Sirturo. Sirturo is available for the treatment of drug resistant TB, when there are an insufficient numbers of other TB drugs available. There is much more about bedaquiline.

The Nitroimidazoles

The Nitroimidazoles are an existing class of drugs known to have antimicrobial activity. Two “next generation” or derivatives of this class of drugs, OPC-67683 (now also known as Delamanid) and PA-824 are under development as potential TB drugs.15“OPC-67683”, www.tbonline.info/

TB drug Delamanid (OPC-67683)

Delamanid is a member of the nitroimidazo-oxazole family, and although early studies showed it to be a potentially effective drug for both drug resistant and drug susceptible TB, it is currently being initially developed by the Otsuka pharmaceutical company as a treatment for multi drug resistant TB.

In July 2012 the results of a phase 2B trial showed delamanid plus a background regimen resulted in more study subjects becoming non-infectious after two months than a placebo plus a background regimen. The trial was conducted in 17 centres in nine countries.16“The New England Journal of Medicine Publishes Efficacy Results of Otsuka’s Delamanid for Multidrug-Resistant Tuberculosis”, Business Wire, www.businesswire.com/news/home/20120606005698/en/England-Journal-Medicine-Publishes-Efficacy-Results-Otsukas Among patients who received a background regimen plus 100 mg of delamanid twice daily, 45.4% had culture conversion at two months as compared with 29.6% of patients who received background plus placebo.17Gler, M. “Delamanid for Multidrug-Resistant Pulmonary Tuberculosis”, New England Journal of Medicine, 7 June 2012, www.nejm.org/doi/full/10.1056/NEJMoa1112433

Patients who took part in two earlier studies were also then able to take part in a 24 month observational study designed to look at treatment outcomes. This observational study found that favourable outcomes were observed in about three quarters of the patients who received Delamanid for more than six months as compared to about half of the patients who received Delamanid for less than two months.18“Delamanid Improves Outcomes and Reduces Mortality for Multidrug-Resistant Tuberculosis”, European Respiratory Journal, //erj.ersjournals.com/content

The Otsuka company has also started a phase three trial of Delamanid. The trial which started in September 2011, is designed to show whether Delamanid is both safe and effective when given as TB drug treatment over a six month period. The completion date for the first tests of effectiveness is August 2013.19“Safety and Efficacy Trial of Delamanid for 6 Months in Patients With Multidrug Resistant Tuberculosis”, FierceBiotech, //clinicaltrialsfeeds.org/

In July 2013 Otsuka was refused approval by the European Medicines Agency for Delamanid to be used as a TB drug.20“Otsuka’s Drug-Resistant TB Treatment Fails to Win EMA Nod”, http://www.bloomberg.com/news/2013-07-26/

TB drug Pretomanid (PA-824)

PA-824 is another nitroimidazo-oxazole currently being developed by the TB Alliance. It also can potentially be used for the treatment of both drug sensitive and drug resistant TB, and it has also shown activity against both latent and active TB. A phase two study of PA-824 is currently being carried out, but there have been some setbacks with the development of this drug and the clinical trials are taking a very long time.21“PA-824”, www.tballiance.org/news/pa-824-has-new-generic-name-pretomanid

TB drug TBA-354

TBA-354 is a drug in the same class as PA-824 but it has been more potent in preclinical studies. It is also said to be longer lasting and has greater activity against resistant strains of the disease. TBA-354 was selected by the TB Alliance for further development.22“Promising New Zealand compound selected as drug candidate for tuberculosis”, University of Auckland, 21 September 2012 https://www.fmhs.auckland.ac.nz/en/faculty/about/news-and-events/news/2012/09/21/promising-new-zealand.html The first human trial of TBA-354 started in February 2015.23www.tballiance.org/news/tb-alliance-advances-next-generation-tb-drug-candidate-clinical-testing The phase 1 trial was started in January 2016 and in March 2016 it was announced that the TB Alliance had voluntarily halted the clinical development program for TBA-354.24“Phase 1 Clinical Trial of TB Drug Candidate TBA-354 Discontinued”, www.tballiance.org/news/phase-1-clinical-trial-tb-drug-candidate-tba-354-discontinued

