6.2 Medicines used in longer MDR-TB treatment regimens

The classification of medicines used in MDR-TB treatment regimens was revised following the evidenceinformed update of the WHO guidelines on drug-resistant TB treatment in 2018. TB medicines to be used for treatment of MDR/RR-TB are categorized into Groups A, B and C (Table 6.1) (1). This new classification is based on drug class, and level of certainty in the evidence on effectiveness and safety (i.e. balance between benefit and risk of harm). The data analysed relate mainly to adult patients who received regimens in recent years. Groups A–C feature the medicines to be used to compose longer MDR-TB regimens (Section 6.3). WHO considers that, under programmatic conditions, only these medicines (Groups A–C) have a role in MDR-TB longer treatment regimens. In addition to agents from Groups A–C, the potential role for clavulanic acid, high-dose isoniazid and gatifloxacin is also discussed (see footnotes of Table 6.1 and “Other medicines” in this section).

 medicines recommended for use

The most notable differences between the current and previous classification of longer regimen components are an upgrade in the priority of bedaquiline, linezolid, clofazimine and cycloserine/ terizidone; placement of delamanid in group C; and lowering of priority for pyrazinamide, amikacin, streptomycin, ethionamide/prothionamide and PAS, relative to other treatment options. A number of agents that were featured previously in these groups are not included any more because they are:

• no longer recommended (e.g. ofloxacin, capreomycin and kanamycin);

• rarely used in longer regimens or unavailable on the market (e.g. high-dose isoniazid and gatifloxacin); or

• an adjunct agent and are not intended to be used alone (e.g. clavulanic acid is used only in combination with the carbapenems).

The new classification facilitates design of the treatment regimen for patients with drug-resistant TB who are eligible for a fully oral longer regimen. Table 6.1 summarizes the general steps to include agents for the longer MDR-TB regimen according to the latest WHO guidance, with more details provided in Table 6.5 for some of the most common situations and patient subgroups that clinicians and NTPs may encounter. The section below provides some background information on the individual agents; the available technical medicine information sheets provide the prescriber with further details on each medicine (5). The updated weight-based dosages for adults and children are provided in Annex I.

Group A

This group includes the fluoroquinolones (levofloxacin and moxifloxacin), bedaquiline and linezolid. These medicines were found to be highly effective in improving treatment outcomes and reducing deaths in the evidence reviewed in 2018 for WHO guidelines (1), and it is strongly recommended that they are included in all longer MDR-TB regimens and used for all MDR/RR-TB patients eligible for longer regimens unless there is a toxicity issue or drug resistance.

Levofloxacin and moxifloxacin are later-generation fluoroquinolones, and their use in the metaanalysis that informed the WHO guidelines (2018 update) resulted in a significantly lower risk of treatment failure or relapse and death (1, 15, 38, 39). Levofloxacin and moxifloxacin are equally effective in fluoroquinolone-sensitive patients, and either of them can be considered for MDR-TB treatment. Ciprofloxacin and ofloxacin are less effective in MDR-TB treatment and are no longer recommended. No quality-assured preparations of gatifloxacin have been commercially available since the drug was removed from the market when an observational study identified dysglycaemia-related safety concerns in patients aged more than 65 years (40).

Fluoroquinolones are known to prolong the QT interval; this may predispose some patients to torsades de pointes, which may result in sudden death. There is variability between the fluoroquinolones in this effect; however, overall, the prolongation is considered minimal or moderate (for moxifloxacin). Cardiac monitoring is required when using drugs that prolong the QT interval (5). Moxifloxacin has a more pronounced effect on QT prolongation than levofloxacin. Levofloxacin and moxifloxacin have also been associated with dysglycaemia metabolic disorders (41, 42). However, most of these reports have been from patients treated for conditions other than MDR/RR-TB, and the benefit-to-harm ratio is expected to be higher when fluoroquinolones are used in MDR/RR-TB (which is outside their usual indication), given the limited alternatives for treating this serious condition.

Rapid molecular DST is available and reliable for levofloxacin and moxifloxacin. If DST to moxifloxacin confirms resistance, or if history suggests that it has not been effective (e.g. if used in a failing regimen for an extended time), it should not be used. Under such circumstances, levofloxacin is also unlikely to be effective and the fluoroquinolones would need to be replaced in the regimen. High-dose moxifloxacin can be used in case of resistance to levofloxacin and low-level resistance to moxifloxacin.

