5.1. Treatment regimens for people with a presumptive or established diagnosis of MDR-TB

Since the 7th edition of the Canadian TB Standards was published, there have been a number of major changes in MDR-TB treatment recommendations. The WHO recommends two options: a standardized, all-oral shorter regimen; and an individualized longer regimen.⁹³ In their combined guidelines, the ATS/CDC/ERS/IDSA recommend a regimen that is similar in composition and duration to the WHO longer regimen.⁹⁴ The following recommendations are largely based on the evidence reviews performed for the WHO and/or ATS/CDC/ERS/IDSA.

5.1.1. Standardized versus individualized approaches

Whether to use a standardized or an individualized approach when constructing regimens for MDR and XDR-TB has been a matter of debate for a number of years. Standardized regimens always use the same combination of drugs for all patients, under the assumption that the regimens will be effective even in the face of resistance to some of the component medications. By contrast, individualized regimens are designed based on results of first- and second-line DST, and avoid administration of medications which show resistance on DST. A large IPD meta-analysis found consistently worse outcomes with regimens that included medications to which the infecting organism was resistant, as compared to regimens that did not use those medications.⁶⁰ Other IPD meta-analyses have shown that when standardized shorter regimens are used in the presence of baseline resistance to component medications, outcomes are worse compared to the absence of such resistance,⁹⁵ and also compared to using individualized longer regimens.⁹⁶ In Canada, all jurisdictions should have access to first- and second-line DST, and patients with MDR and XDR-TB should not be treated with medications for which there is DST-demonstrated resistance (with the exception of high-dose INH in the all-oral standardized shorter regimen, described in the following section).

5.1.2. Choice of medications

Table 5 summarizes the new classification system used by the WHO for grouping medicines recommended in the treatment of MDR and XDR-TB.⁹³ Group A consists of drugs found to be highly effective at reducing risks of treatment failure/relapse and death in an IPD meta-analysis that informed the 2018 WHO guidelines:⁶⁰ levofloxacin and moxifloxacin (later-generation FQN), bedaquiline (a diarylquinoline) and linezolid (an oxazolidinone). Group B consists of drugs that can be orally ingested and that reduce risks of treatment failure or relapse, but whose effectiveness for lowering the risk of death was less certain: clofazimine and cycloserine (or terizidone). Group C consists of anti-TB drugs, as well as repurposed medications, with less certainty on their effectiveness for MDR-TB or that require parenteral administration.

Table 5. Grouping and doses for anti-TB drugs used for the treatment of MDR-TB.

GROUP ^a	MEDICINE		Adults	Children (<15 years old) ^99–102
Group A	Levofloxacin OR Moxifloxacin	LFX	750-1000 mg PO or IV daily	15–20 mg/kg/day (max 750 mg) PO or IV
	Levofloxacin OR Moxifloxacin			MFX	400 mg PO or IV daily	10-15 mg/kg/day (max 400 mg) PO or IV
		Bedaquiline	BDQ	400 mg PO daily x 14 days then 200 mg PO 3 times/week	Use only in patients > 6 years AND > 15 kg; 6-month duration Weight Band: 16-30 kg: 200 mg PO daily x 14 days, 100 mg PO thrice weekly >30 kg: 400 mg PO daily x 14 days, 100 mg PO thrice weekly; 6 mg/kg PO x 14 days followed by 3-4 mg/kg/day PO thrice weekly (max 400 mg)
		Linezolid	LZD	600 mg PO or IV daily	<16kg: 15mg/kg/day PO or IV≥16kg: 10-12mg/kg/day PO or IV (max 600mg)
Group B	Clofazimine	CFZ	100 mg PO daily	2-5 mg/kg/day PO (max 100 mg) Often given on alternate days or thrice weekly due to formulation (see references for specific weight banded dosing)
	Cycloserine OR Terizidone	CS	250–750 mg PO daily to achieve serum levels of 20-35 mg/L	15-20 mg/kg/day PO divided BID (max 1 gram)
	Cycloserine OR Terizidone	TRD	250–750 mg PO daily to achieve serum levels of 20-35 mg/L	15-20 mg/kg/day PO divided BID (max 1 gram)
Group C	Ethambutol	EMB	15 mg/kg PO daily	15-25 mg/kg/day PO (max 800 mg)
	Pyrazinamide	PZA	25-40 mg/kg PO daily	30-40 mg/kg/day PO (max 2000 mg)
	Delamanid	DLM	100 mg PO twice daily	Use only in patients >2 years; use with caution if splitting dose or crushing; use up to 6 months Weight-band: 7-23 kg: 25 mg PO BID 23-34 kg: 50 mg PO BID >34 kg: 100 mg PO BID; 3-4 mg/kg/day PO (max 200 mg)
	Amikacin (OR Streptomycin)	AMS	15mg/kg IV daily or 25mg/kg IV three times weekly^b	15-20 mg/kg/day IV or IM (max 1 gram) ^b20-40 mg/kg/day IV or IM (max 1 gram) ^b
	Amikacin (OR Streptomycin)	Imipenem-cilastatin OR	IPM-CLN	1,000 mg IV BID – QID	Ipm-Cln not used in <15 years old
	Meropenem^c	MPM	1,000 mg IV 3 times daily	Mpm: 20-40 mg/kg IV q8h (max 6 grams)
	Ethionamide	ETO	15–20 mg/kg PO daily divided BID (usually 250–500 mg PO once or twice daily)	15-20 mg/kg/day PO (max 1 gram)
	p-aminosalicylic acid	PAS	4 g PO 2–3 times daily (total 8 to 12 grams per day)	200 mg/kg/day PO once daily OR divided BID (see references for weight-banded dosing)

