448 Indian Medical Gazette — NOVEMBER 2011

Review

Treatment Update for Scrub Typhus

S. N. Kaore,
P. Sharma,
V. K. Yadav,
R. Sharma
— Dept. of Pharmacology, People’s College of Medical Sciences, Bhopal, M.P., India.
N. M. Kaore, Dept. of Microbiology,
People’s College of Medical Sciences, Bhopal, M.P., India.
D. G. Langade, Dept. of Pharmacology,
People’s College of Medical Sciences, Bhopal, M.P., India.

Introduction disease to reduce morbidity and mortality. The conventional

treatment includes broad spectrum antibiotics like
Scrub typhus is a mite-borne infectious disease caused
doxycycline and chloramphenicol, both of which are found
by Orientia tsutsugamushi (previously called Rickettsia
effective for the treatment of scrub typhus, while
tsutsugamushi). It is distributed throughout the Asia Pacific tetracyclines are not recommended in children younger than
region, being endemic in Korea, China, Taiwan, Japan, 8 years of age because of risk of discolouration of teeth.
Pakistan, India, Thailand, Malaysia, and northern portions Though seven days’ treatment is usually effective, but it is
of Australia. However, cases also occur in the United States, essential to monitor chloramphenicol therapy by repeating
Canada and Europe, being imported by tourists returning total blood counts. In severe cases, it is imperative to give
from endemic regions1. appropriate supportive measures to abort progression to
disseminated intravascular coagulation (DIC) or circulatory
Scrub typhus is manifested clinically by high fever, collapse. Azithromycin is an alternative for children.
intense generalized headache, diffuse myalgias, and, in Although tetracyclines or chloramphenicol are the
many patients, rash and an eschar at the site of the chigger recommended drugs of choice for the treatment of scrub
bite. The diagnosis is suggested by the clinical history typhus, reports of Doxycycline-resistant strains have
(including visit to an endemic area) and physical findings prompted a search for alternative treatments. Rifampicin
and confirmed by serologic testing or biopsy of an eschar2. and Azithromycin have been used successfully in areas
where scrub typhus is resistant to the conventional therapy4.
If not treated, fever may subside spontaneously after
2 weeks but the mortality rate may range between 10 – Tetracycline derivatives are the mainstay of scrub typhus
30 %3. treatment. This drug inhibits bacterial protein synthesis by
binding with 30S and possibly 50S ribosomal subunit(s).
Treatment options for scrub typhus Tetracycline derivatives like Doxycycline are employed as
The treatment should be initiated early in the course of 100 -200 mg twice a day for better compliance and quicker

Address for correspondence: Dr S. N. Kaore, Dept. of Pharmacology, People’s College of Medical Sciences, Bhopal, M.P., India.
Indian Medical Gazette — NOVEMBER 2011 449

defervescence. Tetracycline has also caused significant The side effects are mild gastric upset, abdominal pain,
improvement in ARDS, a life threatening complication of headache, dizziness, and elevated serum levels of ALT. It is
scrub typhus5. not found to affect CYP3A4 enzyme, so drug interactions
are less likely with drugs like theophylline, carbamezepine7.
Inflammatory cytokines including TNF-α, IL-1β, and A comparative trial of a single dose of azithromycin
IL-6 are markedly unregulated in patients with scrub typhus. 500 mg versus doxycycline 200 mg for 1 wk daily, given in
Doxycycline treatment rapidly reduces the production of the treatment of mild scrub typhus, suggests that both are
these cytokines, corresponding to the early defervescence equally effective in terms of time taken for defervescence8.
after the start of the treatment6.
Roxithromycin is a semi-synthetic long acting acid- stable
The adult dose for doxycycline is 100 – 200mg twice a drug with good enteral absorption and tissue penetration
day and 5mg/kg/IV twice a day and should not exceed with t ½ of 12 hrs has been also used as an alternative drug
200mg/day. for scrub typhus and found effective and safe in pediatric
population. Its affinity for cytochrome P450 is lower but
Chloramphenicol, the other drug in conventional therapy drug interactions with terfenadine, cisapride and others
also binds to 50 S bacterial-ribosomal subunits and inhibits cannot be ruled out4-9.
bacterial growth by inhibiting protein synthesis. Monitoring
serum levels is a useful aspect and dose can be adjusted to Another study in Thailand showed that rifampicin, an
achieve the therapeutic concentrations (ie, peak 10-20 mcg/ antitubercular drug can be used to treat scrub typhus. But
mL, trough 5-10 mcg/mL)4. The dose is 50-100 mg/kg/d considering the most potential problem of resistance to
orally or intravenous divided in 6 hourly doses. rifampicin monotherapy, the combination of rifampicin with
doxycycline was studied but unfortunately was not found
Aplastic anemia has been reported in all age groups and effective. The same study also suggested that 1 wk 600 mg
is an idiosyncratic reaction. The estimated incidence is about or 900 mg of rifampicin was superior to Doxycycline.
1 in 24,000 to 40,000 courses of therapy. To prevent this These doses produced comparable defervescence, so can
complication, indiscriminate, prolonged or repeated use of be used in areas resistant to the conventional therapy10-11.
the drug should be avoided. The peripheral blood smears
should be examined at least once weekly during therapy Scrub typhus in pregnancy
and treatment should be stopped if the leukocyte count
The infection is uncommon in pregnancy, but when
drops below 4000 cu. mm. or when the proportion of present it has serious consequences both for the mother
granulocytes is reduced below 40 percent. It must be noted and the foetus, if not appropriately controlled. It is difficult
that in life threatening condition the risk-benefit ratio should to validate a safe and an effective therapeutic regimen for
be considered and administration of chloramphenicol in this population since it is not common in pregnancy. A study
pediatric age group and pregnant ladies should be avoided suggests that azithromycin 500 mg single dose has proven
as far as possible. In this selected population, azithromycin effective and was not associated with relapse or any
and roxithromycin serve as good and efficacious unfavourable outcomes12.
alternatives.
Preventive measures13
Azithromycin is a macrolide drug that attaches to 50S
and interferes with translocation and thus inhibits protein 1. The public and physicians should be made aware
synthesis. The remarkable pharmacokinetic properties are that mites transmit disease.
acid stability, rapid oral absorption, marked tissue
2. Avoid mite infested areas.
distribution and intracellular penetration. Concentration in
most tissues exceed that in plasma, particularly high 3. Do not sit or lie on bare ground or grass; use a
concentration are attained inside macrophages and suitable ground sheet or other ground cover.
fibroblasts. Slow release from the intracellular sites Clearing of vegetation and chemical treatment of
contributes to its long terminal t ½ of more than 50 hours. the soil may help to break up the cycle of
It is convenient for once a day dosing and has better gastric transmission from chiggers to humans to other
tolerance. chiggers.
450 Indian Medical Gazette — NOVEMBER 2011

