Treatment Update for Scrub Typhus

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1 448 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 Scrub typhus is a mite-borne infectious disease caused by Orientia tsutsugamushi (previously called Rickettsia tsutsugamushi). It is distributed throughout the Asia Pacific region, being endemic in Korea, China, Taiwan, Japan, Pakistan, India, Thailand, Malaysia, and northern portions of Australia. However, cases also occur in the United States, Canada and Europe, being imported by tourists returning from endemic regions 1. Scrub typhus is manifested clinically by high fever, intense generalized headache, diffuse myalgias, and, in many patients, rash and an eschar at the site of the chigger bite. The diagnosis is suggested by the clinical history (including visit to an endemic area) and physical findings and confirmed by serologic testing or biopsy of an eschar 2. If not treated, fever may subside spontaneously after 2 weeks but the mortality rate may range between % 3. Treatment options for scrub typhus The treatment should be initiated early in the course of disease to reduce morbidity and mortality. The conventional treatment includes broad spectrum antibiotics like doxycycline and chloramphenicol, both of which are found effective for the treatment of scrub typhus, while tetracyclines are not recommended in children younger than 8 years of age because of risk of discolouration of teeth. Though seven days treatment is usually effective, but it is essential to monitor chloramphenicol therapy by repeating total blood counts. In severe cases, it is imperative to give appropriate supportive measures to abort progression to disseminated intravascular coagulation (DIC) or circulatory collapse. Azithromycin is an alternative for children. Although tetracyclines or chloramphenicol are the recommended drugs of choice for the treatment of scrub typhus, reports of Doxycycline-resistant strains have prompted a search for alternative treatments. Rifampicin and Azithromycin have been used successfully in areas where scrub typhus is resistant to the conventional therapy 4. Tetracycline derivatives are the mainstay of scrub typhus treatment. This drug inhibits bacterial by binding with 30S and possibly 50S ribosomal subunit(s). Tetracycline derivatives like Doxycycline are employed as 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.

2 449 defervescence. Tetracycline has also caused significant improvement in ARDS, a life threatening complication of scrub typhus 5. Inflammatory cytokines including TNF-α, IL-1β, and IL-6 are markedly unregulated in patients with scrub typhus. Doxycycline treatment rapidly reduces the production of these cytokines, corresponding to the early defervescence after the start of the treatment 6. The adult dose for doxycycline is mg twice a day and 5mg/kg/IV twice a day and should not exceed 200mg/day. Chloramphenicol, the other drug in conventional therapy also binds to 50 S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting. Monitoring serum levels is a useful aspect and dose can be adjusted to achieve the therapeutic concentrations (ie, peak mcg/ ml, trough 5-10 mcg/ml) 4. The dose is mg/kg/d orally or intravenous divided in 6 hourly doses. Aplastic anemia has been reported in all age groups and is an idiosyncratic reaction. The estimated incidence is about 1 in 24,000 to 40,000 courses of therapy. To prevent this complication, indiscriminate, prolonged or repeated use of the drug should be avoided. The peripheral blood smears should be examined at least once weekly during therapy and treatment should be stopped if the leukocyte count drops below 4000 cu. mm. or when the proportion of granulocytes is reduced below 40 percent. It must be noted that in life threatening condition the risk-benefit ratio should be considered and administration of chloramphenicol in pediatric age group and pregnant ladies should be avoided as far as possible. In this selected population, azithromycin and roxithromycin serve as good and efficacious alternatives. Azithromycin is a macrolide drug that attaches to 50S