BACKGROUND
Bedaquiline (BDQ) resistance presents a critical challenge in the fight against tuberculosis (TB), particularly multidrug-resistant (MDR) strains. The emergence of resistance to BDQ, a key drug in treating MDR-TB, poses significant threats to TB treatment effectiveness.
METHODS
The National Institute of Tuberculosis and Respiratory Diseases in Delhi and the Médecins Sans Frontières clinic in Mumbai provide BDQ, delamanid, and carbapenem-based regimens for patients with suspected or confirmed treatment failure. BDQ phenotypic drug-susceptibility testing (DST) was performed for all BDQ-exposed patients. Treatment regimens were individualized based on exposure history, comorbidities, drug interactions, prior adverse drug reactions, and DST results.
RESULTS
Of 117 BDQ-exposed patients from December 2020–December 2022, 42 (36%) exhibited a BDQ-resistant strain. Median (IQR) age was 24 (22–32) years, with 63 (54%) females and 94% with pulmonary TB. Patients with a BDQ-resistant strain were older (median age: 27 vs 23 years; P = .04), more likely to have lung cavities (risk ratio [RR]: 1.8; 95%-CI: 1.1–3.1; P = .02), and be resistant to clofazimine (RR: 2.3; 95%-CI: 1.5–3.6; P = .001). Overall, 102 patients initiated treatment. Patients with BDQ-resistance had higher risk of unfavorable outcomes compared with BDQ-susceptible patients (RR:2.1; 95%-CI: 1.5–2.8; P < .001). Overall, 87% (33/38) of patients with BDQ-resistance experienced unfavorable treatment outcomes: 15 (40%) died, 15 (40%) had treatment failure, and 3 (8%) were lost-to-follow-up.
CONCLUSIONS
The study highlights a concerning rate of BDQ-resistance among previously treated patients, resulting in poor treatment outcomes. To prevent treatment failure, we recommend implementing BDQ-DST, developing affordable and accurate rapid tests for BDQ-resistance, and intensifying research and development efforts for newer TB drugs.
BACKGROUND
Circulating markers of immune and endothelial activation risk stratify infection syndromes agnostic to disease aetiology. However, their utility in children presenting from the community remains unclear.
METHODS
This study recruited children aged 1-59 months presenting with community-acquired acute febrile illnesses to seven hospitals in Bangladesh, Cambodia, Indonesia, Laos, and Viet Nam. Clinical parameters and biomarker concentrations were measured at presentation. The outcome measure was death or receipt of vital organ support within two days of enrolment. Prognostic performance of endothelial (Ang-1, Ang-2, sFlt-1) and immune (CHI3L1, CRP, IP-10, IL-1ra, IL-6, IL-8, IL-10, PCT, sTNFR-1, sTREM-1, suPAR) activation markers, WHO Danger Signs, and two validated severity scores (LqSOFA, SIRS) was compared.
RESULTS
3,423 participants were recruited. 133 met the outcome (weighted prevalence: 0.34%; 95% CI 0.28-0.41). sTREM-1 exhibited highest prognostic accuracy (AUC 0.86; 95% CI 0.82-0.90), outperforming WHO Danger Signs (AUC 0.75; 95% CI 0.70-0.80; p < 0.001), LqSOFA (AUC 0.74; 95% CI 0.70-0.78; p < 0.001), and SIRS (AUC 0.63; 95% CI 0.58-0.68; p < 0.001). Discrimination of immune and endothelial activation markers was particularly strong for children who deteriorated later in the course of their illness. Compared to WHO Danger Signs, an sTREM-1-based triage strategy improved recognition of children at risk of progression to life-threatening infection (sensitivity: 0.80 vs. 0.72), while maintaining comparable specificity (0.81 vs. 0.79).
CONCLUSIONS
Measuring circulating markers of immune and endothelial activation may help earlier recognition of febrile children at risk of poor outcomes in resource-constrained community settings.
BACKGROUND
Tuberculosis (TB) remains a significant cause of mortality globally, with India accounting for 27% of the estimated number of people with TB. Multidrug-resistant TB (MDR-TB) and isoniazid (INH) resistance pose additional challenges to effective treatment. We aimed to describe treatment outcomes of INH mono-resistant TB patients under programmatic conditions in Mumbai, India.
METHODS
This retrospective cohort study was conducted at Shatabdi Hospital in Mumbai between 2019-2021.We described the clinical and demographic characteristics, treatment outcomes, and risk factors for unfavourable outcomes among patients with INH mono-resistant TB treated with rifampicin, ethambutol, pyrazinamide, and levofloxacin (LfxREZ) for a duration of 6 months.
RESULTS
Among 3105 patients with drug-resistant TB initiated on treatment, 217 (7 %) had INH mono-resistant TB. Of these, 54 % (117/217) were female, with a median age of 26 years (interquartile range: 20-40). The majority (88 %; 191/217) presented with pulmonary TB, and most (87 %; 188/217) had favourable treatment outcomes, including treatment completion (52 %; 112/217) and cure (35 %; 76/217). Unfavourable outcomes, including treatment failure (2.3 %; 5/217), loss to follow-up (9.2 %; 20/217), or death (1.8 %; 4/217), were observed in 13 % (29/217) of patients. A total of ten (5 %) patients experienced at least one non-severe adverse drug reaction. Factors associated with unfavourable outcomes included severe thinness (p = 0.019) and male gender (p = 0.012).
CONCLUSION
Treating INH mono-resistant patients with LfxREZ resulted in satisfactory outcomes and low toxicity. It is important to rule out drug resistance to INH while determining the treatment regimen.
Over half of childhood tuberculosis (TB) remains undiagnosed yearly. TB culture is often unavailable. WHO recommends Xpert-Ultra as first test for diagnosis of paediatric TB, but microbiological confirmation remains low and often requires invasive procedures. We aimed to determine the utility of Xpert-Ultra in stools and urine samples to diagnose TB in children living with HIV (CLWH) in two high-TB burden settings.
METHODS
This cross-sectional multicentric study took place at Simão Mendes hospital, Guinea-Bissau, from July 2019 to April 2020, and in Malakal hospitals, South Sudan, from November 2019 to June 2023. Children 6 months to 15 years with suspected TB underwent clinical and laboratory assessment, with one respiratory or extrapulmonary sample (gold standard (GS)), one stool and one urine specimen per patient analysed with Xpert-Ultra.
RESULTS
A total of 93 HIV-positive children were enrolled from Bissau (n=57) and Malakal (n=36), with 49 (53%) females and median (IQR) age of 3.3 (1.5-10) years. Three-quarters of children had severe acute malnutrition (SAM). A total of 72 (77%) children were on ART at baseline and 26/77 (34%) had CD4 count <200cells/mm3. Confirmation of TB was achieved in 20 (22%); 51 (55%) had unconfirmed TB, and 22 (24%) had unlikely TB. Of 93 children with GS diagnosis, the overall yield of positive TB results was 22% (20/93): 10% (9/90) in pulmonary samples and 20% (1/5) in extrapulmonary samples. A total of 86 and 91 samples were used to evaluate Xpert-Ultra on stools and urine, respectively. Compared to GS, sensitivity and specificity on stools were 87.5% (95%CI:52.9-97.8) and 100% (95%CI: 95.3-100), whereas on urine were 30% (95%CI:10.8-60.3) and 100% (95%CI:95.5-100), respectively. No patients were positive in stools or urine and negative with GS.
CONCLUSIONS
Xpert-Ultra in stools showed high sensitivity and specificity in HIV-infected children when compared to gold standard. Sensitivity of urine was low, but more research is needed to determine its clinical indication.