Antibiotics for treating scrub typhus

  • Review
  • Intervention

Authors


Abstract

Background

Scrub typhus is a bacterial disease in regions of Asia and the Pacific. Antibiotics (chloramphenicol, tetracycline, and doxycycline) have been used to treat the disease. Resistance to these antibiotics has been reported.

Objectives

To evaluate antibiotic regimens for treating scrub typhus.

Search methods

We searched the Cochrane Infectious Diseases Group specialized trials register (January 2010); CENTRAL (The Cochrane Library, Issue 4, 2009); MEDLINE (1966 to January 2010); EMBASE (1980 to January 2010); LILACS (1982 to January 2010); mRCT (January 2010). We checked references and contacted authors for additional data.

Selection criteria

Randomized and quasi-randomized studies comparing antibiotic regimens in people diagnosed with scrub typhus.

Data collection and analysis

Both authors screened the search results, assessed eligibility, quality and extracted data. We used Review Manager (Version 5.0.2), and expressed results as Relative Risk (binary) or weighted mean difference (continuous), with 95% confidence intervals.

Main results

Seven small trials met the inclusion criteria. In one trial, no difference was detected between tetracycline and chloramphenicol in relation to fever at 48 hours (1 patient febrile in each arm; N=60). No difference was detected in two trials that compared doxycycline and tetracycline. Rifampicin was more effective than doxycycline in one trial (participants febrile at 48 hours, RR 0.41, 95% CI 0.22 to 0.77). No difference was detected in two trials evaluated azithromycin against doxycycline, with no difference in fever at 48 hours (RR 1.22, 95% CI 0.17 to 8.92; 150 participants). One trial compared telithromycin with doxycycline, and the effects were similar. No trials reported death or serious complications.

Authors' conclusions

Data are limited because trials are small. There are no obvious differences between tetracycline, doxycycline, telithromycin,or azithromycin; rifampicin may be better than tetracycline in areas where scrub typhus appears to respond poorly to standard anti-rickettsial drugs.

摘要

背景

抗生素用於治療恙蟲病的療效評估

恙蟲病是一種細菌性疾病,分佈在亞洲和太平洋地區,抗生素chloramphenicol, tetracycline,及doxycycline已被用來治療該疾病。有報告顯示此細菌對這些抗生素有抗藥性。

目標

評估以抗生素來治療恙蟲病的效果。

搜尋策略

我們搜查了Cochrane傳染病組專門試驗註冊(2004年8月);CENTRAL(Cochrane圖書館,第3期,2004年);MEDLINE(1966年至2004年8月); EMBASE(1988年至2004年8月); LILACS(2004年8月)。我們檢查了文章中的參考文獻,並和作者連絡,得到額外的數據。

選擇標準

隨機和準隨機研究中有比較抗生素在被診斷出為患有恙蟲病者的治療。

資料收集與分析

一位回顧者篩選搜索的結果,兩位回顧者都評估試驗是否符合條件、試驗品質,並擷取數據。我們利用Review Manager(4.1版)軟體來分析資料,並用RR(類別變項)或加權平均差(連續變項),以95 %CI來呈現其結果。

主要結論

4個試驗有451成人符合納入標準,1個小研究並沒有證實出tetracycline與chloramphenicol的差異(受試者在48小時後沒有發燒,RR為1.00 ; 95 %CI為0.07至15.26)。兩個小試驗並沒有顯示出doxycycline和tetracycline的差異(受試者在48小時後沒有發燒,RR為0.46 ; 95 %CI為0.12至1.75)。1個試驗顯示rifampicin比doxycycline更有效(在去除發燒方面,RR為0.41 ; 95 %CI為0.22至0.77;每一組病人都沒有復發)。

作者結論

在tetracycline和doxycycline的治療上有限的數據並沒有呈現出明顯差異。有限的數據顯示rifampicin對於恙蟲病出現的地區、且用傳統抗立克次體藥物效果不佳時似乎有效。

翻譯人

本摘要由三軍總醫院盧俊吉翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

總結未定

Résumé scientifique

Antibiotiques pour le traitement du typhus des broussailles

Contexte

Le typhus des broussailles est une maladie bactérienne prévalente dans les régions de l'Asie et du Pacifique. Des antibiotiques (chloramphénicol, tétracycline et doxycycline) sont utilisés dans le traitement de cette maladie. Une résistance à ces antibiotiques a été rapportée.

Objectifs

Évaluer les schémas antibiotiques dans le traitement du typhus des broussailles.

Stratégie de recherche documentaire

Nous avons consulté le registre spécialisé des essais cliniques du groupe Cochrane sur les maladies infectieuses (janvier 2010) ; CENTRAL (Bibliothèque Cochrane, numéro 4, 2009) ; MEDLINE (1966 à janvier 2010) ; EMBASE (1980 à janvier 2010) ; LILACS (1982 à janvier 2010) ; mRCT (janvier 2010). Nous avons examiné les références bibliographiques et contacté les auteurs afin d'obtenir des données supplémentaires.

Critères de sélection

Les études randomisées et quasi-randomisées comparant des schémas antibiotiques chez des patients présentant un diagnostic de typhus des broussailles.

Recueil et analyse des données

Les deux auteurs ont examiné les résultats des recherches, évalué l'éligibilité et la qualité, et extrait les données. Nous avons utilisé Review Manager (version 5.0.2) et exprimé les résultats sous forme de risque relatif (résultats binaires) ou de différence moyenne pondérée (résultats continus), avec des intervalles de confiance à 95 %.

Résultats principaux

Sept petits essais remplissaient les critères d'inclusion. Dans un essai, aucune différence n'était détectée entre la tétracycline et le chloramphénicol en termes de fièvre à 48 heures (1 patient fébrile dans chaque bras ; N = 60). Aucune différence n'était détectée dans deux essais comparant de la doxycycline à de la tétracycline. La rifampicine était plus efficace que la doxycycline dans un essai (participants fébriles à 48 heures, RR de 0,41, IC à 95 %, entre 0,22 et 0,77). Aucune différence n'était détectée dans deux essais comparant de l'azithromycine à de la doxycycline, avec une incidence de la fièvre similaire à 48 heures (RR de 1,22, IC à 95 %, entre 0,17 et 8,92 ; 150 participants). Un essai comparant de la télithromycine à de la doxycycline rapportait des effets similaires. Aucun essai ne rapportait de décès ni de complications graves.

Conclusions des auteurs

Les données sont limitées en raison de la petite taille des essais. Aucune différence notable n'est observée entre la tétracycline, la doxycycline, la télithromycine et l'azithromycine ; la rifampicine pourrait être plus efficace que la tétracycline dans les zones où le typhus des broussailles répond mal aux médicaments antirickettsies standard.

Plain language summary

Antibiotics for treating scrub typhus

Scrub typhus is transmitted by chiggers (mites), is a bacterial infection and causes fever and a typical sore on the skin, and is common in the western Pacific region and many parts of Asia, particularly in agricultural workers and travellers in areas where the disease is common, particularly people camping, rafting, or trekking . This review summarize the information from seven small trials about the effects of antibiotics on scrub typhus. Most of the antibiotics tested worked: this includes: doxycycline, tetracycline, telithromycin and azithromycin. Rifampicin seem to be more effective than doxycycline in areas where scrub typhus appears to respond poorly to standard anti-rickettsial drugs.

Résumé simplifié

Antibiotiques pour le traitement du typhus des broussailles

Le typhus des broussailles, transmis par des tiques (acariens), est une infection bactérienne qui provoque de la fièvre et des plaies caractéristiques sur la peau. Cette maladie est fréquente dans le Pacifique occidental et dans de nombreuses régions asiatiques, en particulier chez les travailleurs agricoles et les personnes voyageant dans les zones où la maladie est courante, surtout lorsque ces voyageurs campent ou pratiquent le rafting ou le trekking. Cette revue résume les informations issues de sept petits essais examinant les effets des antibiotiques dans le typhus des broussailles. La plupart des antibiotiques évalués étaient efficaces. Ces antibiotiques incluaient de la doxycycline, de la tétracycline, de la télithromycine et de l'azithromycine. La rifampicine semblait plus efficace que la doxycycline dans les zones où le typhus des broussailles répond mal aux médicaments antirickettsies standard.

Notes de traduction

HISTORIQUE DE LA REVUE (débutée le 4 mars 2002)
4 mars 2002 : Réception de la revue mise à jour par la base éditoriale. Elle inclut un nouvel essai (Watt 2000) et les réponses aux commentaires du rédacteur adjoint et du statisticien : (1) légère modification de l'objectif ; le critère de jugement Nombre et gravité des effets secondaires est désormais intitulé Nombre d'événements indésirables ; Risque relatif utilisé pour les résultats binaires (au lieu du rapport des cotes de Peto)Juin 2010 : Réception de la revue mise à jour par la base éditoriale. Critères de jugement principaux modifiés pour cesser d'inclure les décès. Ajout de nouveaux essais.

Traduit par: French Cochrane Centre 1st April, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Background

Scrub typhus is a bacterial disease caused by Rickettsia tsutsugamushi (Orientia tsutsugamushi). It is transmitted by larval Leptotrombidium mites, which are commonly called chiggers. Infection can cause widespread inflammation of the blood vessels in many organs, especially the lungs, kidneys, and central nervous system (Silpapojakul 1997).

People with scrub typhus develop fever, headache, and a cough. Uncommonly patients develop a characteristic skin lesion, called an eschar (Brown 1976; Sirisanthana 1989), which makes the diagnosis much more likely. The eschar occurs at the site of the bite, starts as a large pimple ('papule'), and then the centre part of the skin dies and turns black, giving it the appearance of a cigarette burn. Laboratory tests are not widely available: the Weil-Felix test (with Proteus OX-K) is insensitive (Sirisanthana 1989), and serodiagnostic tests are only available in reference centres.