Bedaquiline. In the individual patient data meta-analysis used as evidence for the WHO guidelines, bedaquiline use resulted in significantly fewer episodes of treatment failure, relapse and death (3). There is limited experience with the use of bedaquiline in children aged under 6 years but growing experience of its use in adolescents and the elderly, patients with extrapulmonary TB disease and HIV-infected patients in particular. In an early trial, an increased risk of death was observed in patients on bedaquiline-containing regimens (9/79; 11.4%) when compared with the placebo group (2/81; 2.5%), although not all the deaths were directly related to bedaquiline (43, 44). This risk has not been definitively attributed to bedaquiline or any known toxicities (e.g. QT interval prolongation). Additional analyses of observational study data did not reproduce this finding; rather, they highlighted the improved survival of patients treated with regimens containing bedaquiline (45) and the favourable safety profile of bedaquiline when the drug is used alongside other TB medicines, including medicines with the similar QT prolongation (e.g. moxifloxacin, clofazimine and delamanid) (46–51). The recent data review for the WHO consolidated guidelines (1) suggested no additional safety concerns for the use of bedaquiline beyond 6 months, concurrently with delamanid or in pregnancy (1, 48, 93) (see Sections 6.1 and 6.2). The available data suggested that the concurrent use of bedaquiline and delamanid does not increase the risk of clinically meaningful QT prolongation. The emergence of bedaquiline resistance should be monitored in settings where it is used.

Bedaquiline is metabolized by the cytochrome P450 system enzymes in the liver. Drugs that induce or inhibit this system of enzymes will result in drug–drug interactions that can affect the blood levels of bedaquiline. Cytochrome P450 inducers decrease blood levels of bedaquiline, resulting in the possibility of inadequate levels of bedaquiline in the body for elimination of TB infection. Conversely, cytochrome P450 inhibitors increase blood levels of bedaquiline, resulting in the possibility of an increased risk of toxicity. Table 6.2 provides examples of drugs that should be avoided if bedaquiline is used.

Possible drug–drug interactions of bedaquiline with other medicines

 

Linezolid has shown anti-TB activity in vitro and in animal studies, and its effectiveness in humans was demonstrated in the meta-analysis conducted for the WHO guidelines, as well as in recent trials involving XDR-TB patients (1, 56–60). Lowering the dose from 600 mg daily to 300 mg daily may reduce toxicity but its impact on treatment effectiveness is not well known (although early bactericidal activity [EBA] studies suggest that the higher dose is more effective) (61). When serious adverse effects arise, linezolid may need to be stopped. The IPD meta-analysis informing the WHO guidelines (performed in 2018) included information from more than 300 patients who were treated with linezolid for at least 1 month, mostly on 600 mg daily. About 30% of patients received linezolid for 1–6 months, but over 30% received it for more than 18 months, and these patients had the lowest frequency of treatment failure, loss to follow-up and death. This analysis also suggests that the optimal duration of use would be about 20 months, corresponding to the usual total duration of a longer MDR-TB regimen; however, such an analysis does not account for survivorship bias (meaning that those who complete the full length of treatment are more likely to have a successful outcome, given that deaths and losses to follow-up occur earlier) (1)

The evidence from the WHO consolidated guidelines (1) suggests that linezolid be used as long as it is tolerated. If toxicity develops, the drug dosing should be either reduced or stopped (5). There may be improved outcomes if linezolid is used for the full duration of treatment. However, it likely has its greatest added effect (including protection of other second-line drugs against acquired drug resistance) during the first months of treatment when the bacillary load is highest (61).

Major adverse events related to linezolid include anaemia, peripheral neuropathy, gastrointestinal disorders, optic neuritis and thrombocytopenia. These adverse events are well documented to be dose related. The adverse events are significantly more frequent when the linezolid daily dosage exceeds 600 mg (62). The longer a patient uses linezolid, the higher the risk of experiencing a serious adverse effect.

