8.4 Drugs for drug-resistant tuberculosis

 

Drugs used for DR-TB treatment (except bedaquiline) are taken 7 days a week.

8.4.1 Group A drugs

Table 8.3 – Main characteristics of TB drugs Group A

 

TB drugs	Classes	Activity	Resistance
Levofloxacin Moxifloxacin	Fluoroquinolones (FQs)	Bactericidal	Resistance common in some regions. Cross-resistance between FQs.
Bedaquiline	Diarylquinolines	Bactericidal	Partial cross-resistance with Cfz. Growing resistance as use increases.
Linezolid	Oxazolidinones	Bactericidal	Resistance assumed to be rare due to its limited use.

 

Fluoroquinolones (levofloxacin, moxifloxacin)

FQs are usually well tolerated.

They may cause tendinopathy and QT prolongation.

Moxifloxacin is sometimes used at high dose (Mfx^h) in the presence of low-level resistance to FQs.

Bedaquiline

Bedaquiline is usually well tolerated.

It may cause hepatotoxicity and QT prolongation.

Bedaquiline has a long half-life (5.5 months). Therefore, adverse effects can persist after the drug is stopped, and if TB is still active, resistance can develop.

Bedaquiline is metabolized in the liver by the CYP450 system enzymes. Drugs, which induce or inhibit CYP450, can affect bedaquiline plasma concentrations and should be avoided (Appendix 19).

The extent of cross-resistance bedaquiline/clofazimine and the clinical implications are not fully understood [1] Citation 1. Camus Nimmo, James Millard, Lucy van Dorp, et al. Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis. Lancet Microbe 2020; 1: e165–74.
https://doi.org/10.1016/S2666-5247(20)30031-8 [2] Citation 2. Thi Van Anh Nguyen, Richard M Anthony, et al. Bedaquiline Resistance: Its Emergence, Mechanism, and Prevention. Clinical Infectious Diseases, Volume 66, Issue 10, 15 May 2018, Pages 1625–1630.
https://doi.org/10.1093/cid/cix992 [3] Citation 3. Ghodousi A, Rizvi AH, Baloch AQ, et al. Acquisition of Cross-Resistance to Bedaquiline and Clofazimine following Treatment for Tuberculosis in Pakistan. Antimicrob Agents Chemother. 2019 Aug 23;63(9):e00915-19.
https://doi.org/10.1128/aac.00915-19 .

Linezolid

Linezolid may cause myelosuppression, dose- and duration-dependent neuropathy and lactic acidosis.

Pyridoxine supplementation (vitamin B₆) is recommended for all patients on linezolid, although there is no evidence that pyridoxine can prevent linezolid-induced neuropathy.

Adverse effects frequently lead to reducing the dose or discontinuing linezolid. The optimal dose and duration of treatment are not established.

Linezolid has many interactions and overlapping toxicities with other drugs (e.g. risk of serotonin syndrome when administered with serotonergic drugs [4] Citation 4. Quinn DK, Stern TA. Linezolid and serotonin syndrome. Prim Care Companion J Clin Psychiatry. 2009;11(6):353-356. ). However, it is not always possible to avoid concomitant use of these drugs (e.g. even on linezolid, a patient with depression may require an antidepressant).

8.4.2 Group B drugs

Table 8.4 – Main characteristics of TB drugs Group B

 

TB drugs	Classes	Activity	Resistance
Clofazimine	Riminophenazine (anti-leprosy drug)	Probably bacteriostatic	Partial cross-resistance with Bdq. Growing resistance as use increases.
Cycloserine Terizidone	Analogue of D-alanine	Bacteriostatic	Resistance common in areas where it has been used extensively. Full cross-resistance between the 2 drugs.

 

Clofazimine

Clofazimine is a QT-prolonging drug.

Orange-pink to brownish-black discolouration of the skin and body fluids occur in almost all patients. These changes are reversible and not harmful.  

Clofazimine has a long half-life (approximately 70 days). Consequently, its adverse effects can persist for several weeks or months after the drug is stopped.