Incidence

Scrub typhus is common in the western Pacific region and many parts of Asia. It is listed as one of the differential diagnoses of fever of unknown origin in people in endemic areas. In Thailand, some estimates suggest that 10% of people with fever have scrub typhus (Silpapojakul 1997). A seroprevalence study among 200 febrile people attending some malaria clinics in western Thailand has indicated that 59.5% had serology (immunoglobulin M (IgM) and/or immunoglobulin G (IgG)) positive for scrub typhus infection (Chanyasanha 1998). A study conducted in five hospitals in Thailand among patients with undifferentiated febrile illness without focal infection showed that 19.9% had serology positive for scrub typhus (Suttinont 2006). A study among 207 hospitalized patients with febrile illness of 5 to 30 days duration in Southern India indicated that 24% had elevated IgM antibodies of scrub typhus (Varghese 2006).

Risk Factors

The risk of scrub typhus is closely related to occupation. Most cases in Asia are acquired through agricultural exposure to oil palm and rubber plantations in Malaysia, or rice fields in Thailand. Scrub typhus is also associated with travel activities such as camping, rafting, or trekking in endemic areas (Silpapojakul 1997). A number of cases have been reported in 'eco-travellers' from Europe and America (McDonald 1988; Watt 1994). Recently, three cases from Scandinavia were reported from infections acquired in Thailand, Laos, and Sri Lanka respectively (Jensenius 2006). In addition, scrub typhus is an important disease in military personnel undertaking field duties in endemic areas (Deller 1967; Berman 1973). Severe, life threatening scrub typhus has also been reported in neonates as a result of the infection being transmitted from their mothers (Wang 1992; Suntharasaj 1997).

Prognosis and treatment

The severity of the disease is thought to depend on the virulence of the Rickettsia strain, the patient's age and genetic factors, and whether the person has previously been infected. The outbreak of scrub typhus in India reported 17.2%(19/113) mortality (Kumar 2004). Antibiotic treatment is thought to shorten the illness and reduce mortality. It is usually presumptive, being given to febrile individuals where the disease is endemic. Chloramphenicol was the first drug described in a series of studies to reduce the morbidity and mortality associated with the disease (Smadel 1950). Tetracycline and doxycycline have also been used.

Data from case series

To evaluate information about treatment from case series, we systematically searched for case series of people treated for scrub typhus. The search was carried out in 2000, and the results summarised in Table 1. 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 hours, and no relapses occurred in the month following treatment (Supparatpinyo 1990). In children, a good response to tetracycline and chloramphenicol treatment was described in 25 cases, who all became afebrile in 48 hours. Relapse occurred in two children and fever subsided spontaneously in one of them within four days (Sirisanthana 1989).

Table 1. Scrub typhus treatment: Observational studies using serology in diagnosis
Source, yearCountryType of studyParticipantsTreatmentOutcomesResults
Sirisanthana 1989ThailandCase 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 1990ThailandCase 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 1996ThailandCase 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).

In a case series from Chiangrai, northern Thailand, a poor response to a 7-day course of doxycycline was reported; only 5/12 (40%) patients were afebrile at 72 hours. Moreover, the result of doxycycline susceptibility testing in mouse fibroblast cell culture showed that only 39% of the patients had strains that were fully susceptible to doxycycline (Watt 1996) (Table 1).

The new macrolide antibiotic, azithromycin, was recently evaluated in vitro against R. tsutsugamushi. Azithromycin was effective against some strains of R. tsutsugamushi, particularly doxycycline-resistant strains. Azithromycin is considered safer than other antibiotics for use in 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 foetuses (Strickman 1995).

Current debates

Tetracycline or chloramphenicol are generally recommended (CDC 2007). However, the potential advantage of alternative drugs (azithromycin, telithromycin, clarithromycin, and ciprofloxacin) has not been directly established; and length of treatment to prevent recrudescence is not clear. This review aims to summarize the information about the effects of various classes of antibiotics on scrub typhus.

Objectives

To evaluate antibiotic regimens for treating scrub typhus.

Methods

Criteria for considering studies for this review

Types of studies

Randomized and quasi-randomized controlled trials.

Types of participants

People diagnosed with scrub typhus, as defined by the trial authors.

Types of interventions

Any antibiotic treatment that aims to treat scrub typhus, compared with another antibiotic regimens.

Types of outcome measures

Primary

Fever still present 48 hours after treatment started.
Relapse within three months (return of fever or other symptoms during follow up).

Secondary

Treatment failures (persistence of symptoms, fever, and laboratory abnormalities at end of treatment).
Duration of illness.
Duration of fever.
Number of adverse events.

Search methods for identification of studies

We attempted to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress).

Databases

We searched the following databases using the search terms and strategy described in Table 2 : Cochrane Infectious Diseases Group Specialized Register (2 January 2010); Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (Issue 4, 2009); MEDLINE (1966 to 2 January 2010); EMBASE (1980 to 2 January 2010); and LILACS (1982 to 2 January 2010). We also searched the metaRegister of Controlled Trials (mRCT) on 2 January 2010 using 'scrub typhus' or 'orientia tsutsugamushi' as search terms.

Table 2. Detailed search strategies
  1. 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.

