Background: Enteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi, remains a major infectious disease burden in low- and middle-income countries, increasingly complicated by multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Macrolide antibiotics exert immunomodulatory effects beyond bactericidal activity, yet this dimension remains uncharacterized in enteric fever
Objective: To compare immunomodulatory effects of azithromycin versus fluoroquinolone therapy on systemic inflammatory biomarkers, fever clearance, and clinical outcomes in laboratory-confirmed enteric fever.
Methods: A prospective comparative cohort study enrolled 320 laboratory-confirmed enteric fever patients allocated to azithromycin (n = 160) or fluoroquinolone therapy (n = 160). C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and white blood cell (WBC) count were measured at baseline (Day 0) and Day 7. Fever clearance time, treatment failure, and antimicrobial resistance profiles were assessed. Independent samples t-tests, chi-square tests, and multivariable binary logistic regression were applied.
Results: Baseline parameters were comparable across groups (all p > 0.05). Azithromycin was associated with significantly greater reductions in CRP (−37.14 vs. −31.39 mg/L), IL-1β (−58.12 vs. −39.60 pg/mL; ~47% greater reduction; Cohen's d = 1.71), IL-6 (−31.03 vs. −23.76 pg/mL), and TNF-α (−46.70 vs. −30.26 pg/mL; all p < 0.001). Fever clearance was approximately 13 hours shorter in the azithromycin group (121.86 ± 16.58 vs. 134.73 ± 23.64 hours; p < 0.001). WBC reduction was equivalent between groups (p = 0.736). Treatment failure rates did not significantly differ (5.6% vs. 8.1%; p = 0.377). No independent predictor of treatment failure was identified (Nagelkerke R² = 0.038).
Conclusion: Azithromycin was associated with superior inflammatory cytokine resolution and accelerated fever clearance compared to fluoroquinolone therapy, without generalized leukocyte suppression or differential cure rates. These findings suggest antibiotic class selection influences host immune recovery beyond antimicrobial activity alone, supporting consideration of azithromycin's immunomodulatory profile in enteric fever management, particularly in MDR-endemic settings.