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

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™ 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.

Glycated hemoglobin screening identifies patients admitted for retreatment of tuberculosis at risk for diabetes in Tanzania.

INTRODUCTION: World Health Organization recommendations of bidirectional screening for tuberculosis (TB) and diabetes have been met with varying levels of uptake by national TB programs in resource-limited settings. METHODOLOGY: Kibong'oto Infectious Diseases Hospital (KIDH) is a referral hospital for TB from northern Tanzania, and the national referral hospital for multidrug-resistant (MDR)-TB. Glycated hemoglobin (HgbA1c) testing was done on patients admitted to KIDH for newly diagnosed TB, retreatment TB, and MDR-TB, to determine the point prevalence of diabetes (HgbA1c ≥ 6.5%) and prediabetes (HgbA1c 5.7%-6.4%). RESULTS: Of 148 patients hospitalized at KIDH over a single week, 59 (38%) had no prior TB treatment, 22 (15%) were retreatment cases, and 69 (47%) had MDR-TB. Only 3 (2%) had a known history of diabetes. A total of 144 (97%) had successful screening, of which 110 (77%) had an HgbA1c ≤ 5.6%, 28 (19%) had ≥ 5.7 < 6.5, and 6 (4%) had ≥ 6.5. Comparing subjects with prediabetes or diabetes to those with normal A1c levels, retreatment patients were significantly more likely to have a A1c ≥ 5.7% (odds ratio: 3.2, 95% CI: 1.2-9.0; p = 0.02) compared to those without prior TB treatment. No retreatment case was a known diabetic, thus the number needed to screen to diagnose one new case of diabetes among retreatment cases was 11. CONCLUSIONS: Diabetes prevalence by HgbA1c was less common than expected, but higher HgA1c values were significantly more frequent among retreatment cases, allowing for a rational, resource-conscious screening approach.