Search setCIDG SRaCENTRALMEDLINEbEMBASEbLILACSb
1Scrub typhusSCRUB TYPHUSSCRUB TYPHUSSCRUB TYPHUSScrub typhus
2Rickettsia tsutsugamushiScrub typhus [ti, ab]Scrub typhus [ti, ab]Scrub typhus [ti, ab]Rickettsia tsutsugamushi
3Orientia tsutsugamushiOrientia tsutsugamushi [ti, ab]Orientia tsutsugamushi [ti, ab]Orientia tsutsugamushi [ti, ab]Orientia tsutsugamushi
41 or 2 or 3Rickettsia tsutsugamushi [ti, ab]Rickettsia tsutsugamushi [ti, ab]Rickettsia tsutsugamushi [ti, ab]1 or 2 or 3
5 ORIENTIA TSUTSUGAMUSHIORIENTIA TSUTSUGAMUSHIORIENTIA TSUTSUGAMUSHI 
6 1 or 2 or 3 or 4 or 51 or 2 or 3 or 4 or 51 or 2 or 3 or 4 or 5 
7  Limit 6 to HumansLimit 6 to Human 

Reference lists 

We also checked the reference lists of all studies identified by the above methods.

Data collection and analysis

Selection of studies

We screened the results of the search strategy to identify potentially relevant trials, obtained the full reports of these trials and applied the inclusion criteria to assess their eligibility for inclusion in the review. We resolved disagreements by discussion and have given the reason for excluding trials in the 'Characteristics of excluded studies'.

Data extraction and management

We extracted data using a standardized data extraction form and the second author checked data extraction.; we checked the data sources to avoid multiple publication based on the same data. We extracted data to allow for an intention-to-treat analysis where possible. We resolved discrepancies by discussion.

Assessment of risk of bias in included studies

We classed generation of the allocation sequence and allocation concealment as adequate, inadequate, or unclear according to Jüni 2001. We recorded which people were blinded, such as the participants, care providers, or assessors. We considered the inclusion of all randomized participants in the analysis to be adequate if it was greater than or equal to 90% and inadequate if less than 90%. We displayed this information in a table and described it in the text. We resolved inconsistencies through discussion. Both authors participated in the assessment.

Data synthesis

We analysed the data using Review Manager (Review Manager 5). For binary data, we calculated relative risk (RR) and 95% confidence intervals (CIs) using the fixed-effect model; for continuous data, we calculated weighted mean difference and 95% CIs.

We assessed heterogeneity by visually examining the forest plot and through the Chi2 test for heterogeneity using a 10% level of statistical significance, and the I2 statistic to measure inconsistency of results among trials (Higgins 2003). In the event of heterogeneity, we planned to investigate it using the following subgroups: (1) type of antibiotic; (2) dose and length of administration; and (3) whether the trial was conducted before or after antibiotic resistance had been reported. After testing for heterogeneity, the pooled measures were ultimately computed using the random-effects model.

Results

Description of studies

Seven trials met the inclusion criteria (see Characteristics of included studies). Both excluded studies evaluated prophylaxis (see Characteristics of excluded studies). Two ongoing trials compare rifampin with doxycycline, and azithromycin with doxycycline respectively (see Characteristics of ongoing studies).

Sheehy 1973 reported on military servicemen who acquired scrub typhus in Vietnam, and were evacuated "at random" to one of two military hospitals. Participants were recruited in 1966 although the study was not published until 1973. It is not entirely clear whether it was the evacuation that was random or the hospital allocation; pending clarification, we have included the study. A total of 63 participants were enrolled, and three with malaria were then excluded. Participants evacuated to hospital A were given chloramphenicol (n = 30), and those to hospital B were given tetracycline (n = 30); both groups were followed up for three weeks. The outcomes measured by the researchers were participants afebrile by 48 hours, and duration of fever.

Brown 1978 enrolled 149 adult participants in Malaysia presumed to have scrub typhus. They were randomly assigned to receive either doxycycline or tetracycline. In their analysis, the authors then excluded participants with no serological evidence of infection, or participants with serological changes but a co-infection. This left 55 participants (doxycycline n = 31; tetracycline n = 24) with clinical and serological evidence of scrub typhus infection. The outcomes measured by the researchers were disappearance of symptoms, participants afebrile by 48 hours, and any adverse drug effects.

Song 1995conducted a multicentre study in Korea, and enrolled 129 adult participants. Of these, 116 met their serological diagnostic criteria. They were randomly allocated to either doxycycline (n = 66) or tetracycline (n = 50) groups, and followed up for 4 weeks. The outcomes measured by the researchers were failure of treatment and relapse.

Watt 2000 enrolled 126 adult participants in Thailand who were diagnosed with mild scrub typhus. They were randomly assigned to receive either doxycycline, rifampicin, or combined regimen of rifampicin and doxycycline. During the first year of the study there were a number of participants in one arm of the study who had protracted fever more frequently than the others. This led the researchers to perform an interim analysis. The fever clearance time was significantly different between the three treatment groups: 88 hours (n = 8); 35 hours (n = 5); and 24 hours (n = 9). They decided to break the code of the group with the 88 hours clearance time and found that it was a combination group. This regimen was discontinued and participants subsequently recruited to this group were assigned high dose rifampicin (900 mg/day). During the study, the authors excluded participants with adverse treatment effects and those who had illness other than scrub typhus. In their analysis, the participants who had no serological evidence of infection were excluded. This left 78 participants (doxycycline n = 28; standard rifampicin dose n = 26 and high rifampicin dose n = 24). The outcomes measured were duration of fever, participants febrile at 48 hours, relapse, and side effects.

