Whole genome sequencing-based drug resistance predictions of multidrug-resistant Mycobacterium tuberculosis isolates from Tanzania

Mbelele, Peter M.; Utpatel, Christian; Sauli, Elingarami; Mpolya, Emmanuel A.; Mutayoba, Beatrice K.; Barilar, Ivan; Dreyer, Viola; Merker, Matthias; Sariko, Margaretha L.; Swema, Buliga M.; Mmbaga, Blandina T.; Gratz, Jean; Addo, Kennedy K.; Pletschette, Michel; Niemann, Stefan; Houpt, Eric R.; Mpagama, Stellah G. und Heysell, Scott K. (2022): Whole genome sequencing-based drug resistance predictions of multidrug-resistant Mycobacterium tuberculosis isolates from Tanzania. In: JAC Antimicrobial Resistance, Bd. 4, Nr. 2, dlac042

Abstract

Background Rifampicin- or multidrug-resistant (RR/MDR) Mycobacterium tuberculosis complex (MTBC) strains account for considerable morbidity and mortality globally. WGS-based prediction of drug resistance may guide clinical decisions, especially for the design of RR/MDR-TB therapies. Methods We compared WGS-based drug resistance-predictive mutations for 42 MTBC isolates from MDR-TB patients in Tanzania with the MICs of 14 antibiotics measured in the Sensititre (TM) MycoTB assay. An isolate was phenotypically categorized as resistant if it had an MIC above the epidemiological-cut-off (ECOFF) value, or as susceptible if it had an MIC below or equal to the ECOFF. Results Overall, genotypically non-wild-type MTBC isolates with high-level resistance mutations (gNWT-R) correlated with isolates with MIC values above the ECOFF. For instance, the median MIC value (mg/L) for rifampicin-gNWT-R strains was >4.0 (IQR 4.0-4.0) compared with 0.5 (IQR 0.38-0.50) in genotypically wild-type (gWT-S, P < 0.001);isoniazid-gNWT-R >4.0 (IQR 2.0-4.0) compared with 0.25 (IQR 0.12-1.00) among gWT-S (P = 0.001);ethionamide-gNWT-R 15.0 (IQR 10.0-20.0) compared with 2.50 (IQR;2.50-5.00) among gWT-S (P < 0.001). WGS correctly predicted resistance in 95% (36/38) and 100% (38/38) of the rifampicin-resistant isolates with ECOFFs >0.5 and >0.125 mg/L, respectively. No known resistance-conferring mutations were present in genes associated with resistance to fluoroquinolones, aminoglycosides, capreomycin, bedaquiline, delamanid, linezolid, clofazimine, cycloserine, or p-amino salicylic acid. Conclusions WGS-based drug resistance prediction worked well to rule-in phenotypic drug resistance and the absence of second-line drug resistance-mediating mutations has the potential to guide the design of RR/MDR-TB regimens in the future.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch