Dual Therapy Using Doxycycline and Azithromycin Is Superior to Monotherapy for Treating Severe Scrub Typhus

By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC

Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH

SYNOPSIS: A multicenter, randomized, double-blind, controlled trial from India found dual therapy with intravenous doxycycline and azithromycin is more effective than either agent alone for treating severe scrub typhus.

SOURCE: Varghese GM, Dayanand D, Gunasekaran K, et al. Intravenous doxycycline, azithromycin, or both for severe scrub typhus. N Engl J Med 2023;388:792-803.

Scrub typhus is a zoonotic infection caused by the intracellular rickettsial pathogen Orientia tsutsugamushi. It is transmitted by the bite of the chigger mite and is common throughout Asia and areas of rural Australia. Symptoms start with an eschar at the bite site and commonly include fever, headache, myalgias, adenopathy, rash, shortness of breath, and neurological changes. Severe disease develops in approximately one-third of hospitalized patients, with death occurring in approximately one-quarter of these despite therapy.

Doxycycline and azithromycin have been the mainstays of treatment for scrub typhus for many years. However, optimal therapy for severe disease remains uncertain. Varghese and colleagues aimed to determine the efficacy and safety of azithromycin/doxycycline combination therapy compared to monotherapy with either agent for patients with severe scrub typhus.

The study was a randomized, controlled clinical trial conducted at seven clinical sites in India. Patients were included who were at least 15 years of age, had a positive Scrub Typhus Rapid test or an eschar, and had severe disease, which was defined as having at least one organ involved and receiving intravenous therapy. Exclusion criteria were pregnancy or breast feeding, prior treatment with azithromycin, doxycycline, or chloramphenicol for at least 24 hours within three days of recruitment, treatment with rifampicin (because of its activity against O. tsutsugamushi), immune compromise, treatment with contraindicated concurrent drugs, or any previous adverse reaction to a trial drug.

Patients were randomized 1:1:1 to either intravenous (IV) doxycycline 200 mg twice per day on day 1, then 100 mg twice per day for six days; azithromycin 500 mg twice per day on day 1 then 500 mg daily for six days; or both doxycycline and azithromycin in the doses mentioned earlier. The primary outcomes were death from any cause at day 28, persistent complications at day 7, and persistent fever on day 5. The primary analysis was performed on the modified intention-to-treat (mITT) population, which included all the randomized participants except those who withdrew their consent (n = 10) or were found to be ineligible (n = 5).

The mITT population included 724 patients, with 265 in the doxycycline group, 263 in the azithromycin group, and 266 in the combination group. The primary outcome event occurred in 89/266 patients (33%; 95% confidence interval [CI], 28 to 39) in the combination group. It occurred in 124/265 patients (47%; 95% CI, 41 to 53) in the doxycycline group, a risk difference of -13.3 percentage points (95% CI, -21.6 to -5.1; P = 0.002). In the azithromycin group, the primary outcome event happened in 127/263 patients (48%; 95% CI, 42 to 55), a risk difference of -14.8 percentage points (95% CI, -23.1 to -6.5; P < 0.001). There was no significant difference in the primary outcome event between the doxycycline and azithromycin groups. Time to deoxyribonucleic acid (DNA) clearance of O. tsutsugamushi (polymerase chain reaction [PCR] negativity) was shorter in the combination group and azithromycin group compared to the doxycycline group.

There were no significant differences in adverse events between the groups. Treatment was discontinued in 42/724 patients (5%), including 13/265 (5%) in the doxycycline group, 17/263 (7%) in the azithromycin group, and 12/266 (5%) in the combination group. One patient in the combination group had a tonic-clonic seizure, which was considered to be possibly treatment-related.

COMMENTARY

An often-overlooked infection, scrub typhus usually manifests as a mild illness, but a significant minority of patients progress to severe disease. While it is rarely seen by clinicians in the United States, scrub typhus can occur in travelers to endemic areas. Thus, a high index of suspicion is critical to start appropriate therapy and achieve optimal patient outcomes.

It is rare for a single study to change clinical practice. This may be one of those instances. The optimal management of severe scrub typhus has not previously been evaluated rigorously (i.e., with a large, randomized clinical trial). Varghese and colleagues have shown that combination therapy with doxycycline and azithromycin is superior to either agent alone for severe scrub typhus, without an increase in adverse events. One patient in the combination group had a seizure, but is it important to remember that neurologic manifestations are common with severe scrub typhus.

It is not clear from the clinical trial why combination therapy was more effective. The authors postulated that because doxycycline and azithromycin have separate mechanisms for inhibiting messenger ribonucleic acid (mRNA) translation in the bacterial ribosome, this may lead to a more complete block of protein synthesis compared to a single drug. Improved bacterial killing in the first seven days following infection may lead to faster resolution of symptoms. Further investigation is needed to confirm this hypothesis.

In conclusion, the combination of doxycycline and azithromycin appears to be more effective for severe scrub typhus than either agent alone. Further options still are needed for pregnant woman, children, and individuals unable to tolerate doxycycline and/or azithromycin.