Chapter 8: Drug-resistant tuberculosis

Figures & data

Table 1. Drug resistance on initial and follow-up isolates of M. tuberculosis complex, in Canada, 2011-2015. ⁷

	Number	%
All isolates (Total)	6,819	100.00
Fully susceptible isolate to first-line drugs	6,159	90.32
Any resistance to INH	543	7.96
Any resistance to RMP	96	1.41
Any resistance to EMB	39	0.57
Any resistance to PZA	155	2.27
Resistant to ≥1 first line drug	660	9.68
Mono-resistant	562	8.24
Polydrug-resistant	14	0.21
MDR	80	1.17
MDR with FQN-R and SLI-R	4	0.06

Abbreviations: INH, isoniazid; RMP, rifampin; EMB, ethambutol; PZA, pyrazinamide; MDR, multidrug-resistant; FQN-R, fluoroquinolone-resistant; SLI-R, second line injectable-resistant.

Table 2. Mutation rates (per bacterium, per generation) and average mutant frequencies (in an unrelated population of bacteria, the proportions of resistant bacilli) for several commonly used drugs. ¹²

Drug	Mutation rate	Average mutant frequencies
INH (0.2 µg/mL)	1.84 × 10^–8	3.5 × 10^–6
RMP (1.0 µg/mL)	2.20 × 10^–10	1.2 × 10^–8
EMB (5.0 g/mL)	1.00 × 10^–7	3.1 × 10^–5
SM (2.0 µg/mL)	2.90 × 10^–8	3.8 × 10^–6

Abbreviations: INH, isoniazid; RMP, rifampin; EMB, ethambutol; SM, streptomycin.

Table 3. Total TB incidence, prevalence of isoniazid resistance, and prevalence of MDR/RMP resistance among new and previously treated TB cases; reported by the country to WHO, for the most common countries of birth among foreign-born patients diagnosed with TB in Canada.

Country	Total TB incidence per 100,000 ^a	INH-R New ^b	INH-R Previously treated ^b	MDR/RR New ^a	MDR/RR Previously treated ^a
India	193 (132-266)	8.3%	13.5%	2.8% (2.3-3.5)	14% (14-14)
Philippines	554 (311-866)	12.1%	14.9%	1.8% (1.3-2.6)	28% (27-29)
China	58 (50-67)	7.5%	8.2%	7.1% (5.6-8.7)	23% (23-24)
Viet Nam	176 (112-255)	14.3%	9.9%	3.6% (3.4-3.8)	17% (17-18)
Pakistan	263 (187-353)	7.9%	6.6%	4.2% (3.2-5.3)	7.3% (6.8-7.8)
Ethiopia	140 (98-188)	6.1%	13.2%	0.71% (0.62-0.8)	12% (11-13)
Somalia	258 (167-368)	6.0%	8.3%	8.7% (6.1-12)	88% (73-96)
Haiti	170 (130-215)	N/A	N/A	2.1% (0.78-4.1)	12% (7.4-17)
China, Hong Kong SAR	63 (54-72)	5.2%	7.2%	0.81% (0.49-1.3)	2.8% (0.93-6.5)
Afghanistan	189 (122-270)	N/A	N/A	2.6% (1.1-4.7)	24% (21-27)

Abbreviations: TB, tuberculosis; INH-R, isoniazid resistance without rifampin resistance; MDR/RR, multidrug resistance or rifampin resistance without confirmed INH resistance; WHO, World Health Organisation; N/A, data not available; Hong Kong SAR, Hong Kong Special Administrative Region.

a Total TB incidence estimates and MDR/RR estimates are all for 2019, produced by WHO in consultation with countries; ranges represent uncertainty intervals. ⁶ See https://www.who.int/teams/global-tuberculosis-programme/data. . . for other country estimates.

b INH-R estimates are for the following years: India 2016, Philippines 2012, China 2013, Viet Nam 2012, Pakistan 2013, Ethiopia 2005, Somalia 2011, China, Hong Kong SAR 2017. Source Dean et al. ³⁰

Table 4. Treatment regimens for the management of mono or polydrug-resistant TB.