Linezolid can have drug–drug interactions with drugs that affect the body’s serotonin levels. Serotonergic syndrome, which can be serious and life threatening, can result when linezolid is given concomitantly with certain drug classes.

drug interactions of linezolid
Group B

This group of medicines includes clofazimine and cycloserine or terizidone, which were found to be effective in improving treatment outcomes but limited in reducing deaths in the evidence reviewed in 2018 for WHO guidelines (1). One or both drugs can be added to ensure that a longer regimen starts with at least four effective medicines.

Clofazimine. Clofazimine is an anti-leprosy medicine that has shown in vitro activity against M. tuberculosis, and has been used as a second-line TB medicine for several years. The metaanalysis conducted for the WHO guidelines reinforced the evidence for the effectiveness and safety profile of clofazimine (1). When used with drugs that prolong the QT interval (e.g. bedaquiline, fluoroquinolones and delamanid), clofazimine may cause additive QT prolongation. ECG monitoring should be implemented when used with bedaquiline or if several QT prolonging drugs are also part of the regimen. Non-TB drugs that cause QT prolongation should be avoided if possible. Common adverse events are orange or red discolouration of skin, conjunctiva, cornea and body fluids; dry skin, pruritus, rash, ichthyosis and xerosis; gastrointestinal intolerance; and photosensitivity. Patients should be well informed from the outset of the reversible skin colour changes that occur in most patients. The orange-brown skin changes are reversible a few months after the drug is stopped and are not considered dangerous. Dry skin changes can also be common but are not considered dangerous. These skin changes can be quite concerning to patients and reassurance is required. Clofazimine is not recommended for use in pregnancy or breastfeeding owing to limited data (some reports of normal outcomes, some reports of neonatal deaths) and to pigmentation of the infant if the drug is used during breastfeeding. Clofazimine is partially metabolized by the liver; hence, caution or adjustment of the dose is required for patients with severe hepatic insufficiency.

Cycloserine is a bacteriostatic drug that inhibits cell wall synthesis, and it has no known crossresistance to other TB medicines. Terizidone (composed of two molecules of cycloserine) may be used instead of cycloserine. Cycloserine and terizidone are considered interchangeable. Because of difficulties in interpreting DST (there is no reliable genotypic or phenotypic DST for cycloserine or terizidone), cycloserine or terizidone should only be considered when other criteria of likelihood of effectiveness are met; for example, any reliable evidence on population levels of drug resistance, and prior use of cycloserine or terizidone based on a reliable clinical history (see Section 3). Patients should be well informed of the potential adverse events of cycloserine. A major drug adverse event is central nervous system (CNS) toxicity, including inability to concentrate and lethargy. More serious CNS side-effects include seizure, depression, psychosis and suicidal ideation, which usually occur at peak concentrations of more than 35 mcg/mL but may also be seen in the normal therapeutic range. Other side-effects include peripheral neuropathy and skin changes. Skin problems include lichenoid eruptions and Stevens-Johnson syndrome. The use of these drugs in pregnancy has not been well studied, but no teratogenicity has been documented. Cycloserine can be used in pregnant women if there are no other better choices. It can be used while breastfeeding, and the infant should be given vitamin B6 if breastfed (5).

Group C

Group C comprises both TB and repurposed medicines that are positioned at a lower priority than the Group A and B agents, either because they are less effective (ethambutol, delamanid, pyrazinamide, ethionamide/prothionamide and p-aminosalicylic acid) or because they are more toxic and cumbersome to administer parenterally (imipenem-cilastatin, meropenem, amikacin and streptomycin). These drugs are usually included in a longer regimen if it cannot be composed with Group A and B agents alone

Ethambutol is a TB medicine that is used in first-line regimens and may be added to longer MDR-TB regimens. At recommended dosages, the safety profile of ethambutol is good. Due to difficulties in interpreting its DST, ethambutol should only be considered when other criteria of likelihood of effectiveness are met (e.g. evidence on population levels of drug resistance and prior use of ethambutol based on a reliable clinical history) (see Section 3.1).

