Ethionamide cross- and co-resistance in children with isoniazid-resistant tuberculosis.
BACKGROUND
Ethionamide (ETH) is a structural analogue of isoniazid (INH). Both are pro-drugs requiring activation by separate and common enzyme pathways, which could lead to co- and/or cross-resistance.


OBJECTIVE
To characterise paediatric INH-resistant mycobacterial isolates to investigate the presence of ETH resistance and mutations in the katG gene and the inhA promoter region.


METHODS
Forty-five INH-resistant and 19 INH-susceptible Mycobacterium tuberculosis control isolates from children from the Western Cape Province, South Africa, were analysed to quantify INH minimal inhibitory concentration, test for ETH resistance and investigate mutations in the katG gene and/or inhA promoter region.


RESULTS
Among 45 INH-resistant children, ETH resistance was present in 19 of 39 (49%). An inhA promoter mutation was identified in 15 (33.3%); 12/14 (86%) of these isolates were also ETH-resistant. Of the 21 isolates with a katG mutation, six (29%) were ETH-resistant. No isolate had both katG and inhA promoter mutations. Nine (20%) isolates had neither inhA promoter nor katG mutations. Of 15 isolates with inhA promoter mutation, 14 (93%) displayed low- or intermediate-level INH resistance. Among the 19 INH-susceptible isolates, ETH resistance was present in 1/18 (6%) and none showed inhA or katG gene mutations.


CONCLUSIONS
We found a high level of cross- and co-resistance with ETH among INH-resistant M. tuberculosis isolates from children in this geographic area.
Desmond Tutu Tuberculosis Centre, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg Children's Hospital, Tygerberg, South Africa. hss@sun.ac.za
H S
HS
Schaaf
T C
TC
Victor
A
A
Venter
W
W
Brittle
A M
AM
Jordaan
A C
AC
Hesseling
B J
BJ
Marais
P D
PD
van Helden
P R
PR
Donald
D000995:Antitubercular Agents / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000235:genetics; D016022:Case-Control Studies; D002374:Catalase / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D004359:Drug Therapy, Combination; D005000:Ethionamide / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D007223:Infant; D007538:Isoniazid / Q000627:therapeutic use*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D010088:Oxidoreductases / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D013019:South Africa / Q000453:epidemiology; D017211:Treatment Failure; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D010088:Oxidoreductases; D002374:Catalase; C480353:katG protein, Mycobacterium tuberculosis; C085257:InhA protein, Mycobacterium; D005000:Ethionamide; D007538:Isoniazid