and interferes with translocation and thus inhibits. The remarkable pharmacokinetic properties are acid stability, rapid oral absorption, marked tissue distribution and intracellular penetration. Concentration in most tissues exceed that in plasma, particularly high concentration are attained inside macrophages and fibroblasts. Slow release from the intracellular sites contributes to its long terminal t ½ of more than 50 hours. It is convenient for once a day dosing and has better gastric tolerance. The side effects are mild gastric upset, abdominal pain, headache, dizziness, and elevated serum levels of ALT. It is not found to affect CYP3A4 enzyme, so drug interactions are less likely with drugs like theophylline, carbamezepine 7. A comparative trial of a single dose of azithromycin 500 mg versus doxycycline 200 mg for 1 wk daily, given in the treatment of mild scrub typhus, suggests that both are equally effective in terms of time taken for defervescence 8. Roxithromycin is a semi-synthetic long acting acid- stable drug with good enteral absorption and tissue penetration with t ½ of 12 hrs has been also used as an alternative drug for scrub typhus and found effective and safe in pediatric population. Its affinity for cytochrome P450 is lower but drug interactions with terfenadine, cisapride and others cannot be ruled out 4-9. Another study in Thailand showed that rifampicin, an antitubercular drug can be used to treat scrub typhus. But considering the most potential problem of resistance to rifampicin monotherapy, the combination of rifampicin with doxycycline was studied but unfortunately was not found effective. The same study also suggested that 1 wk 600 mg or 900 mg of rifampicin was superior to Doxycycline. These doses produced comparable defervescence, so can be used in areas resistant to the conventional therapy Scrub typhus in pregnancy The infection is uncommon in pregnancy, but when present it has serious consequences both for the mother and the foetus, if not appropriately controlled. It is difficult to validate a safe and an effective therapeutic regimen for this population since it is not common in pregnancy. A study suggests that azithromycin 500 mg single dose has proven effective and was not associated with relapse or any unfavourable outcomes 12. Preventive measures The public and physicians should be made aware that mites transmit disease. 2. Avoid mite infested areas. 3. Do not sit or lie on bare ground or grass; use a suitable ground sheet or other ground cover. Clearing of vegetation and chemical treatment of the soil may help to break up the cycle of transmission from chiggers to humans to other chiggers.

3 Alternatively, prevent contact with infected mites by personal prophylaxis against the mite vector by impregnating clothes and blankets with miticidal chemicals (permethrin and benzyl benzoate) and the application of mite repellents (dibutyl phthalate, benzyl benzoate, diethyl toluamide, diethyltoluamide) to exposed skin surfaces. 5. Remove mites from humans. 6. Eliminate mites from sites by the application of chlorinated hydrocarbons (lindane, dieldrin, 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 7 days Binds to 30S teeth discoloration phototoxicity renal toxicity - drug of choice - early defervescence - markers of inflammation:tnf-α, IL-1β, and IL-6 decrease in 24 hrs after starting treatment Chloramphenicol mg/kg/ d X 7 days aplastic anemia - early defervescence - conventional therapy - can be used in children, pregnant women (except in last trimester) Azithromycin 500 mg single dose mild gastric upset, abdominal pain, headache dizziness - early defervescence comparable to 1 wk doxycycline - safer alternative in pregnancy - less incidence of drug interactions Telithromycin 800 mg once daily X 5 days G.I. disturbances headache, taste disturbances - promising new antimicrobial agent - comparable to 200mg/d - doxycycline given for 5 days - drug interactions likely Roxithromycin mg twice daily diarrhoea, nausea, vomiting - as effective as conventional therapy - safer than conventional therapy - drug interactions more likely - than azithromycin Rifampicin a 600 mg/d X 1 wk OR 900 mg/d X 1 wk Inhibits DNA dep RNA polymerase G.I.upset, rash, fever, chills, dizziness - more effective than Doxycycline - used in resistant cases (more effective in combination with - doxycycline) Levofloxacin b 500 mg once Inhibits DNA gyrase G.I. upset - takes longer time for defervescence, this 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 (Sep ) ISSN: 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

