Antibiotic Combo Better for Severe Scrub Typhus Than Either Drug Alone

A dual antibiotic combination was better than either drug alone for treatment of severe scrub typhus, the randomized INTREST trial showed.

For patients with this tropical mite-borne bacterial illness, intravenous doxycycline and azithromycin reduced incidence of the composite of all-cause mortality at day 28, persistent complications at day 7, and persistent fever at day 5 compared with monotherapy.

The rate was significantly lower than with doxycycline alone or azithromycin alone (33% vs 47% and 48%, respectively, P=0.002 and P<0.001 for the two comparisons), reported George M. Varghese, MD, of Christian Medical College in Vellore, India, and colleagues.

Monotherapy with standard doxycycline wasn’t better than azithromycin alone, which has increasingly been used for milder cases (risk difference 1.5 percentage points, P=0.73), the group noted in the New England Journal of Medicine.

The advantage of combination treatment appeared largely driven by fewer persistent complications at day 7, with lower frequencies of respiratory, renal, hepatic, and central nervous system complications than in either of the monotherapy groups.

Scrub typhus results from the bite of soil-residing mite larvae — commonly known as chiggers — that transmit Orientia tsutsugamushi. Infection causes fever, headache, body aches, and sometimes rash. However, severe infection can result in organ failure and bleeding, which is fatal in up to 70% of cases left untreated and a quarter of those that are treated.

Estimates of 1 million cases a year are likely outdated, with striking increases in incidence in geographic areas where the disease was known to be endemic (Asia and Northern Australia), as well as new areas, noted David H. Walker, MD, and Lucas S. Blanton, MD, both of the Center for Tropical Diseases at the University of Texas Medical Branch in Galveston, in an accompanying editorial.

They called the findings an important advance for a “super-neglected tropical disease” that affects a large expanse of the world.

“Although mortality was similar in the combination-therapy and monotherapy groups, the reduced number of complications at day 7 in the combination-therapy group may translate into important benefits in underdeveloped regions in which scrub typhus is endemic, where the capacity for advanced supportive care is limited,” Walker and Blanton wrote.

The 28-day mortality rates were similar across groups, at 11-13%, as were the requirement for inotropic support, duration of ventilation, and duration of stay in the hospital and ICU.

“In a post hoc analysis in our trial, complications requiring organ support (e.g., ventilatory assistance, supplemental oxygen, or dialysis) were fewer by day 7 in the combination-therapy group than in the monotherapy groups, whereas the resolution of hepatic and renal involvement was more frequent,” Varghese’s group wrote.

Overall results were similar in intent-to-treat and per-protocol analyses.

The trial included 794 patients ages 15 and older seen at seven participating hospitals for severe scrub typhus with at least one organ involvement from Sept. 27, 2018, to Feb. 11, 2022. They were randomized to double-blind treatment with a 7-day course of one of the following regimens: doxycycline alone (200 mg twice daily on day 1, then 100 mg twice daily for 6 days), azithromycin alone (500 mg twice daily on day 1, followed by 500 mg daily for 6 days), or both together (using the same dosing as with monotherapy).

Median patient age was 48 years, and 54% of the participants were men. Fully 99% of patients presented with fever; complications were respiratory for 62%, hepatic for 54%, cardiovascular for 42%, renal for 30%, and neurologic for 20%.

Time to bacterial DNA clearance of O. tsutsugamushi (PCR negativity) was significantly longer with doxycycline than with either the combination regimen or azithromycin monotherapy, but similar between those two.

Overall and serious adverse event rates were similar among the treatment groups, but grade ≥3 events were “marginally more common,” albeit not statistically so, in the azithromycin and combination-therapy groups (11% each) than in the doxycycline group (8%). One combination-therapy group patient had altered behavior and an episode of self-limiting generalized tonic-clonic seizures considered to be possibly treatment-related.

As to why the combination proved better in the trial, the researchers speculated that the different mechanisms through which the two drugs inhibit messenger RNA translation at the bacterial ribosome “may result in a more complete blockade of protein synthesis with a consequently greater effect against O. tsutsugamushi. Better bacterial control during the critical first week of infection may result in prevention and faster resolution of severe manifestations of illness.”

While the editorialists suggested that the findings would likely generalize across scrub typhus-endemic areas around the world, the researchers noted several limitations, including unblinding by treating physicians due to patient clinical complexity in approximately 2% of the patients and exclusion of children and pregnant women.

“Generalizing the safety findings of our trial to young children and pregnant women is not possible, although such extrapolation may be reasonable for the efficacy findings,” Varghese’s group wrote.