Intervention Review

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Antibiotic prophylaxis for leptospirosis

  1. David M Brett-Major1,*,
  2. Robert J Lipnick2

Editorial Group: Cochrane Hepato-Biliary Group

Published Online: 8 JUL 2009

Assessed as up-to-date: 17 FEB 2009

DOI: 10.1002/14651858.CD007342.pub2


How to Cite

Brett-Major DM, Lipnick RJ. Antibiotic prophylaxis for leptospirosis. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD007342. DOI: 10.1002/14651858.CD007342.pub2.

Author Information

  1. 1

    NAVMED MPT&E, Military Tropical Medicine Course, Bethesda, MD, USA

  2. 2

    Armed Forces Health Surveillance Center, Communications, Standards, & Training Division, Silver Spring, MD, USA

*David M Brett-Major, Military Tropical Medicine Course, NAVMED MPT&E, 8901 Wisconsin Avenue, Bethesda, MD, 20889-5611, USA. dmbrettmajor@gmail.com. David.Brett-Major@med.navy.mil.

Publication History

  1. Publication Status: New
  2. Published Online: 8 JUL 2009

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Characteristics of included studies [ordered by study ID]
Gonsalez 1998

MethodsSingle site prospective, pilot, double-blinded randomised trial. Enrollees identified within 48 hours of a single flood.


ParticipantsResidents of rural Cabucu District, Sao Paolo Brazil. Ages ranged from 18 to 74 years. 41% of the participants were men. Exclusion criteria included suspected high risk exposure within the previous six months or allergy to tetracycline.


InterventionsPost-exposure prophylaxis with a single 200 mg dose of doxycycline or placebo.

106 participants were enrolled in the study. Results and analyses were reported on 82 participants who had been followed for approximately six weeks:

Group I: 40 participants - doxycycline.
Group II: 42 participants - placebo.


OutcomesLaboratory confirmed clinical diagnosis.


NotesEnrollees included a large number of participants with baseline IgM+ serological data. The authors reported neither adverse events nor the nature of clinical disease observed (other than a single case of Weil's Disease reported). They did not explain reasons for participants withdrawal when those withdrawals occurred, or how the data from the withdrawn participants were utilized.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskUnclear.

Allocation concealment?Unclear riskUnclear.

Blinding?
All outcomes
Low riskBlinding asserted, though method not described.

Incomplete outcome data addressed?
All outcomes
High riskTwenty-four persons excluded from analysis.

Free of selective reporting?Low riskWhile primary and secondary outcomes were not clearly stated, they reported on the outcomes most likely targeted by their study design.

Free of baseline imbalance?Unclear riskRelevant baseline demographics between groups not discussed.

Free of early stopping?Low riskYes.

Free of academic bias?Low riskYes.

Free of source of funding bias?Unclear riskPfizer provided doxycycline and placebo.

Sehgal 2000

MethodsSingle site prospective, randomised trial.

The trial continued for 12 weeks, though the follow-up period for enrollees was unclear.


ParticipantsArea around Diglipur, Andaman Islands, India. Mix of residents including agricultural workers and adolescent school children. Two out of three participants were between the ages of 15 and 19 years. Gender distribution was not disclosed. Exclusion criteria included pregnancy, lactation, chronic disease, or an ongoing medication regimen of any kind.


InterventionsPre-exposure prophylaxis with weekly administration of two doses of 100 mg doxycycline spaced twelve hours apart or vitamin B complex tablets (intended placebo).

1025 participants were randomised into two groups, though analyses were reported on only 782.

Group I: 386 participants (513 enrolled) - doxycycline.
Group II: 396 participants (512 enrolled) - vitamin B complex tablets as placebo.


OutcomesThe primary outcome was laboratory identified infection.


NotesWithdrawal criteria were broad and included any illness, a missed dose, or the prescription of additional antibiotics. Manner of exclusion of leptospirosis in such instances and the method of subsequent handling of that participant's data was not disclosed.The morning dose was directly observed, and evening dose adherence was logged by a visiting field worker. Approximately twenty-eight per cent of participants in each group had a baseline Leptospira titer greater than 1:100.

Gastric irritation was the most common adverse effect reported. In Group I three participants were withdrawn for adverse events. One of these persons developed an erythematous rash after the first dose, while the other two persons withdrawn experienced gastritis with persistent stomach pain and vomiting. Rates of less severe adverse events were not fully characterized.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskUnclear.

Allocation concealment?Unclear riskSealed envelopes, but no information if they were opaque.