Delamanid Based on current knowledge on the effectiveness and safety of delamanid from the assessment for the WHO guidelines, delamanid is recommended for use as a Group C agent in adults and children aged 3 years or more (1). The available evidence of delamanid use is currently limited to the on-label 6 months duration alongside other medicines in a longer regimen; prolongation beyond 6 months can be considered on a case-by-case basis (1, 8). More evidence on the efficacy of delamanid in different age groups and durations of use would be helpful to better guide its use. Achieving an appropriate dose in children aged 3–5 years will be easier when the special formulation used in trials in these age groups becomes available. The recent data review for the WHO guidelines (1) suggested that there are no additional safety concerns for concurrent use of delamanid with bedaquiline (see Section 6.4). The combined QT effects of bedaquiline and delamanid, compared with bedaquiline or delamanid alone (added to multidrug background therapy), were evaluated in a randomized controlled trial (RCT) of 75 patients (>3000 ECGs). The average QTcF prolongation attributable to bedaquiline was 12.3 ms, and to the combination of bedaquiline and delamanid was 20.7 ms. No participants had grade 3 or 4 of QT prolongation (49).

Pyrazinamide has been routinely added to MDR-TB regimens except where there is a reasonable clinical contraindication for its use (e.g. hepatotoxicity), or other serious adverse effect or drug resistance. However, reliable DST for pyrazinamide is not widely accessible; hence, this drug has often been used without DST or regardless of documented resistance. In the longer regimens, pyrazinamide is recommended for inclusion only when DST results confirm susceptibility, and it is then counted as one of the effective agents; in any other cases, if it is included in the regimen, it is not counted as an effective drug (41, 44).

Imipenem-cilastatin and meropenem are the only carbapenems that have an established role in MDR-TB regimens, although there is limited experience in the use of ertapenem (63). Both drugs are administered intravenously – a major drawback that limits their more widespread use outside hospitals, especially in resource-constrained settings (64–68). Daily intravenous injections are not usually feasible unless there is a surgically fitted port, with a catheter connection to a major vein. Meropenem with clavulanate as part of regimens (usually also containing linezolid) for patients with MDR-TB and XDR-TB has shown improved culture conversion and survival (69–71). Clavulanic acid (as co-amoxyclav) is not a TB medicine but is an adjunct agent given orally each time a carbapenem dose is administered, about 30 minutes before the intravenous infusion. When included in a regimen, clavulanic acid is not counted as one of the TB agents, and it should not be used without the carbapenem.

Amikacin and streptomycin are the only two aminoglycoside antibiotics that are still recommended for use in MDR-TB regimens when options for composition of the treatment regimen are limited. When the evidence of their use in longer MDR-TB regimens was reviewed in 2018, amikacin and streptomycin were associated with lower rates of treatment failure or relapse and death when used in people with M. tuberculosis strains susceptible to amykacin or streptomycin, although they share the disadvantages and serious toxicities (i.e. ototoxicity and nephrotoxicity) of other injectable agents that are no longer recommended (i.e. kanamycin and capreomycin). Amikacin and streptomycin may be used in adults aged 18 years or more, in situations where an effective regimen cannot otherwise be designed using oral agents, when susceptibility is demonstrated, and when adequate measures are in place to monitor for adverse events. Given the profound impact that hearing loss can have on the acquisition of language and the ability to learn at school, the use of injectable agents in children should be exceptional and limited to salvage therapy, and the treatment needs to be provided under strict monitoring to ensure early detection of ototoxicity. Amikacin is preferred over streptomycin, which is used only as a substitute when amikacin is not available or there is confirmed resistance to it. The latest analysis from patients on longer regimens has shown a higher risk of serious adverse events in patients on amikacin than on streptomycin (1). The use of these medicines requires the availability of DST for confirming drug susceptibility, and hearing monitoring for detecting drug toxicity. The patient should be informed about drug toxicity, and consent should be obtained before treatment. Given the high frequency of streptomycin resistance in patients with MDR/RR-TB in many settings, and its extensive historical use as part of older first-line TB regimens in many countries, streptomycin is unlikely to have much use in MDR-TB regimens.

Ethionamide and prothionamide. In WHO guidance, ethionamide and protionamide are considered interchangeable. The WHO consolidated guidelines make a conditional recommendation against their use in longer MDR-TB regimens, reserving them for situations where multiple, more effective agents (e.g. bedaquiline, linezolid and clofazimine) cannot be used.

P-aminosalicylic acid (PAS) can be considered as the last resource for treatment of MDR/RR-TB. The drug is recommended in the WHO consolidated guidelines only for use in the treatment of MDR/ RR-TB patients on longer regimens if bedaquiline, linezolid, clofazimine or delamanid are not used, or if better options to compose a regimen are not possible. There is no indication of cross-resistance of PAS to other anti-TB drugs (1).