^{Abbreviations: TB, tuberculosis; MDR-TB, multidrug-resistant tuberculosis; PO, per oral; IV, intravenous; IM, intramuscular; BID, twice a day; QID, four times a day; q8h, every 8 hours .}

^{a Group A consists of drugs found to be highly effective at reducing risks of treatment failure/relapse and death; Group B consists of drugs that can be orally ingested and that reduce risks of treatment failure or relapse, but whose effectiveness for lowering the risk of death is less certain; Group C consists of anti-TB drugs, as well as repurposed medications, with less certainty on their effectiveness for MDR-TB or that require parenteral administration.93}

^{b Some centers utilize lower doses of amikacin with therapeutic drug monitoring, to minimize ototoxicity. Amikacin/streptomycin should only be used where hearing can be formally monitored.103,104}

^{c Every dose of imipenem-cilastatin or meropenem should be administered with oral clavulanic acid, which is only available in formulations combined with amoxicillin, dosed at 125-250 mg clavulanic acid (BID-QID). Amoxicillin-clavulanic acid is not counted as an additional effective anti-TB drug.}

^{Pyridoxine should be given to patients receiving linezolid or cycloserine.}

^{Cycloserine doses are often divided twice daily to improve tolerance. See The Curry International TB Center Drug-Resistant Tuberculosis: A Survival Guide for Clinicians56for suggestions on how to ramp up to full-dose Cycloserine to improve tolerance. Some experts suggest pyridoxine 50 mg for each 250 mg of cycloserine.}

^{Ethionamide administration at bedtime may help to reduce nausea. See The Curry International TB Center Drug-Resistant Tuberculosis: A Survival Guide for Clinicians56for suggestions on how to ramp up to full-dose ethionamide.}

The IPD meta-analysis included 12,030 patients from 25 countries in 50 studies, and reported the likelihood of treatment success and death associated with the use of individual drugs in the management of MDR-TB. ⁶⁰ In this study:

use of levofloxacin was associated with 15% greater treatment success, compared with failure or relapse (adjusted risk difference 15%; 95% CI 13 to 18%), and moxifloxacin was associated with 11% greater success (95% CI 8 to 14%); use of levofloxacin or moxifloxacin was also associated with 6-7% lower mortality (adjusted risk difference -6%, 95% CI −9 to −4% for levofloxacin and −7%, 95%CI −10 to −4% for moxifloxacin);
bedaquiline use also resulted in 10% greater treatment success (adjusted risk difference 10%, 95% CI 5 to 14%), and a significant reduction in death (−14%, 95% CI −19 to −10%);
linezolid use was also associated with significantly greater treatment success (adjusted risk difference 15%, 95% CI 11 to 18%) and lower mortality (–20%, 95% CI –23 to –16%);
clofazimine use was associated with significantly greater treatment success (6%, 95% CI 1 to 10%), but had no impact on mortality (95% CI –8 to 0);
cycloserine use was associated with significantly greater treatment success (5%, 95% CI 3 to 6%) and lower mortality among patients with susceptible isolates, but was not beneficial in patients with resistant isolates; and
aside from carbapenems, which were significantly associated with treatment success (14%, 95% CI 6 to 21%), but not with mortality, all other drugs studied were associated with only slight or no improvements in outcomes.

