Transmission of extended-spectrum β-lactamase-producing Klebsiella pneumoniae in a Malawian neonatal unit: a clinical and genomic analysis of a prospective cohort study.

BACKGROUND: Klebsiella pneumoniae is an important cause of neonatal sepsis in sub-Saharan Africa and is frequently antimicrobial resistant. In this study, we investigated key transmission routes of extended-spectrum β-lactamase-producing K pneumoniae (ESBL-K pneumoniae) within a single neonatal unit to inform development of contextually appropriate infection prevention and control practices. METHODS: We recruited a prospective mother and neonate cohort of babies admitted for less than 48 h and expected to stay for 24 h or more, where the mother or guardian was aged 18 years or older. Participants were followed up until day 7 of admission or discharge, with samples taken on day 1 and 3, and at the final follow-up (maternal stool, neonatal stool, maternal hands, cots, and swaddling cloth [day 1 only]). We sampled the ward environment weekly and included contemporaneous invasive ESBL-K pneumoniae isolates in our analysis. The primary outcome was ESBL-K pneumoniae colonisation. K pneumoniae single-colony isolates were subjected to single-colony whole-genome sequencing, and plate-sweeps had post-enrichment metagenomics performed, before evaluation of multilocus sequence types and single-nucleotide polymorphisms. Statistical analyses (Kaplan-Meier, state-transition models, source-attribution models, transmission analysis combining single-nucleotide polymorphisms and timing of sample collection, and exponential random graph models) were used to infer whether transmission occurred and from which sources. FINDINGS: We recruited 94 neonate-mother pairs (from July 23, 2019, to March 30, 2020). Median gestational age was 37 (IQR 35-38) weeks, 41 (44%) of the 94 neonates were girls, all were of Black ethnicity, and 69 (73%) of 94 neonates were antibiotic exposed. ESBL-K pneumoniae rapidly colonised neonates (Kaplan-Meier analyses indicated median 5 days [95% CI 4-6]), with 44 (49%) of 90 of neonates being colonised at least once. State-transition model indicated females had increased colonisation risk (hazard ratio 2·33 [95% credible interval 1·07-5·40]). Invasive isolates (13 [76%] of 17) clustered with stool and environmental isolates. Results of transmission analysis using single-colony whole-genome sequencing and post-enrichment metagenomics were consistent with ESBL-K pneumoniae transmission from cots (13-29%), ward surfaces (37-65%; especially sinks and oxygen delivery equipment), mother's hands (6-13%), and other neonates (8-13%). The results of network analysis (exponential random graph models) were consistent with shared cots increasing transmission risk from 5·7 × 10-5 (95% CI 1·4 × 10-5 to 2·3 × 10-4) to 5·9 × 10-4 (3·1 × 10-4 to 1·1 × 10-3). INTERPRETATION: The hospital environment is implicated in colonisation and invasive infection with ESBL-K pneumoniae. Infection prevention and control interventions should focus on containing neonatal stool, maternal hand hygiene, cot decontamination, single-use oxygen delivery equipment, and surface cleaning, particularly sinks. FUNDING: Medical Research Council (UK); National Institute for Health Research (UK); Gates Foundation (USA); Wellcome (UK).