Table 4:

Genomic mutations of Mycobacterium tuberculosis associated with phenotypic drug resistance and their effect on treatment outcome67,109,110

	Gene	High-confidence mutations associated with drug resistance	Sensitivity of the high-confidence mutations as predictors of phenotypic drug susceptibility111	Drug mutations for which a dose increase might be considered to overcome resistance at standard dosing*	Effect on treatment outcome
First-line drug
Rifampicin	rpoB	Most commonly Ser450Leu but >20 other mutations described	93·8%	Asp435Tyr, His445Leu†, Leu452Pro, Leu430Pro, His445Asn, Ile491Phe	rpoB mutations associated with unfavourable first-line regimen treatment outcome; no difference between disputed and undisputed mutations;49,112,114 rpoB mutations have no effect on MDR treatment outcome115
Isoniazid	inhA-mabA	−15 c/t+Ilel94Thr, −15 c/t+Ser94Ala	91·2%‡	−15 c/t	inhA mutations increase relapse after first-line treatment and reduce early bactericidal activity of isoniazid 5 mg/kg; inhA −15 c/t mutation has more of an effect than other mutations in inhA116,118; inhA mutations have no effect on MDR treatment outcome (short or long regimen)115,119,120
Isoniazid	katG	Ser315Ile, Ser315Asn, Ser315Thr	91·2%‡	..	katG 315 mutations are associated with unfavourable first-line regimen treatment outcome (treatment failure or death) and relapse, have more of an effect than inhA mutations,116,115 and have no effect on MDR treatment outcome (short or long regimen)115,120
Group A drug
Bedaquiline	Rv0678	Gln22Leu,Thr33Ala, Ser63Arg, Ile67PheSer, Arg72Trp, Arg135Gly, Leu136Pro	0%§	l85ins_Gln†	Some studies show a negative effect of initial bedaquiline resistance in relation to Rv0678 mutations on treatment outcome whereas others do not; the emergence of Rv0678 mutations during treatment is associated with worse treatment outcome121–123
Bedaquiline	atpE	Asp28Gly, Asp28Val, Ala63Pro	0%§	..	Emergence of atpE mutations during treatment is not always associated with worse treatment outcome124,125
Bedaquiline	pepQ	Insufficient data	0%§	..	Unknown
Levofloxacin and moxifloxacin	gyrA	Gly88Cys, Asp94Gly, Asp94His, Asp94Asn, Asp94Tyr	~85%	Asp89Asn, Ala90Val, Ser91Pro, Asp94Ala	gyrA 94 mutations delay sputum conversion of MDR tuberculosis regimen; gyrA mutations are selected in case of ofloxacin treatment failure and can predict MDR tuberculosis treatment outcome as efficiently as phenotypic drug susceptibility testing; for gyrA mutations associated with unfavourable MDR tuberculosis treatment outcome, the higher the associated fluoroquinolone minimum inhibitory concentration, the higher the negative effect on treatment outcome (failure or relapse Asp94Asn>Asp94Gly>Ala90Val>Asp94Ala)116,126–130
Levofloxacin and moxifloxacin	gyrB	..	..	Asp461His†, Asp461Asn†, Asp499Asp†, Ala504Val†	The clinical effect of gyrB mutations on MDR tuberculosis treatment outcome has not been shown but has been shown in a murine model119,131
Linezolid	rplC	Cys154Arg	38·2%¶	..	rplC mutations are selected in case of linezolid regimen treatment failure132,133
Linezolid	rrl	2299 g/t, 2814 g/t	38·2%¶	..	rrl mutations are selected in case of linezolid regimen treatment failure132,133
Group B drug
Clofazimine	Rv0678	Gln22Leu,Thr33Ala, Ser63Arg, Ile67PheSer, Arg72Ter, Gly25Asp, Leu44Pro, Arg135Gly, Leu136Pro, Ser68Arg, >30 mutations described	0%	..	Unknown
Clofazimine	pepQ	Insufficient data	..	..	Unknown
Cycloserine	alr	−8 c/t, Met319Thr, Tyr364Asp, Tyr364Cys, Arg373Leu,Arg373Gly	..	..	Unknown
Amikacin	rrs	1401 a/g, 1484 a/t	77·3%‖	1402 c/t	rrs mutations are selected in case of kanamycin or capreomycin treatment failure, and predict 4-month sputum culture conversion as efficiently as phenotypic drug susceptibility testing; rrs mutations are not associated with MDR tuberculosis treatment outcome119,126,129,134
Amikacin	eis	..	77·3%‖	−14 c/t	eis mutations are not associated with MDR tuberculosis treatment outcome119,129
Group C drug
Streptomycin	rpsL	Lys43Arg, Lys43Thr, Lys88Gln, Lys88Arg	82·4%**	..	rpsL mutations predict 4-month sputum culture conversion as efficiently as phenotypic drug susceptibility testing134
Streptomycin	rrs	514 a/c, 514 a/t, 462 c/t, 513 c/t, 517 c/t	82·4%**	..	Unknown
Delamanid	fbiA	Asp49Tyr, Lys250Stop	6·l%††	..	Unknown
Delamanid	ddn	Trp88Stop	6·l%††	..	Unknown
Ethambutol	embB	Me306lle, Met306Val, Asp354Ala, Gly406Asp, Gly406Cys, Gly406Ser, Gln497Arg	86·7%††	..	embB mutations have not been associated with M DR tuberculosis treatment outcome in one study119
Ethambutol	embC-embA	−8 c/t, −12 c/t, −16 c/t (often in linkage with embB mutations)	86·7%††	..	Unknown
Ethionamide and prothionamide	inhA	−15 c/t, Ser94Ala	75·7%§§	..	inhA mutations have no impact on MDR tuberculosis treatment outcome (short or long regimen)115,119,120
Ethionamide and prothionamide	ethA	Pooled frameshifts and premature stop codons	75·7%§§	..	ethA mutations are selected in case of ethionamide treatment failure, and are associated with unfavourable MDR tuberculosis treatment outcome119,126
Imipenem and meropenem	Unknown	Insufficient data	..	..	Unknown
P-aminosali cylic acid	folC	Glu153Ala, Glu153Gly, Ser150Gly, Phe152Ser, Ile43Thr, Ile43Ala, Glu40Gly	..	..	Unknown
P-aminosali cylic acid	ribD	−12 g/a	..	..	Unknown
P-aminosali cylic acid	thyA	..	..	..	thyA mutations are selected in case of p-aminosalicylic acid treatment failure126
Pyrazinamide	pncA	>300 mutations described	72·3%	Val180Ile†,Ala170Val†, Asp110GIy†, Ser65Ala†, Glu37Val†	pncA mutations are associated with delayed sputum culture conversion of MDR tuberculosis treatment; the negative impact of pncA mutations on MDR tuberculosis treatment outcome has been shown in one study but not in two others119,129,135

MDR=multidrug resistant.

^*Agent should not count among active drugs.

^†Additional data needed.

^‡When inhA-mabA and katG are studied.

^§When Rv0678, atpE, and pepQ are studied.

^¶When rplC and rrl are studied.

^‖When rrs and eis are studied.

^**When rpsL and rrs are studied.

^††When fbiA and ddn are studied.

^‡‡When embB and embC-embA are studied.

^§§When inhA and ethA are studied.