Doxycycline, azithromycin combo therapy superior to monotherapies for severe scrub typhus: INTREST trial

The superiority was concerning the primary composite outcome of death at day 28, persistent fever at day 5, and persistent complications at day 7 in both the modified intention-to-treat and per-protocol populations

"The superiority of combination therapy was primarily due to a reduced incidence of persistent complications at day 7 when the frequencies of renal, hepatic, respiratory, and central nervous system complications were lower in the combination therapy group than in either monotherapy group," the authors explained. As shown in other studies, the authors noted no difference in the primary outcome between the monotherapy groups.

There must be clarity on the suitable antibiotic treatment for severe scrub typhus, a widespread reemerging zoonotic infection often neglected. To fill this knowledge gap, George M. Varghese from Christian Medical College in Vellore, India, and colleagues aimed to compare the safety and efficacy of three 7-day IV antibiotic treatments (azithromycin, doxycycline, or a combination of both) among patients with severe scrub typhus in INTREST, a double-blind, randomized, controlled clinical trial.

The researchers enrolled patients 15 years or above with severe scrub typhus involving at least one organ. The patients were assigned a 7-day course of IV azithromycins, doxycycline or both (combination therapy). A composite of death from any cause on day 28, persistent fever on day 5, and persistent complications on day seven were determined (primary outcome).

The study led to the following findings:

· Among 794 patients (median age, 48 years) who were included in the modified intention-to-treat analysis, complications included those that were neurologic, respiratory (62%), cardiovascular (42%), hepatic (54%), and renal (30%).

· 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.

· The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of −14.8 percentage points.

· No significant difference was seen between the azithromycin and doxycycline groups (risk difference, 1.5 percentage points).

· The results in the per-protocol analysis were comparable to those in the primary analysis. 28-day mortality and adverse events were similar in the three groups.

The researchers conclude, "combination therapy with intravenous azithromycin and doxycycline was a better therapeutic option for treating severe scrub typhus than monotherapy with either drug alone."

Reference:

The study, "Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus," was published in the New England Journal of Medicine. DOI: 10.1056/NEJMoa2208449