AZD5847

AZD5847 is a potential new TB drug being developed by AstraZeneca. In December 2012 it was announced that the first patient had been enrolled in a Phase 2a trial of the drug in South Africa, to assess the effectiveness of the drug for patients with TB, including patients with HIV and TB coinfection.25“AstraZeneca, Case Western Reserve initiate AZD5847 Phase 2a trial in TB”, 12 December 2012, www.news-medical.net/news/20121212/AstraZeneca-Case-Western-Reserve-initiate-AZD5847-Phase-2a-trial-in-TB The study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the U.S. National Institutes of Health.

The Fluoroquinolones

Several members of the fluoroquinoles class of drugs are currently already used as second line TB drugs for the treatment of multi drug resistant TB. However, the older drugs such as ofloxacin and levofloxacin are often used rather than the newer fluoroquinolones moxifloxacin and gatifloxacin. Moxifloxacin and gatifloxacin are currently being developed for the treatment of drug sensitive TB. Each of these potential TB drugs is currently undergoing evaluation in a phase 3 trial, to see how effective it is when substituted for either ethambutol or isoniazid, to shorten the treatment of drug sensitive TB from the standard six months to four months. The gatifloxacin trial is being conducted by the Oflotub Consortium and moxifloxacin is being developed by Bayer and the TB Alliance.26Ginsberg, A. “Drugs in Development for Tuberculosis”, Drugs, 70(17), 3 December 2010, 2201-2214 adisonline.com/drugs/Fulltext/2010/70170/Drugs_in_Development_for_Tuberculosis

The Rifamycins

The Rifamycins are potent inhibitors of mycobacterial activity. Three semi synthetic rifamycins – rifampicin, rifapentine, and rifabutin – have been used for the treatment of various microbial infections. Rifampicin is a key component of first line drug treatment for TB. Rifapentine is attractive as a possible TB drug for shortening treatment, and for intermittent TB drug treatment, and clinical trials are under way to further assess this.27Zhenkun, Ma. “Global tuberculosis drug development pipeline: the need and the reality”, The Lancet, Vol 375(9731), 12 June 2010, 2011-2109 www.thelancet.com/journals/lancet

TB drug combinations

What is ideally needed is not just one new TB drug but several which can be used together. In July 2012 it was announced that a phase 2A study had been carried out investigating a number of drug combinations including PA-824 over a 14 day period to assess their suitability for further development. The combination of PA-824 moxifloxacin and pyrazinamide had the greatest early bactericidal activity (EBA).

One advantage of this drug combination is that it does not involve either isoniazid or rifampicin. It is therefore suitable for use with patients who are resistant to these drugs. A regimen without rifampicin would greatly simplify the provision of TB treatment alongside HIV antiretroviral therapy.

This three drug combination now needs to be further investigated over a longer period of time, taking into account that PA-824 and moxifloxacin all have at least some potential to cause cardiac side effects.28Diacon, A. “14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial”, The Lancet, 23 July 2012, www.thelancet.com/journals/lancet/article/

