DOI: 10.1097/corr.0000000000004045 ISSN: 0009-921X

Resistance or Virulence: Which Staphylococcus aureus Genes Are Associated With Poor Clinical Outcomes in Pediatric Acute Hematogenous Osteomyelitis?

Sophia Hamada, Brya G. Matthews, Anna C. E. McDonald, Reece Joseph, Jian-ming Lin, Sally Roberts, Jillian Cornish, Simon Swift, Haemish Crawford, Christina Straub
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Background

Pediatric acute hematogenous osteomyelitis (PAHO) is a bone infection usually caused by Staphylococcus aureus , where bacteria spread through the bloodstream and colonize bone tissue. In many countries, including New Zealand, most cases of PAHO are attributed to methicillin-susceptible S. aureus (MSSA). Although standard antibiotic therapy is effective in many cases (uncomplicated infections), some are difficult to resolve, leading to a poor clinical outcome (complicated infections). These patients often require intensive care admission, extended antibiotic treatment, and sometimes develop chronic infection. While antibiotic resistance and host factors are well-known contributors, bacterial genetic determinants remain relatively underexplored and likely play a critical role in disease severity and therapeutic response.

Questions/purposes

(1) Are the MSSA isolates found in children who had complicated infections genetically distinct from those from uncomplicated infections? (2) Is a complicated clinical outcome in PAHO associated with MSSA displaying reduced phenotypic susceptibility to antibiotics or the carriage of known genetic determinants of antimicrobial resistance? (3) Which genes and, in particular, which virulence factors are associated with complicated infections?

Methods

The study cohort comprised 85 MSSA isolates from 85 patients with PAHO collected at New Zealand’s largest children’s hospital. These isolates were split into two groups: complicated (n = 38, from patients with infections that required intensive care admission or were difficult to resolve with standard antibiotic treatment) and uncomplicated (n = 47, from patients with readily cleared infections). Phenotypic antimicrobial susceptibility testing was performed for all isolates. Whole-genome sequencing was performed for molecular typing, identification of antimicrobial resistance genes, and virulence factor genes. Isolate relatedness was identified using phylogenetic analysis. A genome-wide association study was conducted to identify genetic determinants associated with a complicated outcome.

Results

MSSA infections in PAHO are caused by a genetically diverse group of isolates, with no clustering of strains between complicated and uncomplicated infections. No differences in the levels of phenotypic susceptibility and presence of beta-lactam resistance genes between complicated and uncomplicated isolates was observed. However, genome-wide association analysis identified several virulence factors associated with complicated outcomes, including Panton-Valentine leukocidin (PVL) genes lukS-PV and lukF-PV (OR 23; q < 0.001), von Willebrand factor-binding protein (vWbp) (OR 13; q = 0.015), and capsular polysaccharide type 8 genes cap8HIJK (OR 11; q = 0.038). The fosfomycin resistance–associated mutation glpT_L27F was also associated with complicated outcomes.

Conclusion

Our findings suggest that complicated outcomes in MSSA infections in PAHO are associated with specific virulence gene carriage rather than classical antimicrobial resistance mechanisms. In a clinical setting, these findings have the potential to contribute to improved outcomes by molecular detection of high-risk virulence profiles, enabling targeted management in high-risk cases. Future studies could investigate whether biofilm formation and differential virulence factor gene expression contribute to variable clinical outcomes.

Level of Evidence

Level II, therapeutic study.

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