Treatment of drug-susceptible tuberculosis

Most patients are infected by drug-susceptible strains and can be cured with the standard six-month first-line regimen. The preferred regimen for treating adults with tuberculosis (TB) caused by organisms that are not known or suspected to be drug resistant is a regimen consisting of an intensive phase of 2 months of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) followed by a continuation phase of 4 months of INH and RIF. If therapy is being initiated after drug susceptibility test results are known and the patient’s isolate is susceptible to both INH and RIF, EMB is not necessary, and the intensive phase can consist of INH, RIF, and PZA only. Special recommendations on the management of tuberculosis in special situations, (patients having diabetes, HIV infection, or any other immunosuppressing condition, children, TB during pregnancy and breastfeeding, extensive disease, extra pulmonary TB …) are available in Nahid et al. [1]

[1] Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, et al. Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis 2016;63:853–67. doi:10.1093/cid/ciw566.

Treatment of MDR and XDR TB

• Multidrug resistance (MDR) is resistance to at least both isoniazid and rifampicin. • Extensive drug resistance (XDR) is resistance to any fluoroquinolone, and at least one of three second-line injectable drugs (capreomycin, kanamycin and amikacin), in addition to multidrug resistance.

Resistance to TB drugs is a formidable obstacle to effective TB care and prevention globally. The causes for MDR and XDR-TB phenotypes are multifactorial and fuelled by improper treatment of patients, poor management of supply, and quality of drugs, and airborne transmission of bacteria in public places. Case management becomes difficult and the challenge is compounded by catastrophic economic and social costs that patients incur while seeking help and on treatment. World Health Organization Handbook has been developed for the purpose of describing ways to implement established World Health Organization policies relevant for the management of MDR-TB. [1] In May 2016, WHO updated its treatment guidelines for drug-resistant TB including the use of the shorter MDR-TB regimen that has been used in a number of countries showing promising results in selected MDR-TB patients [2].

Shorter MDR-TB regimen composition: 4-6 Km-Mfx-Pto-Cfz-Z-Hhigh-dose-E / 5 Mfx-Cfz-Z-E Km=Kanamycin; Mfx=Moxifloxacin; Pto=Prothionamide; Cfz=Clofazimine; Z=Pyrazinamide; Hhigh-dose= high-dose Isoniazid; E=Ethambutol

1] WHO consolidated guidelines on drug-resistant tuberculosis treatment. World Health Organization; 2019.

[2] Trébucq A, Schwoebel V, Kashongwe Z, Bakayoko A, Kuaban C, Noeske J, et al. Treatment outcome with a short multidrug-resistant tuberculosis regimen in nine African countries. Int J Tuberc Lung Dis 2018;22:17–25. doi:10.5588/ijtld.17.0498.

New drugs and perspectives

New drugs against TB are currently needed to lessen the toxicity and increase the tolerability of current treatments for drug-resistant TB. The past decade has seen some progress in bringing new TB drugs to patients with drug-resistant TB. Thanks to S. Dorman (MOOC Tuberculosis 2018) we describe examples of new drugs that are being used for TB.

Bedaquiline

Bedaquiline is a diarylquinoline and it targets the ATP synthase of Mycobacterium tuberculosis. Bedaquiline has a long half-life and it accumulates in tissues. It also has an important drug-drug interaction with rifampin. The bedaquiline drug development in clinical trial process took place over about 10 to 15 years. Bedaquiline was discovered through a whole-bacterial screening approach. Mouse studies early on suggested a treatment shortening potential. After that, a series of phase-2 studies were undertaken. Interestingly, the early bactericidal activity of bedaquiline was found to be modest and delayed. Nevertheless, it was taken forward into clinical phase-2b studies in which bedaquiline was added to existing treatment for multidrug-resistant tuberculosis. Overall, these phase-2b studies showed that bedaquiline, when added to other drugs for drug-resistant TB, significantly reduced the time to sputum culture conversion. In the second phase-2b trial that was done, there were more deaths in the bedaquiline arm and this led to a warning specific to bedaquiline on the package labeling. Bedaquiline received accelerated USFDA approval in 2012, followed by World Health Organization guidance in 2013.

Nitroimidazoles

Nitroimidazoles inhibit cell-wall synthesis and cellular respiration. They are prodrugs and are selectively active against Mycobacterium tuberculosis complex. Delamanid has been approved for use by the European Medicines Agency and pretomanid remains in clinical trials at this time.

Oxazolidinones

Oxazolidinones include repurposed agents, such as linezolid, and other new chemical entities that are being developed specifically for tuberculosis. As a class, these agents block protein synthesis. A clinical trial performed in 2012, though, clearly showed the activity of linezolid when added to other drugs in the treatment of highly drug-resistant tuberculosis.

Fluoroquinolones (FQ)

FQ are an example of repurposed drugs that were developed for other infections but were then noted to have TB activity. The successive generations of FQ have increasing activity against Mycobacterium tuberculosis. FQ inhibit the activity of the DNA gyrase, a key step during DNA replication. FQ have been commonly used as second-line drugs for drug-resistant TB and also sometimes in patients intolerant of first-line agents. They were safe and well tolerated. With regards to drug-susceptible TB, the activity of FQ in mouse models of TB led to interest in FQ for shortening the duration of treatment for drug-susceptible TB however, phase-3 clinical trials with FQ for treatment of drug-susceptible TB showed that replacing ethambutol with a FQ was not sufficient to shorten drug-susceptible TB treatment to 4 months while still maintaining acceptable cure rates.

The rifamycins

The rifamycins, as a class, are currently used for the treatment of mycobacterial infections including TB. They inhibit the bacterial RNA polymerase and are key sterilizing components of TB treatment. There is hope that increased doses of rifampin may hold promise for shortening the treatment of drug-susceptible TB. Optimization of rifamycin use is underway. There are other ongoing trials that seek to understand whether rifapentine, which is a rifamycin with a longer half-life than rifampin, might shorten the duration of treatment for drug-susceptible TB.

Improving susceptible TB treatment

For drug-susceptible TB, efforts remain underway to shorten therapy to meaningfully less than 6 months of duration. There are an insufficient number of drug candidates at later stages of development. There is also a need for continuing to build mycobacteriology laboratory capacity and quality management to support clinical trials.

J Libardo MD, Boshoff HI, Barry CE. The present state of the tuberculosis drug development pipeline. Curr Opin Pharmacol 2018;42:81–94. doi:10.1016/j.coph.2018.08.001.