Resistance to which first-line drugs:	Drugs to drop	Drugs to add	Regimen	Total duration
Mono-resistance
INH	INH	FQN	6 months daily RMP + EMB + PZA + FQN	6 months from date FQN started
	INH	FQN	2 months daily RMP + EMB + PZA + FQN/4 months daily RMP + EMB + FQN	6 months from date FQN started
RMP	RMP	FQN	2 months daily INH + EMB + PZA + FQN /10-16 months daily INH + EMB + FQN	18 months from date FQN started
	RMP	None	2 months daily INH + EMB + PZA / 16 months INH + EMB daily or thrice weekly	18 months from start of therapy
EMB	EMB	None	2 months daily INH + RMP + PZA /4 months INH + RMP daily or thrice weekly	6 months from start of therapy
PZA	PZA	None	2 months daily INH + RMP + EMB /7 months INH + RMP daily or thrice weekly	9 months from start of therapy
Polydrug-resistance
INH + EMB	INH + EMB	FQN	6 months daily RMP + PZA + FQN	6 months from date FQN started
INH + PZA	INH + PZA	FQN	9 months daily RMP + EMB + FQN	9 months from date FQN started
INH + EMB + PZA	INH + EMB + PZA	FQN + injectable	2 months daily RMP + FQN + injectable /7 months daily RMP + FQN	9 months from date FQN started

Abbreviations: TB, tuberculosis; INH, isoniazid; FQN, fluoroquinolone (moxifloxacin or levofloxacin); RMP, rifampin; EMB, ethambutol; PZA, pyrazinamide.

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
		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)
		TRD
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
		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 Clinicians ⁵⁶ for 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 Clinicians ⁵⁶ for suggestions on how to ramp up to full-dose ethionamide.

Table 6. Adverse events and monitoring recommendations for anti-TB drugs used for the treatment of MDR-TB.

Medicine	Incidence of adverse events resulting in drug discontinuation (95%CI) ^a	Common adverse events^b	Recommended routine monitoring
Levofloxacin	1.3% (0.3–5.0)	MSK (64%), peripheral neuropathy (14%), rash (14%), hypoglycemia (7%), GI disturbance, headache, anxiety, tremulousness, prolonged QT interval	EKG when used in combination with other QT-prolonging drugs
Moxifloxacin	2.9% (1.6–5.0)	Cardiovascular^d (21%), hepatotoxicity (17%), GI disturbance (13%), peripheral neuropathy (11%), MSK (8%), headache, anxiety, tremulousness		EKG when used in combination with other QT-prolonging drugs
Bedaquiline	1.3% (0.3–5.0)	Cardiovascular^d (56%), hepatoxicity (22%), CNS toxicity (11%), MSK (11%), GI disturbance	EKG at baseline and weeks 2, 12, 24. Baseline potassium, magnesium, calcium. Baseline and monthly liver tests
Linezolid	14.1% (9.9–19.6)	Peripheral neuropathy (64%), myelosuppression (22%), optic neuropathy (5%), GI disturbance (2%), rash (2%)	Regular (initially weekly, then at least monthly) complete blood counts Clinical assessment for peripheral neuropathy Visual acuity and color vision monthly
Clofazimine	1.3% (0.3–5.0)	Skin hyperpigmentation (42%), cardiovascular^d (33%), rash (17%), GI disturbance (8%), discoloration of conjunctiva, cornea and body fluids, photosensitivity	EKG when used in combination with other QT-prolonging drugs
Cycloserine, Terizidone	5.7% (4.1–7.8)	Psychiatric (66%) (depression, psychosis, suicidal ideation), CNS toxicity (25%) (seizures, lethargy), GI disturbance (4%), peripheral neuropathy (1%), rash (1%), optic neuritis	Peak concentrations after 1-2 weeks of starting, then intermittently throughout treatment; Screen for psychiatric symptoms
Ethambutol	1.8% (1.0–3.3)	Visual impairment (including optic neuritis) (70%), GI disturbance (17%), MSK (3%), rash (3%), hepatotoxicity (2%)	Baseline and monthly visual acuity and color discrimination
Pyrazinamide	5.1% (3.1–8.4)	MSK (33%), GI disturbance (23%), hepatotoxicity (20%), rash (13%), hyperuricemia (6%)	Monthly liver tests
Delamanid^c	N/A	GI disturbance, dizziness, insomnia, QT prolongation	EKG at baseline and monthly. Baseline potassium, magnesium, calcium, albumin; monthly if risk factors for electrolyte disturbance or QT prolongation
Amikacin	10.2% (6.3–16.0)	Ototoxicity (87%), nephrotoxicity (10%), GI disturbance (1%), MSK (1%), vestibular toxicity, hypokalemia, hypomagnesemia, hypocalcemia	Baseline and monthly assessment of hearing and vestibular system (symptoms, physical exam, audiology) Baseline and regular (at least monthly)
Streptomycin	2.9% (1.3–6.2)	Ototoxicity (83%), peripheral neuropathy (17%), vestibular toxicity, hypokalemia, hypomagnesemia, hypocalcemia		Renal function and electrolytes. Peak and trough concentration at least at baseline if impaired renal function; some monitor routinely
Imipenem-cilastatin, Meropenem	5.1% (3.1–8.4)	Hepatotoxicity (50%), rash (17%), fatigue (17%), pneumonia (7%), GI disturbance, seizure (in CNS infection)
Ethionamide	6.5% (4.1–10.1)	GI disturbance (48%), hepatotoxicity (22%), psychiatric (6%), gynecomastia (5%), MSK (5%), hypothyroidism, neurotoxicity	Monthly liver tests TSH at least every 3 months
p-aminosalicylic acid	11.6% (7.1–18.3)	GI disturbance (79%), hypothyroidism (5%), hepatic dysfunction (4%), rash (4%), nephrotoxicity (3%). Avoid if allergic to aspirin.	CBC, electrolytes Monthly liver tests TSH at least every 3 months

