Antibiotics for treating scrub typhus

 

Characteristics of included studies [ordered by study ID]

Brown 1978

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Methods	Randomized controlled trial
Participants	149 adults with febrile illness admitted to hospital with presumptive diagnosis: 65 met diagnostic laboratory criteria of scrub typhus; 10/65 had co-infections and were excluded. Final participants: doxycycline (n = 31); tetracycline (n = 24).
Interventions	(1) Doxycycline 200 mg single dose. (2) Tetracycline 500 mg 6 hourly for 7 days. No clinical improvement at 48 hours: clinicians given discretion to give any additional treatment.
Outcomes	Afebrile in 48 hours. Disappearance of symptoms: headache; cough; and malaise. Side effects.
Notes	Diagnostic laboratory criteria either: (1) isolation of Rickettsia tsutsugamushi; (2) 4-fold rise in indirect microimmunofluorescent antibody titre, to at least 1:200; (3) a static titre of 1:800 or more; (4) 4-fold rise of Weil-Felix (OX-K) titre to at least 1:200. Follow up: 14 days. Study location: Mentakab district hospital, Malaysia.
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Unclear	"volunteers were randomly assigned"
Allocation concealment?	Unclear	not mentioned
Blinding? All outcomes	Unclear	not mentioned
Incomplete outcome data addressed? All outcomes	No	10/65 (>10%)
Free of selective reporting?	Yes	Main outcome reported

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Kim 2004

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Methods	Randomized controlled trial
Participants	99 adult participants diagnosed mild scrub typhus on the basis of clinical criteria. Four participants who confirmed to have combined infection with other disease, one participant who developed severe vomiting and one participant who was given the wrong dose of medication were excluded. Final participants: azithromycin (n = 47); doxycycline (n = 46)
Interventions	(1) Azithromycin 500 mg single dose. (2) Doxycycline 200 mg/day for 7 days.
Outcomes	Time to defervescence Cure Failure Adverse drug effects.
Notes	Diagnostic laboratory criteria either: (1) A titre of indirect immunofluorescent test IgM antibody 1:10 or higher (2) a 4-fold rising titre of antibody between paired sera. Follow up: 30 days Study location: Chung-nam National University Hospital, Republic of Korea.
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	"the enrolled patients were randomly assigned by computer-generated random sequences"
Allocation concealment?	Unclear	not mentioned
Blinding? All outcomes	No	open-label
Incomplete outcome data addressed? All outcomes	Yes	93/99(<10%)
Free of selective reporting?	Yes	Main outcome reported

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Kim 2007

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Methods	Quasi-randomized controlled trial
Participants	95 adults with a fever higher than 37.5˚C, the concurrent presence of eschar or maculopapular skin rash, and the clear presence of more than two symptoms such as headache, malaise, myalgia, coughing, nausea, and abdominal discomfort were enrolled. 3/95 had concurrent diseases and was excluded. Final participants: doxycycline (n = 45); telithromycin (n = 47). 76/92 participants met diagnostic laboratory criteria of scrub typhus.
Interventions	(1) Doxycycline 200 mg daily for 5 days. (2) Telithromycin 800 mg daily for 5 days.
Outcomes	Fever clearance time. Cure. Failure. Relapse. Toxicity and adverse events.
Notes	Diagnostic laboratory criteria either: (1) A titre of a single indirect immunofluorescent specific immunoglobulin M (IgM) > 1:80 (2) The immunofluorescent antibody assay titre increased more than four times. Follow up: 4 weeks. Study location: Chosun University Hospital in Gwangju, Korea or one of two community-based affiliated hospitals, southwestern Korea.
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	No	"eligible patients were randomly allocated by last digit of a resident registration number"
Allocation concealment?	Unclear	not mentioned
Blinding? All outcomes	No	open-label
Incomplete outcome data addressed? All outcomes	Yes	92/92
Free of selective reporting?	Yes	main outcome reported