Kim 2004 enrolled 99 adult participants in Korea diagnosed mild scrub typhus on the basis of clinical criteria. They were randomly assigned to receive either azithromycin or doxycycline. The authors excluded four participants 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. This left 93 participants (azithromycin n = 47; Doxycycline n = 46) with clinical evidence of scrub typhus infection. Both groups were followed up for 30 days.The outcomes measured by the researchers were time to defervescence, cure, failure, relapse and adverse drug effects.

Kim 2007 conducted a multicenter study in Korea, and enrolled 95 adult patients with possible scrub typhus. Of these, three had concurrent diseases and was excluded. The left 92 participants were randomly allocated to either telithromycin (n = 47) or doxycycline (n = 45) group, and followed up for four weeks. Seventy-six out of the 92 participants met diagnostic laboratory criteria of scrub typhus. The outcomes measured by the researchers were fever clearance time, cure, failure, relapse, toxicity and adverse events.

Phimda 2007 conducted a multicenter study in Thailand, and enrolled 296 adults with suspected leptospirosis or scrub typhus. They were randomly allocated to receive either doxycycline or azithromycin, and the median duration of follow-up was 15 days. The cause of acute fever were obtained for 151 out of 296 patients. Of these, 57 patients (doxycycline n = 27; azithromycin n = 30) met diagnostic laboratory criteria of scrub typhus. The outcomes measured by the researchers were cure, failure, defervescence and adverse events.

Risk of bias in included studies

Our assessment of risk of bias is summarised in Table 3 with individual trial details provided in the 'Characteristics of included studies'. Generation of allocation sequence was adequate in three trials, and one trial had adequate allocation concealment; follow up was classed as adequate in four trials; no trial had blinding.

Table 3. Risk of bias assessment
TrialSequenceConcealmentBlindingParticipants
TrialGeneration of allocation sequenceAllocation concealmentBlindingInclusion of all randomized participants
Sheehy 1973UnclearUnclearUnclearAdequate(60/63)
Brown 1978UnclearUnclearUnclearInadequate (55/65)
Song 1995AdequateInadequateInadequate ("non blinded")Inadequate (116/129)
Watt 2000UnclearUnclearUnclearInadequate (78/126)
Kim 2004AdequateUnclearInadequate (open-label)Adequate (93/99)
Kim 2007InadequateUnclearInadequateAdequate (92/92)
Phimda 2007AdequateAdequateInadequate(open)Adequate (296/296)

The method of random allocation was not clear in Sheehy 1973. The diagnosis of scrub typhus was based on clinical criteria, and only 19/60 participants were tested using the Weil-Felix test with Proteus OX-K agglutinins. This test was the only one available at this time, but is not specific for the disease. While all participants received drugs for at least three days, the total length of treatment was decided by clinicians and not reported. All participants were followed up for three weeks.

The random allocation was not clear in Brown 1978, but entry criteria were more rigorously applied. The authors excluded a large proportion of participants who did not have serological evidence of scrub typhus. Clinicians also had discretion to alter treatment after 48 hours if there was no clinical improvement.

In Song 1995, 129 adult participants were enrolled. They were allocated at random by computer generated numbers, but allocation was not concealed. In total, 76/129 met the diagnostic laboratory criteria. Both groups were similar in relation to severity of disease and clinical manifestations. All participants were followed up for four weeks.

The method of random allocation and concealment was not clear in Watt 2000. The diagnosis of scrub typhus was based on clinical criteria and positive serological dipstick test. After enrolment, a large number of participants were excluded. The protocol was changed during the first year of the study. One intervention group was discontinued and replaced with the other new treatment group. These factors meant the number of participants completing the study in each treatment group was small.

In Kim 2004, computer-generated random sequences was mentioned but no description of concealment or blinding. The diagnosis of scrub typhus was based on clinical and laboratory criteria. After enrolment, a number of participants were excluded. An intention-to-treat analysis was based on 93 participants who completed the treatment. All participants were followed up for 30 days.

Kim 2007 used a quasi-randomized controlled trial design and allocated by last digit of a resident registration number. Concealment of allocation was not clearly documented. Seventy-six out of 92 included patients met the diagnostic laboratory criteria. Results were presented based on the intention-to-treat analysis. All participants were followed up for four weeks.

In Phimda 2007, 296 participants were allocated at random by computer generated numbers, and the random allocation sequences were sealed in an opaque envelope and numbered. A large number of participants were lost to follow-up after discharge from the hospital. In total, 57/296 met the diagnostic laboratory criteria of scrub typhus. Results were presented based on the intention-to-treat analysis.

Effects of interventions

In Sheehy 1973, presence of fever at 48 hours was not different after tetracycline or chloramphenicol (60 participants, Figure 1, Analysis 1.1); mean duration of fever was 28 hours (range 14 to 68 hours) in the tetracycline group, and 35 hours (range 16 to 94 hours) in the chloramphenicol group. The authors did not report the standard deviation or any statistical tests performed on the duration of fever data. Relapse was reported in two participants in the tetracycline group and in five in the chloramphenicol group (60 participants, Analysis 1.2).