Cycloserine or terizidone

Cycloserine and terizidone are structural analogues used at the same dose.

Both drugs may cause psychiatric and nervous system disorders.
To prevent neurotoxicity, pyridoxine (vitamin B₆) should be administered along with these drugs throughout the course of treatment (Appendix 17).

8.4.3 Group C drugs

Table 8.5 – Main characteristics of TB drugs Group C

 

TB drugs	Classes	Activity	Resistance
Delamanid	Nitroimidazooxazines	Bactericidal	Potential cross-resistance with pretomanid. Resistance assumed to be rare due to its limited use.
Ethambutol		Bacteriostatic	High prevalence of resistance among MDR/RR-TB patients (> 49% in some settings [5] Citation 5. Hoek K G P, Schaaf H S, Gey van Pittius N C, van Helden P D, Warren R M. Resistance to pyrazinamide and ethambutol compromises MDR/XDR-TB treatment. SAMJ, S. Afr. med. j. 2009 Nov; 99(11): 785-787. http://www.samj.org.za/index.php/samj/article/view/3522/2557 [6] Citation 6. Arshad Javaid, Nafees Ahmad, Amer Hayat Khan, Zubair Shaheen. Applicability of the World Health Organization recommended new shorter regimen in a multidrug-resistant tuberculosis high burden country. European Respiratory Journal Jan 2017, 49 (1) 1601967. https://doi.org/​​​​​​​10.1183/13993003.01967-2016 ).
Pyrazinamide		Bactericidal	High prevalence among MDR/RR-TB patients (> 80% in some areas [7] Citation 7. Matteo Zignol, Anna S Dean, Natavan Alikhanova, et al. Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project. Lancet Infect Dis 2016; 16: 1185–92. https://doi.org/10.1016/S1473-3099(16)30190-6 [8] Citation 8. Kwok Chiu Chang, Wing Wai Yew, Ying Zhang. Pyrazinamide Susceptibility Testing in Mycobacterium tuberculosis: a Systematic Review with Meta-Analyses. Antimicrobial Agents and Chemotherapy Sep 2011, 55 (10) 4499-4505. https://doi.org/10.1128/AAC.00630-11 ).
Imipenem/cilastatin Meropenem	Carbapenems		Full cross-resistance between carbapenems.
Amikacin Streptomycin	Aminoglycosides	Bactericidal	Partial cross-resistance between the 2 drugs.
Ethionamide Prothionamide	Thionamides	Weak bacteriostatic	Full cross-resistance between thionamides. Cross-resistance with isoniazid if inhA mutation present. High prevalence of resistance among MDR-TB patients in some areas [9] Citation 9. Lange C, Duarte R, Fréchet-Jachym M, Guenther G, Guglielmetti L, Olaru ID, Oliveira O, Rumetshofer R, Veziris N, van Leth F; European MDR-TB database collaboration. Limited Benefit of the New Shorter Multidrug-Resistant Tuberculosis Regimen in Europe. Am J Respir Crit Care Med. 2016 Oct 15;194(8):1029-1031. https://doi.org/10.1164/rccm.201606-1097LE .
Para-aminosalicylate sodium Para-­aminosalicylic acid		Weak bacteriostatic	Common in some regions.
Isoniazid high-dose			Cross-resistance with thionamides if inhA mutation present.

 

Delamanid

Delamanid is usually well tolerated.

It may cause QT prolongation [10] Citation 10. Dooley KE, Rosencrantz SL, Conradie F, et al. QT effects of bedaquiline, delamanid or both in patients with rifampicin-resistant-tuberculosis: a phase 2, open-label, randomised, controlled trial. Lancet Infect Dis. 2021.
https://doi.org/10.1016/S1473-3099(20)30770-2 . 

It is particularly useful in patients with pre-existing hepatic disease (no reported hepatotoxicity) or HIV infection (no significant drug interactions or overlapping toxicities with antiretrovirals).

It is also useful for replacing a Group A or B drug causing toxicity.

Ethambutol

See Section 8.3.1. Vision monitoring is required when ethambutol is administered for more than 2 months (risk of optic neuritis).