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Phimda 2007

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Methods	Randomized controlled trial
Participants	296 adults with suspected leptospirosis or scrub typhus, that is, patients with acute fever (oral temperature ≥38.0˚C for < 15 days) in the absence of an obvious focus of infection were randomised. 57 patients met diagnostic laboratory criteria of scrub typhus. Final participants of diagnostic scrub typhus: doxycycline (n = 27); azithromycin (n = 30).
Interventions	(1) Doxycycline 200 mg followed by 100 mg twice daily for 7 days. (2) Azithromycin 1 g followed by 500 mg once daily for 2 days.
Outcomes	Cure. Failure. Defervescence. Adverse events.
Notes	Diagnostic laboratory criteria either: (1) A fourfold or greater rise in immunofluorescent assay titres between paired serum samples. (2) A titre of at least 1:400 or greater on a single specimen. Follow up: median duration was 15 days. Study location: four hospitals in Thailand.
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	by computer-generated random sequences
Allocation concealment?	Yes	central randomisation, sealed, opaque envelope
Blinding? All outcomes	No	open
Incomplete outcome data addressed? All outcomes	Yes	296/296
Free of selective reporting?	Yes	main outcome reported

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Sheehy 1973

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Methods	Randomized controlled trial
Participants	63 adults with symptoms of scrub typhus admitted to hospital; 3/63 had coexistent malaria and were excluded. Final participants: chloramphenicol (n = 30)tetracycline (n = 30).
Interventions	(1) Chloramphenicol 3 g daily for 3 days. (2) Tetracycline 2 g daily for 3 days. Continuation of treatment beyond 3 days was decided by physicians.
Outcomes	Duration of fever. Afebrile in 48 hours. Relapse.
Notes	Diagnosis was based on clinical findings, a rising titre of Weil-Felix (OX-K) test. Follow up: 3 weeks. Study location: Two military hospitals in Vietnam.
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Unclear	"patients were evacuated at random to one of the two supporting units"
Allocation concealment?	Unclear	not mentioned
Blinding? All outcomes	Unclear	not mentioned
Incomplete outcome data addressed? All outcomes	Yes	60/63 (<10%)
Free of selective reporting?	Yes	main outcome reported

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Song 1995

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Methods	Randomized controlled trial
Participants	129 adults with clinical findings of acute high fever, rash, and eschar were enrolled. 13/129 were excluded as indirect micro-immunofluorescent antibody titres did not meet the criteria. Final participants: doxycycline (n = 66); tetracycline (n = 50).
Interventions	(1) Doxycycline 100 mg every 12 hours for 3 days. (2) Tetracycline 500 mg every 6 hours for 7 days.
Outcomes	Treatment failure. Relapse. Duration of fever. Disappearance of symptoms: fever; headache; and malaise. Toxicity and side effects.
Notes	Diagnostic laboratory criteria either: (1) A titre of micro-immunofluorescent, immunoglobulin G antibody > 1:80 (2) a 4-fold rising titre between paired sera. Follow up: 4 weeks. Study location: 8 branch hospitals of the Asian Foundation in Korea.
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	by computer-generated random orders
Allocation concealment?	No	central randomisation but not remote from trial location
Blinding? All outcomes	No	non blinded
Incomplete outcome data addressed? All outcomes	No	116/129(>10%)
Free of selective reporting?	Yes	main outcome reported

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Watt 2000

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Methods	Randomized controlled trial
Participants	126 adults diagnosed mild scrub typhus with seropositive by a dot-blot enzyme-linked immunosorbent assay (ELISA) rapid test. Participants were excluded when the indirect immunoperoxidase test did not meet the criteria, or co-infections or side effects occurred. Final participants: doxycycline (n = 28); standard rifampicin dose (600 mg/day) (n = 26) high rifampicin dose (900 mg/day) (n = 24).
Interventions	(1) Doxycycline 200 mg followed by 100 mg twice daily for 7 days. (2) Rifampicin 300 mg twice daily for 7 days. (3) Combination of doxycycline and rifampicin. This regimen was withdrawn and replaced with high dose rifampicin (450 mg twice daily) after one year period of the study.
Outcomes	Afebrile in 48 hours. Median fever clearance time. Relapse. Side effects.
Notes	Diagnostic laboratory criteria was indirect immunoperoxidase test, immunoglobulin M titre >1:400 or immunoglobulin G >1600. Study location: Chiangrai regional hospital, Thailand.
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Unclear	"patients were randomly assigned"
Allocation concealment?	Unclear	not mentioned
Blinding? All outcomes	Unclear	not mentioned
Incomplete outcome data addressed? All outcomes	No	78/126(>10%)
Free of selective reporting?	Yes	main outcome reported