In 2018, the WHO removed the second-line injectable agents from first line MDR-TB treatment regimens.⁹³^,⁹⁴ This is because of evidence demonstrating the greater effectiveness, and better tolerability, of newer and repurposed drugs for treating MDR-TB. Additionally, the IPD meta-analysis described above found that patients treated with certain second-line injectable drugs (kanamycin and capreomycin) had worse outcomes when compared to patients who did not receive any injectable anti-TB drugs. The only second-line injectable currently recommended for use is amikacin, which was associated with greater chance of success (adjusted risk difference 6%, 95% CI 4 to 8%), but had no effect on death.⁶⁰

Based on the aforementioned considerations, the WHO currently recommends that MDR-TB regimens consist of the following 4 drugs: levofloxacin or moxifloxacin, bedaquiline, linezolid and clofazimine or cycloserine (an alternative WHO-recommended regimen is discussed later in this section). ATS/CDC/ERS/IDSA recommends an initial 5-drug regimen consisting of a quinolone (either levofloxacin or moxifloxacin) plus bedaquiline, linezolid, clofazimine and cycloserine. These combinations are based on the effectiveness of each individual drug; there are few data, and no randomized trials that have evaluated the recommended combinations. We favor an approach similar to ATS/CDC/ERS/IDSA; an initial five-drug regimen for most patients, with the option to use an initial four-drug regimen for those patients with less extensive TB disease.

In the absence of prior treatment, resistance to bedaquiline, linezolid, clofazimine and cycloserine is expected to be rare. Hence the MDR-TB regimens recommended by the WHO and ATS/CDC/ERS/IDSA could be initiated even in the absence of second-line DST, as soon as RMP resistance has been detected. Even if fluoroquinolone (levofloxacin or moxifloxacin) resistance (which is more common) is later detected, the initial regimen is likely sufficiently strong to prevent amplified resistance.

In situations where one or more of the drugs in the preferred initial regimen cannot be used due to intolerance, contra-indications, unavailability or resistance, such as in pre-XDR or XDR, then one or more of the following Group C drugs (see also Table 5) should be included in the regimen in order to ensure the provision of at least five effective (or likely effective) drugs: EMB, PZA, delamanid, amikacin, imipenem-cilastatin or meropenem (plus clavulanic acid), ethionamide or p-aminosalicylic acid, chosen in that order. Clinicians may feel uncomfortable including cycloserine in the initial treatment regimen due to the risk of neuropsychiatric adverse events; in this circumstance, a Group C drug can be used in place of cycloserine.

The WHO currently recommends that its guidance on longer treatment regimens also applies to drug-resistant extra-pulmonary TB.⁹³ Data on the use of bedaquiline in extra-pulmonary TB is limited to small numbers of cases included in case series.⁹⁷^,⁹⁸ Bedaquiline is not available in Canada for extra-pulmonary TB; while we suggest its use for extra-pulmonary TB, if it cannot be obtained then we suggest adding a Group C drug to replace it, using the approach previously described.

Unfortunately, in Canada, bedaquiline, cycloserine, and clofazimine are often only available several days to weeks after the indication to use them has become evident. This is due to the lengthy process needed to obtain these medicines, which involves applications to Health Canada’s Special Access Program and to the pharmaceutical companies that hold proprietary claims on them. As such, while waiting to gain access to bedaquiline, cycloserine and clofazimine, it is reasonable to initiate (or continue) other drugs used to treat MDR-TB (see Table 5) for which there is DST-proven susceptibility or the likelihood of resistance is judged to be very low.

We encourage federal and provincial government agencies and pharmaceutical companies operating in Canada to facilitate timely access to second-line drugs for MDR and XDR-TB by eliminating existing administrative obstacles, such as the requirement for Special Access Program approval for drugs recommended by WHO for drug-resistant TB treatment, and the current (2021) limitations on the use of bedaquiline for extra-pulmonary TB.