4 451 mine buildings, and other populated zones in endemic areas. 7. Advise individuals travelling to endemic areas to wear protective clothing. 8. Antibiotic prophylaxis may be indicated to produce active immunity to scrub typhus. Chemoprophylaxis using doxycycline in high-risk groups (eg. military personnel) has been successful. Doses are weekly and must be started before exposure and continued for 6 weeks after exposure. Studies are underway. As per WHO, it has been shown that a single oral dose of chloramphenicol or tetracycline given every five days for a total of 35 days, with 5-day non-treatment intervals, actually produces active immunity to scrub typhus. This procedure is recommended under special circumstances in certain areas where the disease is endemic 14. Vaccine The historical aspects of vaccine development can be traced back to 1937, when it was first attempted by Wellcome foundation, United Kingdom and was tried finally in 1945 in human subjects in India for use by the Allied Land Forces, South-East Asia Command, in June 1945 (Wellcomes laboratory at Ely Grange, Frant, Sussex) 15,16,17. The major hurdle in vaccine production is existence of a large number of immunotypic and genotypic variants among the strains of O. tsutsugamushi and immunity to one strain does not confer immunity to another 18,19,20,21. An ideal vaccine should provide protection to all the strains present locally, in order to give an acceptable level of protection. This means that a vaccine developed for one locality may not be protective in another locality, because of antigenic variation. This complexity continues to hamper efforts to produce a viable vaccine 22. A truncated recombinant 56-kDa outer membrane of the Karp strain of Orientia tsutsugamushi (Kp r56) was evaluated in cynomolgus monkeys (Macaca fascicularis) for immunogenicity and safety as a vaccine candidate for the prevention of scrub typhus. This recombinant antigen induced strong humoral and cellular immune responses in two monkeys and was found to be well tolerated 23. Conclusion Without treatment the fever generally lasts for 14 days. In some cases the initial symptoms are lymphadenopathy and a rash that begins on the trunk and spreads outwards. The case fatality rate depends on the area, strain of rickettsia, and previous exposure to the disease but is consistently higher in the elderly. Death can occur from the primary infection or from secondary complications (e.g., pneumonitis, encephalitis, circulatory failure). Most fatalities occur by the end of the second week of infection 13. This infection is treated with antibiotics, the drug most commonly used is doxycycline and chloramphenicol is an alternative. A combination therapy with doxycycline and rifampicin should be used in areas where drugs used alone are not effective 24. Azithromycin or chloramphenicol is useful to treat infection in children or pregnant women, while doxycycline is relatively contraindicated in children. Antibiotic therapy brings about prompt defervescence. If the antibiotic treatment is discontinued too quickly, especially in patients treated within the first few days of the fever, relapses may occur. Secondary infections, such as bacterial pneumonia, should be treated appropriately. Total duration of antibiotic therapy can be adjusted on case to case basis depending upon the severity of the disease. No significant morbidity or mortality occurs in patients who receive appropriate treatment. Other alternative drugs include macrolides like azithromycin, roxithromycin, telithromycin and the antitubercular drug rifampicin. Rifampicin is used in resistant cases. Since no effective vaccine is available, it is prudent that case identification, public education, rodent control and habitat modification are the mainstay of strategies aimed at controlling the impact of scrub typhus on the human population. References 1. Padbidri V.S., Gupta N.P. Rickettsiosis in India: A review. J Indian Med Assoc 1978; 71 : , Seong S., Choi M. & Kim I. Orientia tsutsugamushi infection: overview and immune responses. Microbes and Infection. 3(1): 11 21, McPhee S.J., Papadakis M.A. Current Medical