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Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Olson 1980	A randomized double blind study estimated the effect of 200 mg doxycycline weekly on the prevention of scrub typhus in hyperendemic area. The trial, conducted in military subjects, compared the incidence rate of scrub typhus between the doxycycline and placebo group.
Twartz 1982	A randomized double blind study conducted in 20 volunteers assigned to receive either 200 mg doxycycline weekly or placebo before exposure to Leptotrombidium fletcheri chiggers infected with Rickettsia tsutsugamushi and continued for 6 weeks after exposure. The incidence of scrub typhus was compared between groups.

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Characteristics of ongoing studies [ordered by study ID]

IRB043-31

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Trial name or title	Controlled Trial: 5-Day Course of Rifampin Versus Doxycycline for the Treatment of Mild to Moderate Scrub Typhus
Methods	Randomized controlled trial
Participants	Inclusion criteria: - Adults aged 18 years or older - A fever of higher than 37.5˚C - The concurrent presence of eschar or a maculopapular skin rash; and the clear presence of more than two symptoms such as headache, malaise, myalgia, coughing, nausea and abdominal discomfort. - Patients were hospitalised at Chosun University Hospitalin Kwangju, Korea or one of its two community-based affiliated hospitals which are all located in southwestern Korea between 2006 and 2009. Exclusion criteria: - An inability to take oral medications - Pregnancy - Hypersensitivity to the trial drugs - Previous drug therapy with potential anti-rickettsial activity (e.g., rifampicin, chloramphenicol, macrolides, fluoroquinolones or tetracyclines) within 48 h prior to admission - Severe scrub typhus (shock requiring vasopressor therapy for more than one hour - A stuporous or comatose level of consciousness - Respiratory failure requiring mechanical ventilation or renal failure requiring immediate dialysis) (4, 10). - For the differential diagnosis of scrub typhus from other diseases with similar symptoms (e.g., murine typhus, leptospirosis, hemorrhagic fever with renal syndrome and systemic lupus erythematosus), patients underwent diagnostic tests. We thus excluded patients with concurrent infections who had the risk of causing different outcomes.
Interventions	1. 5-day rifampin therapy 2. 5-day doxycycline therapy
Outcomes	1. the fever clearance time. 2. Cure 3. Failure 4. Relapse
Starting date	September 2006 Expected completion: December 2009
Contact information	Prof. Dong-Min Kim ([e-mail]), Chosun University Hospital, Gwang-Joo, Jeollanamdo
Notes	Location: Chosun University Hospital, or one of its two community-based affiliated hospitals which are all located in southwestern Korea Study ID numbers: IRB043-31

