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Intravenous Doxycycline & Azithromycin for Severe Scrub Typhus

Compared with either agent given alone, the combination of intravenous doxycycline and azithromycin was more effective for treating severe scrub typhus, researchers report. The zoonotic bacterial infection is “a public health challenge that extends beyond the so-called Tsutsugamushi Triangle, the region where this infection has traditionally been endemic in Asia and Northern Australia,” explain the authors.

The multicenter, double-blind, randomized, controlled trial included patients 15 years of age or older with severe scrub typhus with involvement of at least 1 organ. A 7-day course of intravenous doxycycline, azithromycin, or both had these effects on a primary outcome of a composite of death from any cause at day 28, persistent complications at day 7, and persistent fever at day 5: “Among 794 patients (median age, 48 years) who were included in the modified intention-to-treat analysis, complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%). The use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively), for a risk difference of −13.3 percentage points (95% confidence interval [CI], −21.6 to −5.1; P = 0.002). The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of −14.8 percentage points (95% CI, −23.1 to −6.5; P <0.001). No significant difference was seen between the azithromycin and doxycycline groups (risk difference, 1.5 percentage points; 95% CI, −7.0 to 10.0; P = 0.73). The results in the per-protocol analysis were similar to those in the primary analysis. Adverse events and 28-day mortality were similar in the three groups.”

Editorial: “Because the reservoir in nature is soil-residing mites that maintain O. tsutsugamushi vertically by transovarian transmission and emerge from the soil as larvae (the only stage to inoculate organisms during a meal from the skin of a vertebrate host), the causative agent is unlikely to be eradicated,” editorialists write. “Aside from diagnosis and treatment, the third potential biomedical intervention is prevention. Unfortunately, few scientists are studying the potential vaccine antigens of O. tsutsugamushi and the mechanisms of immunity. Major challenges to vaccine development include immunity after a clinical course of scrub typhus that is neither cross-protective nor long-lasting. In addition, few scientists have the research experience and expertise to study Orientia tsutsugamushi. Notable exceptions are the groups of scientists in South Korea, Thailand, and the United Kingdom who continue to study this disease. Greater effort and support will be needed to provide answers to all the unresolved issues regarding scrub typhus. However, the current consolidation of data from the trial by Varghese et al. represents important progress in defining the appropriate treatment for the severe form of this disease.”

Source: New England Journal of Medicine