5 452 Diagnosis & Treatment; Rickettsial Diseases 48th edition, published by McGraw- Hill, pg emedicine, Fernandez A.D., Liang J.R. Scrub Typhus; updated on Jun 29, 2009: available at emedicine.medscape.com/article/ overview. 5. Izumo T., Yamaguchi M., Onizawa S., Kiguchi T., Nagai A. Severe case of Tsutsugamushi disease with disseminated intravascular coagulation and acute respiratory distress syndrome : Nihon Kokyuki Gakkai Zasshi.2008 May; 46(5): Chung D.R., Lee Y.S., Lee S.S. Kinetics of inflammatory cytokines in patients with scrub typhus receiving doxycycline treatment, J. Infect Jan; 56 (1):44-50 Epub 2007 Oct Zuckerman J.M. Macrolides and Ketolides: Azithromycin, clarithromycin, telithromycin. Infect Dis Clin North Am. 18:621, Kim Y.S., Yun H.J., Shim S.K., Koo S.H., Kim S.Y., Kim S. A comparative trial of a single dose of azithromycin versus doxycycline for the treatment of mild scrub typhus. Clin Infect Dis. 1;39(9): , 2004 Nov. 9. Epub 2004 Oct 11. Lee K.Y., Lee H.S., Hong J.H., Hur J.K., Whang K.T. Roxithromycin treatment of scrub typhus (tsutsugamushi disease) in children. Pediatr Infect Dis J. 22(2): , Feb 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 (Sep ) ISSN: Panpanich R., Garner P. Antibiotics for treating scrub typhus. The Cochrane Database of Systematic Reviews Issue 3. mrw.interscience.wiley.com/cochrane/ clsyrev/ articles/cd002150/frame.html. 12. Yeon-Sook Kim, Hyo Jin Lee, Meayoung Chang, Sung Kyong Son, Yun Ee Rhee, Soo Kyong Shim Scrub Typhus during pregnancy and its treatment: A case series and review of literature. Am. J. Trop. Med. Hyg. 75(5), pp , Disease Control and Prevention, Public Health Notifiable Disease Management Guidelines June 2005, available at ND-Typhus-Scrub.pdf. 14. Available at CDS_faq_Scrub_ Typhus. pdf. 15. AWIC Newsletter: The Cotton Rat In Biomedical Research. newsletters/v5n2/5n2princ.htm#toc Far East Report. Hansard. 2 April hansard.millbanksystems.com/ written_answers/ 1946/apr/02/scrub-typhus-vaccine-far-east. 17. Kelly et al. The Past & Present Threat of Rickettsial Diseases to Military Medicine & International Public Health. Clinical Infectious Diseases. Vol. 34, SuppL. 4 : June 15, Shirai A., Tanskul P.L., Andre, R.G., et al. Rickettsia tsutsugamushi strains found in chiggers collected in Thailand. Southeast Asian J Trop Med Public Health. 12 (1): 1 6, Kang J.S., Chang W.H. Antigenic relationship among the eight prototype and new serotype strains of Orientia tsutsugamushi revealed by monoclonal antibodies. Microbiol Immunol. 43 (3): , Akira Tamura, Norio Ohashi, Yoko Koyama, Masahiro Fukuhara, Fumihiko Kawamori, Masamitsu Otsuru, Ping-Fuai Wu, Shen-Yu Lin Characterization of Orientia tsutsugamushi isolated in Taiwan by immunofluorescence and restriction fragment length polymorphism analyses, FEMS Microbiology Letters, Volume 150, Issue 2, 15 May 1997, Pages P.E. Fournier Genetic Variability of Orientia tsutsugamushi; International Journal of Infectious Diseases. Volume 12, Supplement 1, Pages e20-e21, December Kelly D.J., Fuerst P.A., Ching W.-M., Richards A.L. Scrub typhus: The geographic distribution of phenotypic and genotypic variants of Orientia tsutsugamushi. Clinical Infectious Diseases. 48 (s3): S203 S230, Chattopadhyay S., Jiang J., Chan T.C., Manetz T.S., Chao C.C., Ching W.M., Richards A.L. Scrub typhus vaccine candidate Kp r56 induces humoral and cellular immune responses in cynomolgus monkeys. Infect Immun. 73(8): , Aug Panpanich R., Garner P. Antibiotics for treating scrub typhus. Cochrane Database Syst Rev. (1): CD002150, 2009.

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