Using Genomic and Traditional Epidemiologic Approaches to Define Complex Transmission Pathways of Klebsiella pneumoniae Infection in a Neonatal Unit in Botswana, 2022–2023

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Abstract Background Klebsiella pneumoniae ( Kpn ) is a major cause of infant mortality worldwide, with most transmission occurring among hospitalized neonates in low-and middle-income countries where infections caused by multidrug-resistant Kpn (MDR- Kpn ) are increasingly common. We hypothesized that integrating laboratory surveillance for neonatal colonization and infection, real-time epidemiologic investigations, and whole-genome sequencing (WGS) could identify transmission pathways to guide targeted infection prevention and control (IPC) strategies. Methods and Findings We conducted Kpn surveillance in a 36-bed neonatal unit in Botswana over 12 months (2022–2023). WGS was performed on Kpn isolates from bloodstream infections (BSIs), and MDR- Kpn isolates collected from environmental sampling during outbreaks and twice-monthly colonization screenings (skin and perirectal swabs) using culture media selective for MDR- Kpn (CHROMagar Extended-spectrum beta-lactamase [ESBL]/SuperCarba). WGS data were analyzed using multilocus sequence typing (MLST), pangenome and reference-based single-nucleotide polymorphism (SNP) analyses, and Bayesian phylogenetics. We identified 55 Kpn BSIs during the 12-month surveillance period and the median prevalence of MDR- Kpn colonization was 28%. Kpn was recovered from multi-use intravenous (IV) fluid bags during a Kpn outbreak (41 BSIs, 10 deaths), which was controlled by implementing a 24-hour discard policy for IV medications. Among 270 Kpn isolates available (28 BSI, 232 colonizing, 10 environmental [six IV fluid, four sink drain]), WGS confirmed over half of BSI genomes (n=17) were ST1414, a clone susceptible to third-generation cephalosporins not detected during MDR- Kpn colonization screening, but closely related (<25 SNPs) to six Kpn isolates from contaminated IV fluids. Conclusions This study reinforces the value of integrating WGS with real-time epidemiologic investigations to understand transmission dynamics and guide IPC. Colonization surveillance focused solely on MDR- Kpn may overlook drug-susceptible but outbreak-prone strains.