4. Alternatively, prevent contact with infected mites diethyltoluamide) to exposed skin surfaces.
by personal prophylaxis against the mite vector by
5. Remove mites from humans.
impregnating clothes and blankets with miticidal
chemicals (permethrin and benzyl benzoate) and 6. Eliminate mites from sites by the application of
the application of mite repellents (dibutyl phthalate, chlorinated hydrocarbons (lindane, dieldrin,
benzyl benzoate, diethyl toluamide, chlordane) to the ground and vegetation in camps,

Table 1
Drug treatment strategies for scrub typhus
Drug Dose MOA ADR Remarks
Doxycycline 200 mg/d X Binds to 30S teeth - drug of choice
7 days & Inhibits discoloration - early defervescence
protein phototoxicity
synthesis renal toxicity - markers of inflammation:TNF-α , IL-1β, and
IL-6 decrease in 24 hrs after starting treatment
Chloramphenicol 50 - 100 mg/kg/ Binds to 50S aplastic anemia - early defervescence
d X 7 days & Inhibits - conventional therapy
protein
- can be used in children, pregnant women
synthesis
(except in last trimester)
Azithromycin 500 mg single Binds to 50S mild gastric - early defervescence comparable to 1 wk
dose & Inhibits upset, doxycycline
protein abdominal pain, - safer alternative in pregnancy
synthesis headache
- less incidence of drug interactions
dizziness
Telithromycin 800 mg once Binds to 50S G.I. - promising new antimicrobial agent
daily X 5 days & Inhibits disturbances - comparable to 200mg/d
protein headache, taste
- doxycycline given for 5 days
synthesis disturbances
- drug interactions likely
Roxithromycin 150 – 300 mg Binds to 50S diarrhoea, - as effective as conventional therapy
twice daily & Inhibits nausea, - safer than conventional therapy
protein vomiting
- drug interactions more likely
synthesis
- than azithromycin
Rifampicin a 600 mg/d X 1 wk Inhibits DNA G.I.upset, rash, - more effective than Doxycycline
OR dep RNA fever, chills, - used in resistant cases (more effective in
900 mg/d X 1 wk polymerase dizziness combination with
- doxycycline)
Levofloxacin b 500 mg once Inhibits DNA G.I. upset - takes longer time for defervescence, this
gyrase may contribute to fatality
Note : Total duration of antibiotic therapy can be adjusted on case to case basis depending upon the severity of the disease.
a. Watt G, Kantipong P, Jongsakul K, Watcharapichat P, Phulsuksombati D, Strickman D. Doxycycline and rifampicin for mild
scrub-typhus infections in northern Thailand: a randomised trial. Lancet (Lancet) Vol. 356 Issue 9235 Pg. 1057-61 (Sep 23
2000) ISSN: 0140-6736.
b. Chen-Chi Tsai, Chorng-Jang Lay, Chun-Lung Wang, Yu-Huai Ho, Lih-Shinn Wang, Li-Kuang Chen, Levofloxacin versus
tetracycline antibiotics for the treatment of scrub typhus; International Journal of Infectious Diseases: article in press, available
at http://www.ijidonline.com/article/PIIS1201971209001477/abstract?showOmimLinks=true
Indian Medical Gazette — NOVEMBER 2011 451