Figure 1.

Forest plot of comparison: 1 Tetracycline vs chloramphenicol, outcome: 1.1 Febrile after 48 hours.

Two trials compared doxycycline with tetracycline (N = 171; Brown 1978, Song 1995). No difference in fever at 48 hours was detected in the one study (Brown 1978) measuring this (55 participants, Figure 2, Analysis 2.1) and no relapses were reported in either group. Treatment failure was reported by Song 1995: 4/66 participants in the doxycycline group and 0/50 in the tetracycline group, but the difference was not statistically significant (116 participants, Analysis 2.4). The length of fever between the two treatment groups was similar 34.0 (standard deviation 26.5) hours compared to 37.0 (standard deviation 26.6) hours, respectively, and not statistically significantly different.

Figure 2.

Forest plot of comparison: 2 Doxycycline vs tetracycline, outcome: 2.1 Febrile after 48 hours.

One trial compared doxycycline with rifampicin (Watt 2000). Fewer patients in the rifampicin group remained febrile at 48 hours (RR 0.41, 95% CI 0.22 to 0.77; 78 participants, Figure 3, Analysis 3.1). This result was calculated by combining the standard and high-dose rifampicin groups). The median fever clearance time in the doxycycline group was 52 hours (range 4 to 108) compared to 27.5 hours (range 4 to 84) in the standard rifampicin group, and 22.5 hours (3 to 76) in high-dose rifampicin group (P = 0.01). Relapse was reported only in the doxycycline group (2/28) over a one-month period of follow-up (Analysis 3.2). Mild gastrointestinal symptoms were common in all groups (10 (50%) in doxycycline group; 8 (31%) in standard rifampicin group and 14 (43%) in high-dose rifampicin group).

Figure 3.

Forest plot of comparison: 3 Rifampicin vs doxycycline, outcome: 3.1 Febrile after 48 hours.

In the comparison between high and low rifampicin dose in the same trial, there was no statistically significant difference of effect on participants being febrile at 48 hours (50 participants, Analysis 4.1).

Two trials compared azithromycin with doxycycline (Kim 2004, Phimda 2007). No difference was detected between azithromycin and doxycycline for fever at 48 hours (150 participants, 2 trials, Figure 4, Analysis 6.1). No difference in median fever clearance time was found between azithromycin group (21 hours, range 1 to 120 in Kim 2004; 60 hours, range 12 to 128 in Phimda 2007) and doxycycline group (29 hours, range 4 to 176 in Kim 2004; 48 hours, range 16 to 120 in Phimda 2007). No relapses were reported in either group. Gastrointestinal side effects were reported by Kim 2004 in the azithromycin group (7/47) and in the doxycycline group (12/46, RR 0.57, 95% CI 0.25 to 1.32; 93 participants, Analysis 6.3). Treatment failure was reported by Phimda 2007: 1/30 participants in the azithromycin group and 0/27 in the doxycycline group, but the difference was not statistically significant (57 participants, Analysis 6.4).

Figure 4.

Forest plot of comparison: 6 Azithromycin vs doxycycline, outcome: 6.1 Febrile after 48 hours.

One trial compared telithromycin with doxycycline (Kim 2007). The length of fever between the two treatment groups was similar 20.5 (standard deviation 12.9) hours compared to 22.6 (standard deviation 21.4) hours, respectively, and the difference was not statistically significant (92 participants, Analysis 7.1). Relapse was reported only in the doxycycline group (1/45) over a two-week period of follow-up (92 participants, Analysis 7.3). Adverse events were reported in the telithromycin group (7/47) and in the doxycycline group (11/45, RR 0.61; 95% CI 0.26 to 1.43; Analysis 7.4). Gastrointestinal side effects were reported in the telithromycin group (3/47) and in the doxycycline group (6/45, RR 0.48, 95% CI 0.13 to 1.80; Analysis 7.5). No treatment failure was reported.

No trials reported deaths or serious complications.

Discussion

There are several trials of scrub typhus treatment with antibiotics. The diagnostic criteria for scrub typhus in Sheehy 1973 study was based on mostly clinical features, so it is not clear how many participants actually had scrub typhus. Two trials (Brown 1978 and Song 1995) had more strictly laboratory diagnostic criteria, although the Weil-Felix test with Proteus OX-K is relatively insensitive. In Watt 2000, a serological dipstick test was used to screen mild scrub typhus for enrolment. The researchers then conducted a separate test to confirm the diagnosis. This led to some participants being excluded from the study after randomization. The other three trials (Kim 2004; Kim 2007; Phimda 2007) were based on WHO criteria to screen mild scrub typhus for enrolment. In Kim 2004 and Kim 2007, among participants who completed the treatment, not all of them were confirmed scrub typhus, however, the intention to treat analysis was performed based on participants who complete the treatment.

The uncertainty around diagnosis causes problems in clinical decision making, as well as in evaluating antibiotics. It appears in these studies participants with other infectious diseases were excluded, increasing the certainty of the diagnosis, but this remains a problem until better tests are more widely available.

