β-lactam antibiotics trigger TLR2-dependent Jarisch-Herxheimer reaction in leptospirosis: bacteriostatic antibiotics offer a safer alternative

Leptospirosis is a reemerging neglected zoonotic disease causing 1 million cases and 60,000 deaths annually. Antibiotic treatment can trigger a detrimental inflammatory Jarisch-Herxheimer reaction (JHR). We investigated the effects and mechanisms of different antibiotics and consequences of JHR in leptospirosis. In a mouse model of severe infection and in healthy human whole-blood infected with bioluminescent Leptospira interrogans , we compared bactericidal β-lactams (amoxicillin, ceftriaxone) with bacteriostatic agents (azithromycin, doxycycline). We assessed bacterial survival, cytokine levels, pathophysiology, and JHR mechanism using neutralizing antibodies and Toll-like receptor (TLR) knockout mice. β-lactams induced profound pro-inflammatory cytokine release whereas bacteriostatic antibiotics did not, despite effective killing. Progressive β-lactam dosing and corticosteroids mitigated inflammation. In humans, this inflammation was largely dependent on TLR2 (the lipoprotein receptor) and TLR5 (the flagellin receptor). In mice, amoxicillin exacerbated disease severity within hours, notably worsening myocarditis. Only the stealthy virulent clinical isolates of Leptospira interrogans induced JHR, which was also observed with Borrelia burgdorferi . These findings demonstrate that β-lactam-induced JHR is driven by TLR recognition of released spirochaetal components, worsening outcomes, evoking a cytokine storm. They challenge the World Health Organization’s recommendations favouring β-lactams as first-line therapy, advocating instead for bacteriostatic antibiotics to prevent JHR and improve patient outcomes worldwide.