Blinding?
All outcomes
Unclear riskPatient and laboratory were explicitly identified as blinded, but whether clinical evaluators were blind to participants' assignment was not clear. Also, the degree to which the vitamin B complex tablets used for placebo resembled the intervention medication was not disclosed.

Incomplete outcome data addressed?
All outcomes
High risk243 enrollees were not included in analyses nor were their data reported. While laboratory findings were relayed in detail, clinical findings were not.

Free of selective reporting?Low riskDeath and adverse events were included in their reporting of the data.

Free of baseline imbalance?Unclear riskAge was well disclosed, though gender distribution was less clear. Also, the nature of potential exposures was not delineated by group - for instance, distribution of agricultural workers and students between the two groups.

Free of early stopping?Unclear riskUnclear.

Free of academic bias?Low riskYes.

Free of source of funding bias?Unclear riskPfizer provided doxycycline.

Takafuji 1984

MethodsSingle site prospective, randomised trial executed in two phases with sequentially deployed troops to the area of interest.


ParticipantsActive duty army soldiers deployed to the Fort Sherman training area in Panama. During this period, likely all men predominantly less then 30 years of age. Exclusion criteria were narrow- allergy to tetracycline or receiving other antibiotic at time of enrolment.


InterventionsPre-exposure prophylaxis with weekly administration of a single dose of two 100 mg doxycyline hyclate capsules or identical placebo.

1079 participants were randomised into two groups, though 109 participants (distribution among groups unknown) were excluded during the study for concomitant antibiotic use. Following ranged from three to nine weeks.

Group I: 469 participants - doxycycline.

Group II: 471 participants - placebo.


OutcomesThe primary outcome was laboratory identified infection.


NotesWithdrawal occurred if participant was placed on any antibiotic over the course of the study. Manner of exclusion of leptospirosis in such instances and the method of subsequent handling of that participant's data was not disclosed. In three week period post-deployment, participants carried instructions on leave and clinical symptoms relied on self-report with uncertain validation. Thirteen per cent of participants had pre-existing Leptospira immunity though geographic exposures were not identified or specific serovar typing performed in order to assess potential impact. Also, distribution of these pre-immune participants across intervention and control groups was not disclosed. Reports of clinical disease appear to have been mixed with other cases presenting outside of the study during the same period and so unable to evaluate intervention's effect on clinical outcomes.

Among those participants for who data was reported and analysed, thirteen in Group I and one in Group II experienced vomiting. All thirteen of these participants in Group I had ingested the doxycycline five to seven hours after their most recent meal whereas typically administration was within two hours of eating.


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Low riskComputer generated random assignments. Block randomisation employed.

Allocation concealment?Unclear riskNo information.

Blinding?
All outcomes
Low riskAsserted double blinded trial design and reported use of identical placebo.

Incomplete outcome data addressed?
All outcomes
High riskOutcomes sought not explicitly stated. Also, analyses excluded 107 enrollees.

Free of selective reporting?High riskIn clinical outcomes in particular results confused with reporting of non-enrolled cases. Baseline serologic differences between the groups were not disclosed.

Free of baseline imbalance?Unclear riskDistribution of pre-existing immunity not disclosed.

Free of early stopping?Unclear riskSample size calculations not disclosed, though following time for serologies appeared robust.

Free of academic bias?Low riskYes.

Free of source of funding bias?Unclear riskPfizer provided doxycycline and placebo.

 
Comparison 1. Pre-exposure prophylaxis with doxycycline

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Laboratory identified infection21722Odds Ratio (M-H, Random, 95% CI)0.28 [0.01, 7.48]

 2 Adverse events, minor21722Odds Ratio (M-H, Fixed, 95% CI)11.33 [2.12, 60.46]

 3 Clinical infection, laboratory confirmed1782Odds Ratio (M-H, Fixed, 95% CI)0.44 [0.22, 0.88]

 4 Death1782Odds Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 2.83]

 5 Laboratory identified infection, baseline IgM titer zero1356Odds Ratio (M-H, Fixed, 95% CI)1.19 [0.70, 2.00]

 6 Laboratory identified infection, baseline IgM titer non-zero1426Odds Ratio (M-H, Fixed, 95% CI)1.21 [0.81, 1.81]

 
Comparison 2. Post-exposure prophylaxis with doxycycline

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Laboratory identified infection182Odds Ratio (M-H, Fixed, 95% CI)1.36 [0.52, 3.52]

 2 Clinical infection, laboratory confirmed182Odds Ratio (M-H, Fixed, 95% CI)0.39 [0.07, 2.13]

 3 Clinical infection, laboratory confirmed when IgM+ at baseline removed171Odds Ratio (M-H, Fixed, 95% CI)0.52 [0.09, 3.01]