5.1.2.1. Initial and continuation phases of treatment

In prior MDR-TB guidelines, treatment was divided into two phases: the initial phase was defined as the period when an injectable was used, and the continuation phase was the period when only oral medications were utilized. In its most recent guidance, because longer regimens may now be all oral, WHO no longer divides treatment into initial and continuation phases. By contrast, ATS/CDC/ERS/IDSA suggest an initial phase during which a greater number of drugs are used, followed by a continuation phase during which fewer drugs are used. Clinical, microbiologic, and radiologic responses to treatment should be assessed before deciding to reduce the number of drugs in a regimen. We favor an approach that includes an initial phase with more drugs and reduces the number of drugs once there is evidence of a good response to treatment.

Bedaquiline is marketed as a medication that is to be used for only 6 months, based on the initial randomized controlled trials, in which it was used only for 6 months. Most patients will have shown substantial improvement, and some may have experienced culture conversion by the time bedaquiline has been given for 6 months, hence it is a reasonable time to stop. In its most recent guidance, WHO judged that there is sufficient evidence to support the safe use of bedaquiline beyond 6 months as long as appropriate follow-up monitoring is pursued, but also that there is insufficient evidence of bedaquiline’s efficacy beyond 6 months.⁹³ If clinicians judge the benefits of extending bedaquiline use beyond 6 months outweigh the benefits of stopping bedaquiline, and an informed patient prefers to continue bedaquiline beyond 6 months over alternative treatment modifications, it would be reasonable to extend the use of bedaquiline as long as best practices for off-label use are followed.

5.1.2.2. Duration of treatment

For its longer regimen, the WHO recommends a total duration of 18-20 months. ATS/CDC/ERS/IDSA recommends an intensive phase of between 5 and 7 months after culture conversion, and a total treatment duration between 15 and 21 months after culture conversion. In other words, the 2 guidelines are quite similar in their recommendations for total treatment duration for the longer regimen. In patients with smear-positive or cavitary disease or who were severely ill at the time treatment was initiated, we suggest switching to the continuation phase 5-to-7 months after culture conversion, provided there are other signs of improvement.

Recommendations

We strongly recommend, for the treatment of MDR-TB:
1. use of regimens that include bedaquiline, for all patients;
2. use of regimens that include linezolid, for all patients; and
3. use of regimens that include either levofloxacin or moxifloxacin, for all patients (good evidence).
We strongly recommend, for the treatment of MDR-TB, against use of drugs to which the infecting strain has drug susceptibility testing-proven resistance (with the exception of high-dose isoniazid in the all-oral standardized shorter regimen) (good evidence).
We conditionally recommend, for the treatment of MDR-TB, the following five drugs as the initial regimen in the absence of drug susceptibility testing-proven resistance or contraindications: (levofloxacin or moxifloxacin) AND bedaquiline AND linezolid AND clofazimine AND cycloserine (poor evidence).
We conditionally recommend, for patients with less extensive MDR-TB disease (smear negative, without cavitary lesions) that is solely pulmonary or occurring at a site where TB is usually paucibacillary, that the initial regimen could include only 4 drugs, consisting of (levofloxacin OR moxifloxacin) AND bedaquiline AND linezolid AND (clofazimine OR cycloserine) (poor evidence).
We conditionally recommend, for the treatment of MDR-TB, that 5-to-7 months after culture conversion occurs, any one of the drugs in the regimen could be dropped, continuing the other 4; for patients whose initial phase consisted of (levofloxacin OR moxifloxacin) AND bedaquiline AND linezolid AND (clofazimine OR cycloserine), any one of the drugs can be dropped so that the continuation phase consists of three drugs (poor evidence).
We conditionally recommend, for the treatment of MDR-TB, a total treatment duration of 18 to 20 months, although this can be modified based on response to therapy (poor evidence).
We conditionally recommend, for the treatment of pre-extensively drug-resistant or extensively drug-resistant TB, or in situations where one or more of the Group A and B drugs cannot be used due to side-effects, contra-indications, unavailability or resistance, adding 1 or more Group C drugs to ensure at least 5 drugs are in the regimen. The order of preference for the addition of Group C drugs is (from most to least preferred): ethambutol, pyrazinamide, delamanid, amikacin, imipenem-cilastatin or meropenem (plus clavulanic acid) ethionamide or p-aminosalicylic acid (poor evidence).
We conditionally recommend, unless explicitly stated otherwise, that for the treatment of extra-pulmonary MDR-, pre-extensively drug-resistant and extensively drug-resistant TB, the same treatment approach be utilized as for pulmonary TB (poor evidence).