References

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1. “Treatment of Tuberculosis guidelines”, WHO, Geneva, 2010, 85 www.who.int/tb/en/
2. “Treatment of Tuberculosis Guidelines”, WHO, Geneva, 2010, 30 www.who.int/tb/
3. “Treatment of Tuberculosis Guidelines”, WHO, Geneva, 2010, 84 www.who.int/tb/
4. Steenhuysen, J. “Drug showed promise in clearing drug-resistant tuberculosis”, Reuters, 17 October 2012 www.reuters.com/article/2012/
5. “Global Tuberculosis Control 2012”, WHO, Geneva, 2012, www.who.int/tb/publications/global_report/
6. Anand, Geeta “Shortages of Drugs Threaten TB Fight”, The Wall Street Journal, 6 June 2013 online.wsj.com/article/
7. Ginsberg, A. “Drugs in Development for Tuberculosis”, Drugs, 70(17), 3 December 2010, 2201-2214 adisonline.com/drugs/Fulltext/2010/70170/Drugs_in_Development_for_Tuberculosis
8. “Phases of clinical research”, Wikipedia https://en.wikipedia.org/wiki/Phases_of_clinical_research
9. “Understanding Clinical Trials”, U . S. National Institutes of Health clinicaltrials.gov/
10. Hafner, R. “NIAID TB Therapeutic Clinical Research Priorities”, Working Group on New TB Drugs 2011 Annual Meeting, 25-26 October 2011 www.newtbdrugs.org/meetings/annual-meeting-2011
11. O’Brien, R. “New Tuberculosis Drug Development How Can We Do Better?”, Am. J. Respir. Crit. Care Med., 157(6), 1 June 1998, 1705-1707 ajrccm.atsjournals.org/
12. Zhenkun, Ma. “Global tuberculosis drug development pipeline: the need and the reality”, The Lancet, Vol 375(9731), 12 June 2010, 2011-2109 www.thelancet.com/journals/lancet
13. www.newtbdrugs.org/pipeline.php
14. www.newtbdrugs.org/pipeline-hold.php
15. “OPC-67683”, www.tbonline.info/
16. “The New England Journal of Medicine Publishes Efficacy Results of Otsuka’s Delamanid for Multidrug-Resistant Tuberculosis”, Business Wire, www.businesswire.com/news/home/20120606005698/en/England-Journal-Medicine-Publishes-Efficacy-Results-Otsukas
17. Gler, M. “Delamanid for Multidrug-Resistant Pulmonary Tuberculosis”, New England Journal of Medicine, 7 June 2012, www.nejm.org/doi/full/10.1056/NEJMoa1112433
18. “Delamanid Improves Outcomes and Reduces Mortality for Multidrug-Resistant Tuberculosis”, European Respiratory Journal, //erj.ersjournals.com/content
19. “Safety and Efficacy Trial of Delamanid for 6 Months in Patients With Multidrug Resistant Tuberculosis”, FierceBiotech, //clinicaltrialsfeeds.org/
20. “Otsuka’s Drug-Resistant TB Treatment Fails to Win EMA Nod”, http://www.bloomberg.com/news/2013-07-26/
21. “PA-824”, www.tballiance.org/news/pa-824-has-new-generic-name-pretomanid
22. “Promising New Zealand compound selected as drug candidate for tuberculosis”, University of Auckland, 21 September 2012 https://www.fmhs.auckland.ac.nz/en/faculty/about/news-and-events/news/2012/09/21/promising-new-zealand.html
23. www.tballiance.org/news/tb-alliance-advances-next-generation-tb-drug-candidate-clinical-testing
24. “Phase 1 Clinical Trial of TB Drug Candidate TBA-354 Discontinued”, www.tballiance.org/news/phase-1-clinical-trial-tb-drug-candidate-tba-354-discontinued
25. “AstraZeneca, Case Western Reserve initiate AZD5847 Phase 2a trial in TB”, 12 December 2012, www.news-medical.net/news/20121212/AstraZeneca-Case-Western-Reserve-initiate-AZD5847-Phase-2a-trial-in-TB
26. Ginsberg, A. “Drugs in Development for Tuberculosis”, Drugs, 70(17), 3 December 2010, 2201-2214 adisonline.com/drugs/Fulltext/2010/70170/Drugs_in_Development_for_Tuberculosis
27. Zhenkun, Ma. “Global tuberculosis drug development pipeline: the need and the reality”, The Lancet, Vol 375(9731), 12 June 2010, 2011-2109 www.thelancet.com/journals/lancet
28. Diacon, A. “14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial”, The Lancet, 23 July 2012, www.thelancet.com/journals/lancet/article/