Scrub typhus is an acute, febrile disease, caused by O. tsutsugamushi, which is transmitted to humans by bites of larval-stage trombiculid mites known as chiggers. An eschar and regional lymphadenopathy often develop at the site of inoculation, and may be followed by a systemic infection ranging in severity from symptomless to fatal. The annual incidence of this disease has increased sharply in Korea; 6,784 cases were reported in 20051.

Response to treatment with doxycycline or chloramphenicol is generally rapid and life-saving2. O. tsutsugamushi infection is generally so responsive to treatment that if fever has not abated within 48 hours after therapy, the diagnosis is considered to be unlikely3.

The authors report a 43-year-old male with possible doxycyline-resistant scrub typhus, who continued to have fever and myalgia 96 hours after doxycycline treatment, but promptly responded to treatment with substituted clarithromycin.

This 43-year-old male farmer presented with complaints of fever, generalized myalgia and headache for 3 days duration. He drank frequently alcohol and took medicine for depression. On examination, he was febrile with a temperature of 37.8℃. There were generalized maculopapular rashes and eschar on the right chest, but no conjunctival suffusion and lymphadenopathy. The cardiopulmonary and neurologic examinations were unremarkable.

Laboratory results were as follows: WBC count was 7,470/mm³; hemoglobin, 13.1 g/dl; hematocrit, 37%; platelets, 159,000/mm³; ESR, 20 mm/hr; C-reactive protein, 12.49 mg/dL; BUN, 13.8 mg/dL; and creatinine, 0.9 mg/dL; albumin, 3.7g/dl; aspartate transaminase, 58 U/L; alanine transaminase, 38 U/L; LDH, 526 U/L. Chest X-ray and urine were normal.

He was empirically started on doxycycline for possible scrub typhus. However, he continued to have persistent fever, myalgia, and headache while receiving doxycycline treatment for 96 hours. Antibody titer against O. tsutsugamushi by using passive hemagglutinin test was 1:80, and serologic tests of leptospirosis and hemorrhagic fever with renal syndrome were all negative. Considering the possibility of doxycycline-resistant scrub typhus, doxycycline was discontinued and he was started on clarithromycin. Since then, he responded well to the treatment with subsidence of the fever and myalgia (Figure 1). Clarithromycin (1,000 mg/d) was given for a total of 7 days. Blood culture was sterile. Convalescent antibody titer against O. tsutsugamushi performed during the second week was 1:320.

Scrub typhus is a chigger-borne disease caused by the rickettsia Orientia tsutsugamushi. The disease is endemic in Asia and remains an important public health problem. Most cases of scrub typhus occur in rural areas, but cases may also occur in suburban areas. It is listed as one of the differential diagnoses of fever of unknown origin in endemic areas during the months of October and November4. The illness varies in severity from mild and self-limiting to fatal. After an incubation period of 6 to 21 days, the acute febrile onset is characterized by headache, sweating, conjunctival injection, and lymphadenopathy. There may be an accompanying maculopapular rash, an eschar at the site of chigger feeding.

Antibiotic treatment is thought to shorten the illness and reduce mortality. O. tsutsugamushi was previously thought to be so highly susceptible to tetracycline drugs that the rapidity of defervescence after the initiation of treatment was used to confirm a presumptive diagnosis. After a single oral dose of 200 mg of doxycycline, 90% of patients were afebrile within 48 hours5. In one study involving 42 adults treated with a single dose of 200 mg doxycycline, 88% became afebrile and all clinical symptoms disappeared within 72 hours6. In two series in Vietnam, fever resolved with tetracycline within 48 hours in 90% and 100% of patients, respectively7,8.

The slow response to treatment could have resulted from infection by more virulent strains of O. tsutsugamushi, from infection by resistant strains, or both. Song et al reported treatment failure in 4/66 participants in the doxycycline group9. In a case series from Thailand, strains of O. tsutsugamushi with reduced susceptibility to doxycycline were reported; the median fever clearance time for patients with doxycycline-resistant strains of O. tsutsugamushi was 80 hours10. Kim et al found that 7 patients (15.2%) were reported with fever persisted for more than 80 hours among doxycycline-treated group11. Based on above-mentioned data, we might suspect doxycycline resistant case because of the sustained fever and myalgia after 96 hours of doxycycline treatment.

The new macrolide antibiotic, azithromycin was effective against some strains of O. tsutsugamushi, particularly doxycycline resistant strains12. Azithromycin causes no known harm to young children and pregnant women. It has advantages over chloramphenicol, which occasionally causes bone marrow suppression, and tetracycline, which affects the growing bones and teeth of children and fetuses. Clarithromycin, with which we substituted doxycycline, was also reported to be effective for O. tsutsugamushi13,14. Because the annual incidence of scrub typhus has increased sharply, there is also growing concern about the possibility of doxycycline resistant strain in Korea. Therefore, it is necessary to test the susceptibility of O. tsutsugamushi to doxycycline. However, culture of O. tsutsugamushi can be performed in specialized centers with the necessary laboratory facilities and diagnostic reagents. Unfortunately feasible microbiological diagnostic tests are unavailable in Korea.

Sustained fever in this case may be caused by another condition, such as more virulent strain and poor drug absorption, other than drug resistant scrub typhus. Therefore, besides antibiotic susceptibility test, serum drug concentration also needs to be tested if available. However, otherwise, there was no apparent focus of persistent fever on examination, and sustained fever with myalgia despite doxycycline trial disappeared promptly to substituted clarithrimycin. This case shows clinically the possibility of doxycycline resistant scrub typhus in Korea although not confirmed microbiologically. There is a need to characterize doxycycline resistant scrub typhus in the near future.

Doxycycline-resistant strain of O. tsutsugamushi has not been isolated in Korea. But the risk of emerging of doxycycline resistant scrub typhus may be expected. Therefore, it is important to suspect clinically doxycycyline-resistant scrub typhus if there is a sustained fever without identifiable cause after doxycycline trial and alternative antibiotics may be considered.