mine buildings, and other populated zones in Conclusion

endemic areas.
Without treatment the fever generally lasts for 14 days.
7. Advise individuals travelling to endemic areas to In some cases the initial symptoms are lymphadenopathy
wear protective clothing. and a rash that begins on the trunk and spreads outwards.
The case fatality rate depends on the area, strain of rickettsia,
8. Antibiotic prophylaxis may be indicated to produce and previous exposure to the disease but is consistently
active immunity to scrub typhus. higher in the elderly. Death can occur from the primary
Chemoprophylaxis using doxycycline in high-risk infection or from secondary complications (e.g.,
groups (eg. military personnel) has been successful. pneumonitis, encephalitis, circulatory failure). Most fatalities
Doses are weekly and must be started before occur by the end of the second week of infection13.
exposure and continued for 6 weeks after exposure.
This infection is treated with antibiotics, the drug most
Studies are underway.
commonly used is doxycycline and chloramphenicol is an
As per WHO, it has been shown that a single oral dose alternative. A combination therapy with doxycycline and
of chloramphenicol or tetracycline given every five days rifampicin should be used in areas where drugs used alone
for a total of 35 days, with 5-day non-treatment intervals, are not effective24. Azithromycin or chloramphenicol is
actually produces active immunity to scrub typhus. This useful to treat infection in children or pregnant women,
procedure is recommended under special circumstances while doxycycline is relatively contraindicated in children.
in certain areas where the disease is endemic14. Antibiotic therapy brings about prompt defervescence. If
the antibiotic treatment is discontinued too quickly, especially
Vaccine in patients treated within the first few days of the fever,
relapses may occur. Secondary infections, such as bacterial
The historical aspects of vaccine development can be pneumonia, should be treated appropriately. Total duration
traced back to 1937, when it was first attempted by of antibiotic therapy can be adjusted on case to case basis
Wellcome foundation, United Kingdom and was tried finally depending upon the severity of the disease. No significant
in 1945 in human subjects in India for use by the Allied morbidity or mortality occurs in patients who receive
Land Forces, South-East Asia Command, in June 1945 appropriate treatment.
(Wellcomes laboratory at Ely Grange, Frant, Sussex)15,16,17.
Other alternative drugs include macrolides like
The major hurdle in vaccine production is existence of azithromycin, roxithromycin, telithromycin and the anti-
a large number of immunotypic and genotypic variants tubercular drug rifampicin. Rifampicin is used in resistant
among the strains of O. tsutsugamushi and immunity to cases.
one strain does not confer immunity to another18,19,20,21. An
Since no effective vaccine is available, it is prudent that
ideal vaccine should provide protection to all the strains
case identification, public education, rodent control and
present locally, in order to give an acceptable level of
habitat modification are the mainstay of strategies aimed at
protection. This means that a vaccine developed for one
controlling the impact of scrub typhus on the human
locality may not be protective in another locality, because
population.
of antigenic variation. This complexity continues to hamper
efforts to produce a viable vaccine22. References
A truncated recombinant 56-kDa outer membrane protein 1. Padbidri V.S., Gupta N.P. — Rickettsiosis in India: A
of the Karp strain of Orientia tsutsugamushi (Kp r56) was review. J Indian Med Assoc 1978; 71 : 104-107, 1978.
evaluated in cynomolgus monkeys (Macaca fascicularis)
2. Seong S., Choi M. & Kim I. — Orientia tsutsugamushi
for immunogenicity and safety as a vaccine candidate for
infection: overview and immune responses. Microbes
the prevention of scrub typhus. This recombinant antigen
and Infection. 3(1): 11–21, 2001.
induced strong humoral and cellular immune responses in
two monkeys and was found to be well tolerated23. 3. McPhee S.J., Papadakis M.A. — Current Medical
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Diagnosis & Treatment; Rickettsial Diseases 48th 14. Available at http://www.searo.who.int/LinkFiles/

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4. eMedicine, Fernandez A.D., Liang J.R. — Scrub 15. AWIC Newsletter: The Cotton Rat In Biomedical
Typhus; updated on Jun 29, 2009: available at http:// Research”. http://www.nal.usda.gov/awic/
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5. Izumo T., Yamaguchi M., Onizawa S., Kiguchi T., 16. Far East Report. Hansard. 2 April 1946. http://
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17. Kelly et al. — The Past & Present Threat of
Zasshi.2008 May; 46(5):385-389.
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20. Akira Tamura, Norio Ohashi, Yoko Koyama, Masahiro
9. Epub 2004 Oct 11. Lee K.Y., Lee H.S., Hong J.H., Fukuhara, Fumihiko Kawamori, Masamitsu Otsuru,
Hur J.K., Whang K.T. — Roxithromycin treatment Ping-Fuai Wu, Shen-Yu Lin — Characterization of
of scrub typhus (tsutsugamushi disease) in children. Orientia tsutsugamushi isolated in Taiwan by
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P., Phulsuksombati D., Strickman D. — Doxycycline Volume 150, Issue 2, 15 May 1997, Pages 225-231.
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21. P.E. Fournier — Genetic Variability of Orientia
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