Abbreviations: MDR-TB, multidrug-resistant tuberculosis; MSK, musculoskeletal; EKG, electrocardiogram; GI, gastrointestinal; CNS, central nervous sytem; TSH, thyroid stimulating hormone; CBC, complete blood count.

Note: The complete list of possible adverse events and monitoring parameters is not provided. Please refer to The Curry International TB Center Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, 3^rd Edition. ⁵⁶

a Incidence of adverse events taken from an Individual Patient Data Meta-analysis (IPD-MA) including 9178 patients from 35 studies; adverse events as defined here were those that resulted in permanent discontinuation of the drug. ¹¹⁵

b Estimates of frequencies of adverse events taken from an IPD-MA ¹¹⁵ and include only those that resulted in permanent discontinuation of the drug, therefore the frequency of occurrence of adverse events that can be managed without drug discontinuation may differ from those reported here. Adverse events shown in the table without associated frequencies are from, ^{56 , 93} not the IPD-MA.

c Adverse events associated with delamanid were not reported in the IPD-MA.

d Further details regarding the type of cardiovascular adverse event were not provided in the IPD-MA; ¹¹⁵ however these drugs are known to cause QT prolongation.

Table 7. Drug-drug interactions with second-line anti-TB drugs.

Drug interactions Increased risk of neurotoxicity from cycloserine has been associated with concomitant use of isoniazid, ethionamide and fluoroquinolones. ^113 ^, ^114 P-aminosalicylic acid and ethionamide have each been associated with hypothyroidism. The probability of hypothyroidism is increased when both agents are used together. ^12 Linezolid should generally not be administered to patients taking serotonergic agents, such as monoamine oxidase inhibitors or selective serotonin reuptake inhibitors, as the combination could result in serious reactions such as serotonin syndrome or neuroleptic malignant syndrome-like reactions. 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 serum levels of bedaquiline. Conversely, cytochrome P450 inhibitors increase blood levels of bedaquiline, resulting in the possibility of an increased risk of toxicity. ^93

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