The concealment of allocation was poorly reported, and only one study included in this review (Phimda 2007) reported adequate allocation concealment. Studies were small. Three recent studies used intention-to-treat analysis (Kim 2004; Kim 2007; Phimda 2007).

Overall, broad spectrum antibiotics are known to be effective in this condition, but trials are currently insufficient to determine whether and under what conditions one is more effective than another.

Authors' conclusions

Implications for practice

The antibiotics tested appear to cure the condition, and there seem to be little to choose between the broad spectrum antibiotics tested, but trials are small.

Rifampicin seem to be more effective than doxycycline in areas where scrub typhus appears to respond poorly to conventional antibiotics (tetracycline and chloramphenical), and where doxycycline-resistance strain is suspected.

Clinicians should monitor the progress of patients in the light of reports of drug resistance.

Implications for research

Further research is required to evaluate antibiotics for scrub typhus. Trials would be more easily interpreted if reliable diagnostic tests were available. Such research could examine whether a single dose of doxycycline is as effective as a three to five day course of treatment.

Regimens for severe disease need to be evaluated, for example, comparing intravenous chloramphenicol with intravenous tetracycline.

Studies are also needed to evaluate alternative antibiotics, particularly in areas where scrub typhus appears to respond poorly to conventional antibiotics.

Acknowledgements

We would like to thank Professor Paul Garner for his great contribution to the previous version of this review.

We wish to thank Prof Virat Sirisanthana, Dr George Watt, and Dr George Wyatt for their advice and comments.

This document is an output from a project funded by DFID for the benefit of developing countries. The views expressed are not necessarily those of DFID.The authors take sole responsibility for the data presented and the views expressed.

Data and analyses

Download statistical data

Comparison 1. Tetracycline vs chloramphenicol
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Febrile after 48 hours1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Relapse1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 1.1.

Comparison 1 Tetracycline vs chloramphenicol, Outcome 1 Febrile after 48 hours.

Analysis 1.2.

Comparison 1 Tetracycline vs chloramphenicol, Outcome 2 Relapse.

Comparison 2. Doxycycline vs tetracycline
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Febrile after 48 hours1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Relapse1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Duration of fever1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4 Treatment failure1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 2.1.

Comparison 2 Doxycycline vs tetracycline, Outcome 1 Febrile after 48 hours.

Analysis 2.2.

Comparison 2 Doxycycline vs tetracycline, Outcome 2 Relapse.

Analysis 2.3.

Comparison 2 Doxycycline vs tetracycline, Outcome 3 Duration of fever.

Analysis 2.4.

Comparison 2 Doxycycline vs tetracycline, Outcome 4 Treatment failure.

Comparison 3. Rifampicin vs doxycycline
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Febrile after 48 hours1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Relapse1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 3.1.

Comparison 3 Rifampicin vs doxycycline, Outcome 1 Febrile after 48 hours.

Analysis 3.2.

Comparison 3 Rifampicin vs doxycycline, Outcome 2 Relapse.

Comparison 4. High rifampicin dose vs standard rifampicin dose
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Febrile after 48 hours1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Relapse1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 4.1.

Comparison 4 High rifampicin dose vs standard rifampicin dose, Outcome 1 Febrile after 48 hours.

Analysis 4.2.

Comparison 4 High rifampicin dose vs standard rifampicin dose, Outcome 2 Relapse.

Comparison 5. Doxycycline vs standard rifampicin dose vs high rifampicin dose
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Number of participants febrile after 48 hours  Other dataNo numeric data
2 Median fever clearance time (hours)  Other dataNo numeric data
3 Number of participants with a relapse  Other dataNo numeric data

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
StudyDoxycyclineStandard rifampicinHigh rifampicin
Watt 200015/286/265/24

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)
StudyDoxycyclineStandard rifampicinHigh rifampicin
Watt 200052 (range 4 to 108)27.5 (4 to 84)22.5 (3 to 76)

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
StudyDoxycyclineStandard rifampicinHigh rifampicin
Watt 20002/280/260/24
Comparison 6. Azithromycin vs doxycycline
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Febrile after 48 hours2150Risk Ratio (M-H, Random, 95% CI)0.99 [0.30, 3.27]
2 Relapse2150Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Gastrointestinal side effect1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Treatment failure1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 6.1.

Comparison 6 Azithromycin vs doxycycline, Outcome 1 Febrile after 48 hours.

Analysis 6.2.

Comparison 6 Azithromycin vs doxycycline, Outcome 2 Relapse.

Analysis 6.3.

Comparison 6 Azithromycin vs doxycycline, Outcome 3 Gastrointestinal side effect.

Analysis 6.4.

Comparison 6 Azithromycin vs doxycycline, Outcome 4 Treatment failure.

Comparison 7. Telithromycin vs doxycycline
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Duration of fever1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2 Failure1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Relapse1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Adverse effects1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5 Gastrointestinal side effects1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 7.1.

Comparison 7 Telithromycin vs doxycycline, Outcome 1 Duration of fever.

Analysis 7.2.

