Distinct systemic metabolic phenotypes associated with blood culture positivity and bacterial etiology in community-acquired pneumonia (CAP).

INTRODUCTION

Community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality worldwide, particularly among young children and older adults. Bacterial pathogens account for a substantial proportion of CAP cases, yet early identification of bacteremia and etiologic agents remains challenging. Blood cultures are slow and often have a limited clinical impact. We hypothesized that plasma metabolomics can capture systemic metabolic signatures associated with blood culture positivity and bacterial etiology at the time of hospital admission.

METHODS

Plasma samples from 80 patients with bacterial CAP (40 culture-positive and 40 age- and sex-matched culture-negative) were collected on the first day of admission. Metabolomic profiling was performed using complementary platforms, including untargeted 1H-NMR, GC-MS, and targeted LC-DIMS/MS. Multivariate and univariate analyses were applied to identify discriminating metabolic features.

RESULTS

Distinct metabolic phenotypes were observed between culture-positive and culture-negative patients across all platforms. OPLS-DA models demonstrated significant discrimination, with GC-MS and 1H-NMR showing strong internally cross-validated discriminatory performance (Q² > 0.45, AUROC > 0.90). Culture-positive CAP was characterized by increased phenylalanine, urea, and mannose, alongside decreased amino acids and fatty acids, indicating coordinated alterations in nitrogen metabolism, energy pathways, and lipid remodeling. Furthermore, metabolomic profiles enabled discrimination of Streptococcus pneumoniae from other bacterial causes, with GC-MS and LC-DIMS/MS achieving strong internal discrimination (Q² ≈ 0.4, AUROC > 0.90).

CONCLUSIONS

Plasma metabolomics identified distinct systemic metabolic patterns associated with blood culture positivity and, in exploratory analysis, with S. pneumoniae etiology. These discovery-stage findings demonstrate reproducible systemic metabolic patterns associated with blood culture positivity and bacterial etiology and support further validation of targeted metabolite signatures in independent CAP cohorts.