Antibiotic Antagonism in Orientia tsutsugamushi Infection: A Narrative Review

Orientia tsutsugamushi causes scrub typhus (tsutsugamushi disease), an acute febrile disease. The infection has been effectively treated with antibiotics since chloramphenicol was introduced. However, occasional reports of treatment failures or delayed responses occur in scrub typhus, and their underlying causes remain poorly understood. This narrative review assesses whether antibiotic antagonism between β-lactam and anti-rickettsial antibiotics delays the resolution of scrub typhus. To address this, we reviewed historical changes in antibiotic use, pitfalls in interpreting study results, in vitro antagonism data, and relevant clinical reports. In subtropical regions, doxycycline and ceftriaxone are frequently used concurrently for the empirical treatment of severe acute undifferentiated fever, targeting scrub typhus and typhoid fever. However, an in vitro study demonstrated that cefotaxime reduces the effects of anti-rickettsial antibiotics, including doxycycline, by at least 25%. This potential antibiotic antagonism may delay fever resolution by 1-5 days, a minor difference often difficult to detect in individual patients. Even when detected, it is frequently misinterpreted as antibiotic resistance or attributed to severe disease or atypical clinical manifestations. Furthermore, this phenomenon may contribute to mortality in cases with life-threatening complications.