Pyrazinamide

See Section 8.3.1.

Carbapenems (imipenem/cilastatin, meropenem)

Imipenem is always combined with cilastatin. Cilastatin has no antibacterial activity, its role is to inhibit a renal enzyme that inactivates imipenem. 

Meropenem does not need to be combined with cilastatin, as it is metabolised through a different pathway.

High cost and difficulty with administration limits the use of carbapenems.

Carbapenems may cause gastrointestinal disturbances, nervous system disorders and hypersensitivity reactions.

Meropenem should be used in children and adolescents under 15 years, and if possible, in patients with epilepsy or TB meningitis (risk of seizures lower than with imipenem/cilastatin).

The first dose is always administered in a health facility so that an eventual hypersensitivity reaction can be managed. If conditions permit, carbapenems can be continued as an outpatient.

Amoxicillin/clavulanic acid is routinely administered prior to carbapenems, as clavulanic acid prevents the development of carbapenem resistance.

Aminoglycosides (amikacin, streptomycin)

Aminoglycosides should only be used when no alternative is available. Most patients with DR-TB can be treated without aminoglycosides, including some cases of extensively drug-resistant TB (XDR-TB).
Aminoglycosides are nephrotoxic and ototoxic drugs. Streptomycin is less nephrotoxic than other aminoglycosides, but causes vestibular toxicity [11] Citation 11. British Thoracic Society. Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease. Prepared by members of the Guideline Group on behalf of the British Thoracic Society. Standards of Care Committee and Joint Tuberculosis Committee, Thorax 2010;65:559e570.
https://doi.org/10.1136/thx.2009.133173 more frequently. If an aminoglycoside is used, close monitoring is essential (audiometry, electrolytes and renal function). If close monitoring cannot be ensured, aminoglycosides should not be used.

 

Note: kanamycin and capreomycin are no longer recommended, as their use is associated with higher rates of treatment failure and death [12] Citation 12. World Health Organization. WHO consolidated guidelines on drug resistant tuberculosis treatment. Geneva: World Health Organization; 2019.
https://apps.who.int/iris/bitstream/handle/10665/311389/9789241550529-eng.pdf?ua=1, accessed 20 March 2020 .

Thionamides (ethionamide, prothionamide)

Ethionamide and prothionamide are used at the same dose.
They may cause gastrointestinal disturbances, hypothyroidism (especially if co-administered with para-­aminosalicylic acid), neuropathy and hepatotoxicity.
In patients with diabetes, the dose of antidiabetics may need to be adjusted.

Para-aminosalicylate sodium or para-aminosalicylic acid

PAS often causes gastrointestinal disturbances and can decrease the absorption of other TB drugs. It may also cause hypothyroidism, especially when co-administered with a thionamide.

High-dose isoniazid

See Section 8.3.1. There is limited evidence to support the use of high-dose isoniazid.
High-dose isoniazid may cause more adverse effects than the standard dose.
It has overlapping toxicity with linezolid (neuropathy) and hepatotoxic drugs.
To prevent peripheral neuropathy, pyridoxine (vitamin B₆) should be administered to all patients throughout the course of treatment (Appendix 17).

8.4.4 Ungrouped drugs

Pretomanid

Pretomanid belongs to the same class as delamanid and has bactericidal activity.

It is used only as part of standard regimens for DR-TB in the following combinations: BPaLM, BPaL (and BPaLC in operational research conditions), see Chapter 10.

Regimens that include bedaquiline, pretomanid and linezolid may cause hepatotoxicity, lactic acidosis, myelosuppression, neuropathy and QT prolongation.
Pretomanid/delamanid cross-resistance is likely.

8.4.5 Other drugs

Amoxicillin/clavulanic acid

Amoxicillin/clavulanic acid is administered before each dose of carbapenem.

The clavulanic acid component prevents the development of carbapenem resistance.

Only formulations with a ratio of 4:1 (e.g. 500/125 mg) or 2:1 (e.g. 250/125 mg) are suitable for this indication. Do not use formulations with a ratio of 8:1 or 7:1.