Comparison 7 Telithromycin vs doxycycline, Outcome 2 Failure.

Analysis 7.3.

Comparison 7 Telithromycin vs doxycycline, Outcome 3 Relapse.

Analysis 7.4.

Comparison 7 Telithromycin vs doxycycline, Outcome 4 Adverse effects.

Analysis 7.5.

Comparison 7 Telithromycin vs doxycycline, Outcome 5 Gastrointestinal side effects.

What's new

DateEventDescription
27 May 2010New search has been performedNew search and new studies added. Primary outcomes amended.

History

Protocol first published: Issue 2, 2000
Review first published: Issue 2, 2000

DateEventDescription
8 June 2009AmendedConverted to new review format.
3 January 2007New citation required and conclusions have changedSubstantive amendment

Contributions of authors

Ratana Panpanich: involved with the design and writing of the protocol, duplication of screening of titles and abstracts, inclusion/exclusion of full text papers, quality assessment of included studies, data extraction and analysis, initial draft of the review.

Qin Liu: co-ordinated the review update, involved with the duplication of screening of titles and abstracts, inclusion/exclusion of full text papers, quality assessment of included studies, data extraction, updated the data analysis and draft of the review.

Declarations of interest

We certify that we have no affiliations with or involvement in any organization or entity with a direct financial interest in the subject matter of the review (eg, employment, consultancy, stock ownership, honoraria, and expert testimony).

Sources of support

Internal sources

  • Faculty of Medicine, Chiang Mai University, Thailand.

  • Liverpool School of Tropical Medicine, UK.

External sources

  • Department for International Development, UK.

  • European Union Directorate General XII, Belgium.

Notes

REVIEW HISTORY (started 4 March 2002)
4 March 2002: Updated review received by editorial base. This includes a new trial (Watt 2000), and responses to comments from Assistant Editor and statistician: (1) slight change to the objective; adverse outcomes changed from "Number and seriousness of side effects" to "Number of adverse events"; Relative Risk used for binary outcomes (previously Peto odds ratio)

June 2010: Updated review received by editorial base. Primary outcomes amended so no longer include "death" as primary outcome. Added new trials.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Brown 1978

MethodsRandomized 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
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear risk"volunteers were randomly assigned"
Allocation concealment?Unclear risknot mentioned
Blinding?
All outcomes
Unclear risknot mentioned
Incomplete outcome data addressed?
All outcomes
High risk10/65 (>10%)
Free of selective reporting?Low riskMain outcome reported

Kim 2004

MethodsRandomized 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
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Low risk"the enrolled patients were randomly assigned by computer-generated random sequences"
Allocation concealment?Unclear risknot mentioned
Blinding?
All outcomes
High riskopen-label
Incomplete outcome data addressed?
All outcomes
Low risk93/99(<10%)
Free of selective reporting?Low riskMain outcome reported

Kim 2007

MethodsQuasi-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
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?High risk"eligible patients were randomly allocated by last digit of a resident registration number"
Allocation concealment?Unclear risknot mentioned
Blinding?
All outcomes
High riskopen-label
Incomplete outcome data addressed?
All outcomes
Low risk92/92
Free of selective reporting?Low riskmain outcome reported

Phimda 2007

MethodsRandomized 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
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Low riskby computer-generated random sequences
Allocation concealment?Low riskcentral randomisation, sealed, opaque envelope
Blinding?
All outcomes
High riskopen
Incomplete outcome data addressed?
All outcomes
Low risk296/296
Free of selective reporting?Low riskmain outcome reported

Sheehy 1973

MethodsRandomized 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
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear risk"patients were evacuated at random to one of the two supporting units"
Allocation concealment?Unclear risknot mentioned
Blinding?
All outcomes
Unclear risknot mentioned
Incomplete outcome data addressed?
All outcomes
Low risk60/63 (<10%)
Free of selective reporting?Low riskmain outcome reported

Song 1995

MethodsRandomized 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
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Low riskby computer-generated random orders
Allocation concealment?High riskcentral randomisation but not remote from trial location
Blinding?
All outcomes
High risknon blinded
Incomplete outcome data addressed?
All outcomes
High risk116/129(>10%)
Free of selective reporting?Low riskmain outcome reported

Watt 2000

MethodsRandomized 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
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear risk"patients were randomly assigned"
Allocation concealment?Unclear risknot mentioned
Blinding?
All outcomes
Unclear risknot mentioned
Incomplete outcome data addressed?
All outcomes
High risk78/126(>10%)
Free of selective reporting?Low riskmain outcome reported

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Olson 1980A 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 1982A 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.

Characteristics of ongoing studies [ordered by study ID]

IRB043-31

Trial name or titleControlled Trial: 5-Day Course of Rifampin Versus Doxycycline for the Treatment of Mild to Moderate Scrub Typhus
MethodsRandomized 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 informationProf. Dong-Min Kim
(drongkim@chosun.ac.kr), 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

ISRCTN47812566

Trial name or titleOral doxycycline versus oral azithromycin in the treatment of Scruband Murine Typhus in Laos
MethodsRandomized 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)

Interventions1. 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

(paul@tropmedres.ac), 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)