Contribution of nosocomial transmission to Klebsiella pneumoniae neonatal sepsis in Africa and South Asia: analysis of infection clusters inferred from pathogen genomics and temporal data

  1. Erkison Ewomazino Odih
  2. Jabir A Abdulahi
  3. Anne V Amulele
  4. Matthew Bates
  5. Eva Heinz
  6. Weiming Hu
  7. Kajal Jain
  8. Rindidzani Magobo
  9. Courtney P Olwagen
  10. John M Tembo
  11. Tolbert Sonda
  12. Jonathan Strysko
  13. Caroline C Tigoi
  14. Kyle Bittinger
  15. Jennifer Cornick
  16. Ebenezer Foster-Nyarko
  17. Wilson Gumbi
  18. Steven M Jones
  19. Chileshe L Musyani
  20. Carolyn M McGann
  21. Ahmed M Moustafa
  22. Patrick Musicha
  23. James CL Mwansa
  24. Moreka L Ndumba
  25. Thomas D Stanton
  26. Donwilliams O Omuoyo
  27. Oliver Pearse
  28. Laura T Phillips
  29. Paul J Planet
  30. Charlene MC Rodrigues
  31. Fatou Secka
  32. Kirsty Sands
  33. Erin Theiller
  34. Allan M Zuza
  35. Sulagna Basu
  36. Grace J Chan
  37. Kenneth C Iregbu
  38. Jean-Baptiste Mazarati
  39. Semaria Solomon Alemayehu
  40. Timothy R Walsh
  41. Rabaab Zahra
  42. Angela Dramowski
  43. Sombo Fwoloshi
  44. Appiah-Korang Labi
  45. Lola Madrid
  46. Noah Obeng-Nkrumah
  47. David Ojok
  48. Boaz D Wadugu
  49. Andrew C Whitelaw
  50. Anudita Bhargava
  51. Atul Jindal
  52. Ramesh K Agarwal
  53. Alexander M Aiken
  54. James A Berkley
  55. Susan E Coffin
  56. Nicholas A Feasey
  57. Nelesh P Govender
  58. Davidson H Hamer
  59. Shabir A Madhi
  60. M Jeeva Sankar
  61. Kelly L Wyres
  62. Kathryn E Holt
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Abstract

Background

Klebsiella pneumoniae is the leading cause of sepsis among neonates in low- and middle-income countries (LMICs) in Africa and Asia, contributing substantially to the overall burden of antimicrobial resistant (AMR) infections and mortality among neonates globally. Pathogen sequencing has been used to investigate case clusters and confirm nosocomial transmission in a small number of neonatal units. Here we utilise pathogen sequence data to estimate the fraction of K. pneumoniae neonatal sepsis attributable to nosocomial transmission in African and South Asian countries.

Methods and Findings

We estimated the proportion of invasive K. pneumoniae disease involved in nosocomial transmission clusters in a given neonatal unit, using single-linkage clustering based on pairwise temporal and genetic distances estimated from bacterial whole-genome sequences aggregated from 10 contributing studies. Analysing 1,523 K. pneumoniae isolates from 27 units in 13 countries in Africa and South Asia between 2013 and 2023, we inferred 156 nosocomial transmission clusters, ranging from 2 to 188 neonates each (83 of the clusters comprised ≥3 cases). Overall, we estimated that 1,035 neonatal infections (68.0%) were part of nosocomial transmission clusters. Excluding the first infection in each cluster as a potential index case, we estimate at least 879 (57.7%) infections were acquired via nosocomial transmission. Sensitivity analyses showed that results were robust to the choice of genetic distance estimation methods and thresholds used to define clusters, and cluster estimates were stable over temporal distance thresholds ranging from 2 to 8 weeks. Isolates were mostly extended-spectrum beta-lactamase (ESBL) producers (90.9%) and included 172 multi-locus sequence types (STs). Fourteen STs, including several globally recognised multidrug-resistant lineages, were associated with transmission clusters at multiple units and these were collectively responsible for two-thirds of all infections. Carriage of carbapenemase genes (adjusted odds ratio, aOR = 2.08 [95% confidence interval, CI: 1.04–4.14], p=0.02) and ESBL genes (aOR = 2.48 [95% CI: 1.26–4.90] p=0.006) were significantly positively associated with transmission.

Conclusions

Nosocomial transmission contributes to a substantial proportion of K. pneumoniae sepsis in neonatal care units in Africa and South Asia. Reducing transmission within these settings through improved infection prevention and control and other measures could substantially reduce the neonatal sepsis burden. A high burden of transmission clusters is associated with the same drug-resistant lineages that are recognised as high-risk clones associated with hospital outbreaks in high-income countries, indicating global connectivity of the AMR pathogen population.

Author Summary

Why Was This Study Done?

  • Klebsiella pneumoniae is the leading cause of sepsis among neonates in low- and middle-income countries (LMICs) in Africa and Asia, and the infections are difficult to treat due to rising rates of antimicrobial resistance.

  • Invasive bacterial diseases are typically transmitted to neonates from their mothers before, during or soon after birth (vertical transmission) or from the hospital environment and healthcare workers (horizontal transmission).

  • The fraction of K. pneumoniae neonatal sepsis cases attributable to horizontal transmission is unknown, but this information is important to understand the role of infection prevention and control (IPC) measures in lowering disease burden.

What Did the Researchers Do and Find?

  • We developed a simple method to detect transmission clusters from genetic and temporal distance data and found the method to be robust to the choice of genetic and temporal distance thresholds.

  • We applied this method to detect transmission clusters among 1,523 K. pneumoniae neonatal sepsis cases from 10 studies and 27 hospitals across Africa and South Asia.

  • We estimate over half of sepsis cases (68.0%) were part of a transmission cluster, and by excluding the hypothetical index case for each cluster we estimate at least 57.7% of infections were acquired via nosocomial transmission.

  • Most of the isolates (90.9%) were extended-spectrum beta-lactamase (ESBL) producers (conferring resistance to third-generation cephalosporin antibiotics), and carriage of ESBL and carbapenemase genes (conferring resistance to carbapenem antibiotics) were positively associated with transmission.

  • Fourteen genetic lineages were associated with clusters in multiple neonatal units, together accounting for two-thirds of all infections.

  • Many of these same lineages are common causes of drug-resistant hospital outbreaks in high-income countries.

What Do These Findings Mean?

  • A substantial proportion of K. pneumoniae neonatal sepsis cases are potentially preventable with improvements in IPC in neonatal units.

  • Further work is needed to identify and better understand transmission routes and risk factors for transmission to support the implementation of effective and scalable IPC solutions.

  • Our findings highlight the importance of genomic surveillance to support IPC interventions for K. pneumoniae and other pathogens, and reveal many of the same ‘drug-resistant problem clones’ are responsible for hospital outbreaks across high-and low-income countries.

  • The high rates of ESBL gene carriage among isolates in this study indicates that empirical treatment based on the current WHO guidelines may result in high rates of treatment failure.

  • The limitations of this study include the lack of sufficient clinical data to allow high-resolution investigation of transmission dynamics, as well as facility-level data to investigate contributors to the observed differences in transmission burden across sites.

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