Prospective Genomic Surveillance of Severe Febrile Illness in Tanzanian Children Identifies High Mortality and Resistance to First-Line Antibiotics in Bloodstream Infections.

Severe febrile illness (SFI), a major cause of child mortality in Sub-Saharan Africa (SSA), is frequently caused by bloodstream infections (BSI), increasingly caused by antimicrobial-resistant organisms. However, antimicrobial resistance (AMR) prevalence and patterns in this population are largely unknown. We conducted a prospective cohort study of children aged 28 days to 14 years with SFI at a referral hospital in Tanzania (July 2022-September 2023) to determine the prevalence, pathogen profile, and AMR patterns of BSIs. Blood cultures were performed on all participants. Isolates underwent AMR testing and whole genome sequencing (WGS) to identify AMR genes and assess genetic relatedness. The association between BSI and mortality was assessed using logistic regression. Among the 392 enrolled children (median age 17.8 months), 5.2% (n = 20) had culture-confirmed BSI, with a case fatality rate of 45%. Gram-negative bacteria predominated (Escherichia coli, Klebsiella pneumoniae), with 79% of isolates exhibiting phenotypic resistance to ceftriaxone, a first-line antimicrobial. WGS revealed extended-spectrum β-lactamase genes (CTX-M-15, CTX-M-27) in most Enterobacterales isolates and identical isolates among 2/4 patients with Streptococcus pneumoniae and 2/3 Candida albicans infections. Children with BSI had significantly higher mortality than those without BSI (adjusted odds ratio 3.9; 95% CI: 1.5-10.1, P <0.01). These findings emphasize the urgent need for expanded AMR surveillance systems, empiric antibiotic regimens tailored to local AMR patterns, and culture-independent diagnostics in SSA. These data are critical for understanding the cause of severe infection and have the potential to guide policy aimed at reducing child mortality from BSI.