Low birthweight neonates and those with long hospital stays are most at risk of antimicrobial-resistant Klebsiella pneumoniae infection in Malawi: implications for antibiotic prescribing

Background Klebsiella pneumoniae (Kpn) is a major cause of neonatal sepsis in Africa. 3rd generation cephalosporin and gentamicin resistant Kpn is the norm in many sites, rendering WHO recommended first- and second-line antimicrobials ineffective. An understanding of which neonates and infants are most at risk of sepsis caused by Kpn would support the case for improved access to WHO watch and reserve antimicrobials (i.e. carbapenems) for patients most likely to benefit from them. Methods A prospective case-control study was conducted at Queen Elizabeth Central Hospital, Malawi. Cases were infants <3 months of age with blood or CSF culture confirmed Kpn infection. Controls were healthy infants from the same wards and were matched 2:1. Univariate and multivariate logistic regression were performed on mean-centred data to determine risk factors for infection with Kpn. Results We analysed data from 38 cases and 76 controls between August 2021 and April 2023. Mortality at 3 months of age was 21/38 (29%) for cases, with 14/38 (37%) identified postmortem and 6/76 (7.9%) for controls (OR 14.0 (95% CI 4.59, 49.2, p>0.001). Cases were more likely to be born out of QECH than controls (42% vs. 24%, p = 0.043), and cases had lower birthweights (median 2200g vs. 2850g, p = 0.005). Multivariate logistic regression analysis revealed that increasing birthweight was protective against Kpn infection (OR: 0.858 [95% CI: 0.745, 0.987] per 100g increase), while longer hospital stay was associated with increased odds of infection (OR: 1.148 [95% CI: 1.012, 1.1.303] per additional day). Most infecting isolates (34/38 [89%]) were resistant to first- and second-line antimicrobial agents, but all were sensitive to meropenem and 33/36 [92%] to amikacin. Conclusion Low birthweight infants with prolonged hospital stay were at greatest risk of Kpn infections that were typically resistant to WHO first- and second-line antimicrobial therapy. These infants should be prioritised for antibiotics that have the potential to be life-saving. The overlapping and evolving nature of these risk factors makes it difficult to design a simple tool to support empiric initiation of meropenem. Neonates critically ill with Kpn sepsis cannot, however, afford to wait for blood culture confirmation before receiving effective treatment. This highlights the need for empiric decision making frameworks that allow rapid initiation of effective therapy in high-risk neonates.