Good practice statement

In designing a treatment regimen for MDR-TB, the potential cross-resistances, drug interactions and toxicities should be taken into account.

5.1.3. All-oral standardized shorter regimen

Since 2016, WHO guidelines have included a standardized shorter regimen as a potential option for treating MDR-TB. The initial shorter regimen that the WHO recommended in those guidelines had an intensive phase with a second-line injectable, but in the 2020 update of its guidelines, WHO changed this recommended shorter regimen to an all-oral regimen, with bedaquiline being used instead of the second-line injectable.⁹³ The change was based on data from South Africa’s National TB Programme, in which the outcomes of 891 patients who received the shorter all-oral regimen was compared to 987 patients treated with that based on injectable medication use.⁹³ In that analysis, it was found that use of the all-oral shorter regimen was associated with higher treatment success rates (73% versus 60%), adjusted odds ratio 2.1 (95% CI 1.1–4.0) for the treatment outcomes of success versus failure/recurrence. Rates of loss to follow-up were also lower among the group who received the all-oral regimen (9.9% vs 17.3%; aOR 0.5, 95% CI 0.4–0.7).

The outcomes of the 891 patients who were treated with the all-oral shorter regimen were also compared to those of 1,437 patients treated with longer regimens without any new drugs (such as bedaquiline, delamanid, linezolid or carbapenems) and 474 patients treated with longer regimens including bedaquiline.⁹³ The all-oral shorter regimen performed significantly better than the longer regimen without any new drugs, across all outcomes and all subgroups. When the shorter regimen was compared to the longer regimen with bedaquiline, there were no marked differences in the outcomes observed. However, the shorter regimen performed slightly better; aOR: 3.9; 95% CI: 1.7–9.1 for success versus failure/recurrence; aOR: 1.6; 95% CI: 1.2–2.2 for success versus all unfavorable outcomes; aOR: 0.5; 95% CI: 0.4–0.8 for loss to follow-up.

Per the WHO, eligibility for treatment with the all-oral shorter standardized regimen requires that resistance to any component medications (with the exception of INH) be excluded by DST (or considered very unlikely); that patients have not previously been treated with second-line drugs for more than one month; and that patients do not have extensive disease or severe extra-pulmonary TB. Pregnant women and children under six-years-old are excluded.

The all-oral shorter regimen for MDR-TB treatment that is recommended by the WHO consists of an initial 4-to-6 month phase with bedaquiline, levofloxacin, clofazimine high-dose INH, ethionamide, PZA and EMB; and a 5-month continuation phase of levofloxacin, clofazimine, PZA and EMB. Eligibility requirements are strict because the shorter regimen is standardized and the effectiveness of alternative drug combinations is unknown. If used, the all-oral standardized regimen must be prescribed and monitored according to WHO recommendations; this means that no modifications to the regimen are permitted. If a patient is started on the all-oral shorter standardized regimen and subsequently needs the regimen altered, they should be switched to a longer regimen rather than making modifications to the shorter one.⁹³ Note that this regimen utilizes high-dose INH even in the presence of INH resistance; it is the only exception to our prior recommendation against using drugs when there is demonstrated resistance to them.

The decision to choose the all-oral standardized shorter regimen over the longer regimen among eligible patients should be made jointly between patient and provider. While the shorter duration is an advantage, the shorter regimen requires a greater number of drugs to be taken (7 drugs initially vs 5). This results in a greater risk of adverse drug reactions. It is important to note that premature discontinuation of any drugs in the short regimen will necessitate switching to a longer regimen.

Recommendation

We conditionally recommend, for the treatment of MDR-TB, the all-oral standardized shorter regimen recommended by the World Health Organization as an alternative to the preferred longer regimen, for patients who meet all eligibility requirements and for whom routine treatment monitoring can be assured (poor evidence).

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