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ISRCTN47812566

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Trial name or title	Oral doxycycline versus oral azithromycin in the treatment of Scruband Murine Typhus in Laos
Methods	Randomized controlled trial
Participants	Inclusion criteria: 1. Adult (greater than 15 years) non-pregnant patients with suspected typhus. Suspected typhus will be defined as undifferentiated fever (aural temperature greater than 37.5C), with or without an eschar, with a positive scrub typhus Lateral Flow IgM result or a murine typhus IgM Dip-S-Ticks result 2. Written informed consent to the study 3. Able to stay in hospital for the duration of the treatment (up to 7 days) and high likelihood of completing at least 4 weeks follow up 4. Able to take oral medication 5. A negative urinary pregnancy test for all women of child bearing age 6. None of the exclusion criteria Exclusion criteria: 1. Known hypersensitivity to tetracycline, doxycycline or azithromycin 2. Administration of chloramphenicol, doxycycline, tetracycline, fluoroquinolones or azithromycin during the preceding week 3. Pregnancy or breast feeding 4. Contraindications to doxycycline: severe hepatic impairment, known systemic lupus erythematosus (SLE) 5. Contraindications to azithromycin: severe hepatic impairment 6. Severe typhus defined as: 6.1. Reduced level of consciousness 6.2. Clinical jaundice 6.3. Shock (blood pressure [BP] systolic less than 80 mmHg) 6.4. Vomiting sufficient to disallow the use of oral medication 6.5. Clinical or radiological evidence for lung involvement 6.6. Clinical evidence for meningitis/encephalitis or the need for a lumbar puncture (LP) 6.7. Any other syndrome which in the opinion of the admitting doctor constitutes severe typhus (reason must be stated)
Interventions	1. Oral doxycycline 100 mg every 12 hours for 7 days (after a 200 mg loading dose) 2. Doxycycline 100 mg every 12 hours for 3 days (after a 200 mg loading dose) 3. Oral azithromycin 500 mg on day 1 and then 250 mg every 24 hours for 2 more days
Outcomes	1. Fever clearance times 2. Frequencies of treatment failure 3. Frequencies of relapse 4. Treatment failure frequency 5. Relapse frequency
Starting date	4 August 2003 End of follow-up date: 31 December 2009
Contact information	Dr Paul Newton ([e-mail]), Ministry of Health, Mahosot Hospital, Mahosot Road, Vientiane, Laos
Notes	Location: Mahosot Hospital, Vientiane, Laos Registration number: ISRCTN47812566 Sources of funding: The Wellcome Trust (UK) (grant ref: 066828)

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Comparison 1. Tetracycline vs chloramphenicol

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Febrile after 48 hours	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
2 Relapse	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected

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Comparison 2. Doxycycline vs tetracycline

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Febrile after 48 hours	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
2 Relapse	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
3 Duration of fever	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4 Treatment failure	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected

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Comparison 3. Rifampicin vs doxycycline

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Febrile after 48 hours	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
2 Relapse	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected

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Comparison 4. High rifampicin dose vs standard rifampicin dose

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Febrile after 48 hours	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
2 Relapse	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected

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Comparison 5. Doxycycline vs standard rifampicin dose vs high rifampicin dose

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of participants febrile after 48 hours			Other data	No numeric data
2 Median fever clearance time (hours)			Other data	No numeric data
3 Number of participants with a relapse			Other data	No numeric data

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Analysis 5.1 Comparison 5 Doxycycline vs standard rifampicin dose vs high rifampicin dose, Outcome 1 Number of participants febrile after 48 hours.
Number of participants febrile after 48 hours

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Study	Doxycycline	Standard rifampicin	High rifampicin
Watt 2000	15/28	6/26	5/24

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Analysis 5.2 Comparison 5 Doxycycline vs standard rifampicin dose vs high rifampicin dose, Outcome 2 Median fever clearance time (hours).
Median fever clearance time (hours)

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Study	Doxycycline	Standard rifampicin	High rifampicin
Watt 2000	52 (range 4 to 108)	27.5 (4 to 84)	22.5 (3 to 76)

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Analysis 5.3 Comparison 5 Doxycycline vs standard rifampicin dose vs high rifampicin dose, Outcome 3 Number of participants with a relapse.
Number of participants with a relapse

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Study	Doxycycline	Standard rifampicin	High rifampicin
Watt 2000	2/28	0/26	0/24

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Comparison 6. Azithromycin vs doxycycline

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Febrile after 48 hours	2	150	Risk Ratio (M-H, Random, 95% CI)	0.99 [0.30, 3.27]
2 Relapse	2	150	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
3 Gastrointestinal side effect	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
4 Treatment failure	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected

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Comparison 7. Telithromycin vs doxycycline

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Duration of fever	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2 Failure	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
3 Relapse	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
4 Adverse effects	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
5 Gastrointestinal side effects	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected

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Table 1. Scrub typhus treatment: Observational studies using serology in diagnosis

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Source, year	Country	Type of study	Participants	Treatment	Outcomes	Results
Sirisanthana 1989	Thailand	Case series in Chiang Mai (n = 25).	Children with scrub typhus, diagnosed by clinical symptoms (15/25 confirmed by Weil Felix test (OX-K titre) of 1:160 or more, or 4-fold rise of titre).	Tetracycline (n=16) or chloramphenical (n=9) for 7 to 10 days.	Fever clearance time; relapse.	Mean fever clearance 38 hours; 2 had relapse after one week discontinuation of antibiotic.
Supparatpinyo 1990	Thailand	Case series in Chiang Mai (n = 42).	Adults with mild to moderate severe disease, diagnosed by eschar or a rise of Weil Felix (OX-K titre) of 1:320 or more, or 4-fold rise.	Doxycycline 200 mg single dose.	Afebrile in 72 hours; relapse.	37/42 (88%) afebrile in 72 hours, no relapse in a month after treatment (follow-up rate 52%).
Watt 1996	Thailand	Case series in Chiangrai (n = 12) and Maesot (n = 7).	Adults with mild disease with indirect immunoperoxidase test; IgM 1 in 400 or greater and/or IgG 1 in 1600 or greater.	Doxycycline 200 mg stat; then 100 mg 12 hourly for 7 days.	Fever clearance time.	Median fever clearance 80 hours (Chiang Rai); 30 hours (Maesot).

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Table 2. Detailed search strategies

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Search set	CIDG SR^a	CENTRAL	MEDLINE^b	EMBASE^b	LILACS^b
1	Scrub typhus	SCRUB TYPHUS	SCRUB TYPHUS	SCRUB TYPHUS	Scrub typhus
2	Rickettsia tsutsugamushi	Scrub typhus [ti, ab]	Scrub typhus [ti, ab]	Scrub typhus [ti, ab]	Rickettsia tsutsugamushi
3	Orientia tsutsugamushi	Orientia tsutsugamushi [ti, ab]	Orientia tsutsugamushi [ti, ab]	Orientia tsutsugamushi [ti, ab]	Orientia tsutsugamushi
4	1 or 2 or 3	Rickettsia tsutsugamushi [ti, ab]	Rickettsia tsutsugamushi [ti, ab]	Rickettsia tsutsugamushi [ti, ab]	1 or 2 or 3
5		ORIENTIA TSUTSUGAMUSHI	ORIENTIA TSUTSUGAMUSHI	ORIENTIA TSUTSUGAMUSHI
6		1 or 2 or 3 or 4 or 5	1 or 2 or 3 or 4 or 5	1 or 2 or 3 or 4 or 5
7			Limit 6 to Humans	Limit 6 to Human

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 ^aCochrane Infectious Diseases Group Specialized Register
^b Search terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Lefebvre 2008); Upper case: MeSH or EMTREE heading; Lower case: free text term.

 

Table 3. Risk of bias assessment

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Trial	Sequence	Concealment	Blinding	Participants
Trial	Generation of allocation sequence	Allocation concealment	Blinding	Inclusion of all randomized participants
Sheehy 1973	Unclear	Unclear	Unclear	Adequate(60/63)
Brown 1978	Unclear	Unclear	Unclear	Inadequate (55/65)
Song 1995	Adequate	Inadequate	Inadequate ("non blinded")	Inadequate (116/129)
Watt 2000	Unclear	Unclear	Unclear	Inadequate (78/126)
Kim 2004	Adequate	Unclear	Inadequate (open-label)	Adequate (93/99)
Kim 2007	Inadequate	Unclear	Inadequate	Adequate (92/92)
Phimda 2007	Adequate	Adequate	Inadequate(open)	Adequate (296/296)

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