Other medicines

A number of medicines previously recommended as potential components of MDR-TB longer treatment regimens do not feature in Groups A–C. This section outlines the reasons for this, and provides some background information about these medicines (dosing details are also included in the revised schedules in Annex I).

Gatifloxacin use in MDR-TB was largely limited to the earlier studies of the standardized shorter MDR-TB regimen in Bangladesh and Cameroon (33, 72). Dysglycaemia in elderly patients receiving gatifloxacin as a broad-spectrum antibiotic led to its withdrawal from the market (40, 73). Although it is possible to use gatifloxacin in a programme with well-organized aDSM, the lack of quality-assured formulations on the market precludes its use.

High-dose isoniazid (10–15 mg/kg) is not included in Groups A–C given the rarity of its use in contemporary longer regimens for adults. It is also a relatively safe medicine, as shown recently in experience with its use at the 10 mg/kg dose, where only 0.5% of 1006 patients in a multicentric observational study of the shorter MDR-TB regimen reported grade 3 or 4 neurotoxicity (74). Other evidence suggests that it may also be useful in the longer MDR-TB regimens. First, in the systematic review and IPD meta-analysis commissioned by WHO in 2015 to describe treatment outcomes in children with MDR-TB (which included 975 children in 18 countries), the use of high-dose isoniazid was associated with treatment success among children with confirmed MDR-TB (adjusted odds ratio [aOR] 5.9, 95% confidence interval [CI]: 1.7–20.5, P=0.007) (75). Second, in a randomized, double-blinded, placebocontrolled clinical trial among adults with MDR-TB, participants who received high-dose isoniazid (16–18 mg/kg) (added to kanamycin, levofloxacin, prothionamide, cycloserine and PAS) were significantly more likely to experience culture conversion at 6 months of treatment than those receiving placebo or standard-dose isoniazid (5 mg/kg) (73.8% versus 48.8% or 45.0%, respectively), with median time to culture conversion significantly reduced in the high-dose isoniazid arm (3.4 versus 6.6 or 6.4 months, respectively). Genotypic DST was not performed, but about 60% of participants had M. tuberculosis isolates for which isoniazid MICs were between 0.2 and 5 mcg/mL. Peripheral neuropathy was more common with high-dose isoniazid, but pyridoxine was not given in the trial (76). Third, a more recent EBA study among patients with MDR-TB – wherein the isoniazid resistance was mediated by isolated inhA mutations – who were randomized to receive isoniazid at 5, 10 or 15 mg/kg, demonstrated that doses of 10–15 mg/kg of isoniazid daily exhibited bactericidal activity similar to standard-dose isoniazid (5 mg/kg) given to patients with drug-susceptible TB (77). Strains with isolated katG or both katG and inhA mutations are unlikely to respond even to high-dose isoniazid, given the typically high isoniazid MICs in those strains. The WHO consolidated guidelines recommend that high-dose isoniazid can also be used in the regimens of adults and children with confirmed susceptibility to isoniazid, or in the presence of mutations that do not confer high-level resistance to isoniazid (i.e. isolated inhA mutations) (1, 15).

Kanamycin and capreomycin are injectable agents that are no longer recommended components for any MDR-TB regimen, following the data analysis for the update of WHO guidelines in 2018, which showed an increased risk of treatment failure, relapse or death when their use was compared with regimens without them (1). In addition, these agents present a considerable inconvenience to the patient, and are associated with serious toxicities that may result in permanent damage to hearing and kidney function unless the outcomes are closely monitored.

The risk of serious adverse events from second-line TB medicines was reported in the results of a metaanalysis of the individual IPD for the WHO guidelines update, presented in Table 6.4 (1). The level of serious adverse event provides important information on the likelihood that a certain medicine may need to be stopped at some point during treatment because of its intolerability (particularly linezolid, which has the highest risk of serious adverse events).

 adverse events in patients

DST: drug susceptibility testing; ECG: electrocardiography; GDG: guideline development group; IPD-MA: individual patient data metaanalysis; MDR-TB: multidrug-resistant TB.

ᵃ This table is intended to guide the design of longer MDR-TB regimens (the composition of the recommended shorter MDR-TB regimen is largely standardized, as detailed in Section 5). Medicines in Group C are ranked by decreasing order of usual preference for use subject to other considerations. The 2018 IPD-MA for longer regimens included no patients on thioacetazone (T) and too few patients on gatifloxacin (Gfx) and high-dose isoniazid (Hh) for a meaningful analysis. No recommendation on perchlozone, interferon gamma or sutezolid was possible owing to the absence of final patient treatment outcome data from appropriate studies (see online Annex 8 of the WHO consolidated guidelines)(1).

ᵇ Bedaquiline is usually administered 400 mg orally once daily for the first 2 weeks, followed by 200 mg orally three times per week for 22 weeks (total duration of 24 weeks). Evidence on the safety and effectiveness of bedaquiline use beyond 6 months and in patients below the age of 6 years was insufficient for review in 2018. Therefore, the use of bedaquiline beyond 6 months was then implemented following best practices in “off-label” use (37). New evidence on the safety profile of bedaquiline use beyond 6 months was available to the GDG in 2019. The GDG could not assess the impact of prolonged bedaquiline use on efficacy, owing to the limited evidence and potential residual confounding in the data. However, the evidence supports the safe use of bedaquiline beyond 6 months in patients who receive appropriate schedules of baseline and follow-up monitoring. The use of bedaquline beyond 6 months still remains as offlabel use, and in this regard best practices in off-label use still apply.

ᶜ Evidence on the concurrent use of bedaquiline and delamanid was insufficient for review in 2018. In 2019, new evidence on both the safety and effectiveness of concurrent use of bedaquiline and delamanid was made available to the GDG. With regard to safety, the GDG concluded that the data suggested no additional safety concerns regarding concurrent use of bedaquiline and delamanid. Both medicines may be used concurrently among patients who have limited other treatment options available to them, and if sufficient monitoring (including baseline and follow-up ECG and electrolyte monitoring) is in place. The data on the effectiveness of concurrent use of bedaquiline and delamanid were reviewed by the GDG, but due to the limited evidence and potential residual confounding in the data, the GDG could not proceed with a recommendation on effectiveness (1).

ᵈ Use of Lzd for at least 6 months was shown to increase effectiveness, although toxicity may limit its use. The analysis suggested that using Lzd for the whole duration of treatment would optimize its effect (about 70% of patients on Lzd with data received it for more than 6 months, and 30% for 18 months or the whole duration). No patient predictors for early cessation of Lzd could be inferred from the IPD subanalysis.

ᵉ Evidence on the safety and effectiveness of Dlm beyond 6 months and in patients below the age of 3 years was insufficient for review. Use of Dlm beyond these limits should follow best practices in “off-label” use (8).

ᶠ Z is only counted as an effective agent when DST results confirm susceptibility.

ᵍ Every dose of Imp-Clv and Mpm is administered with oral clavulanic acid, which is only available in formulations combined with amoxicillin (Amx-Clv). Amx-Clv is not counted as an additional effective TB agent and should not be used without Imp-Cln or Mpm.

ʰ Am and S are only to be considered if DST results confirm susceptibility and high-quality audiology monitoring for hearing loss can be ensured. S is to be considered only if Am cannot be used (unavailable or documented resistance) and if DST results confirm susceptibility (S resistance is not detectable with second-line molecular line probe assays and phenotypic DST is required). Kanamycin (Km) and capreomycin (Cm) are no longer recommended for use in MDR-TB regimens.

ᶦ These agents only showed effectiveness in regimens without Bdq, Lzd, Cfz or Dlm, and are thus only proposed when other options to compose a regimen are not possible.

GDG: guideline development group; IPD: individual patient data.

ᵃ From an “arm-based network” meta-analysis of a patient subset from the 2016 IPD for which adverse events resulting in permanent discontinuation of a TB medicine (27 studies) or classified as grade 3–5 (3 studies) were reported. Slight differences between the final estimates cited in the resultant publication (78) and the values derived at the time of the GDG as shown in this table are due to the fact that an expanded dataset was used in the publication – these differences bear no consequence on the conclusions drawn on the use of these medicines. There were insufficient records on delamanid, imipenem–cilastatin and meropenem to estimate risks. Agents that are not in Groups A–C are italicized.

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