Antibiotics For Leptospirosis (Review) : Brett-Major DM, Coldren R

Antibiotics for leptospirosis (Review)
Brett-Major DM, Coldren R
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 2
http://www.thecochranelibrary.com
Antibiotics for leptospirosis (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 27
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Antibiotics for leptospirosis (Review) i

[Intervention Review]
Antibiotics for leptospirosis
David M Brett-Major1 , Rodney Coldren2

1 U.S. Military Tropical Medicine, Navy Medicine Manpower, Personnel, Training and Education Command (NAVMED MPT&E),
Bethesda, MD, USA. 2 Department of Preventive Medicine and Biometrics, Uniformed Services University, Bethesda, USA
Contact address: David M Brett-Major, U.S. Military Tropical Medicine, Navy Medicine Manpower, Personnel, Training and Ed-
ucation Command (NAVMED MPT&E), 8901 Wisconsin Avenue, Bethesda, MD, 20889-5611, USA. [email protected].
[email protected].
Editorial group: Cochrane Hepato-Biliary Group.

Publication status and date: New, published in Issue 2, 2012.
Review content assessed as up-to-date: 16 January 2012.
Citation: Brett-Major DM, Coldren R. Antibiotics for leptospirosis. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.:
CD008264. DOI: 10.1002/14651858.CD008264.pub2.
ABSTRACT
Background
Leptospirosis has a wide-ranging clinical and public health impact. Leptospira are globally distributed. Case attack rates are as high as
1:4 to 2:5 persons in exposed populations. In some settings mortality has exceeded 10% of infected people. The benefit of antibiotic
therapy in the disease has been unclear.
Objectives
We sought to characterise the risks and benefits associated with use of antibiotic therapy in the management of leptospirosis.
Search methods
We searched the The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials
(CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded regardless of study language.
This was augmented by a manual search. The last date of search was November, 2011.
Selection criteria
To be included in assessment of benefits, trials had to specifically assess the use of antibiotics in a randomised clinical trial. A broad
range of study types were incorporated to seek potential harms.
Data collection and analysis
Included trials were systematically abstracted, as were excluded studies for the purposes of assessing harms. Analyses were conducted in
accordance with The Cochrane Handbook and practices of The Cochrane Hepato-Biliary Group.
Main results
Seven randomised trials were included. Four trials with 403 patients compared an antibiotic with placebo or no intervention. Three
trials compared at least one antibiotic regimen with another antibiotic regimen. The trials all had high risk of bias. The trials varied
in the severity of leptospirosis among trial patients. The ability to group data for meta-analysis was limited. While all four trials that
compared antibiotics with placebo reported mortality and used parenteral penicillin, there were no deaths in two of them. Since odds
ratio calculations cannot employ zero-event trials, only two trials contributed to this estimate. The number of deaths were 16/200
(8.0%) in the antibiotic arm versus 11/203 (5.4%) in the placebo arm giving a fixed-effect OR 1.56 (95% CI 0.70 to 3.46). The
Antibiotics for leptospirosis (Review) 1
random-effects OR is 1.16 (95% CI 0.23 to 5.95). The heterogeneity among these four trials for the mortality outcome was moderate (I
2 = 50%). Only one trial (253 patients) reported days of hospitalisation. It compared parenteral penicillin to placebo without significant
effect of therapy (8.9 versus 8.8 days; mean difference (MD) 0.10 days, 95% CI -0.83 to 1.03). The difference in days of clinical
illness was reported in two of these trials (71 patients). While parenteral penicillin therapy conferred 4.7 to 5.6 days of clinical illness in
contrast to 7.7 to 11.6 days in the placebo arm, the size of the estimate of effect increased but statistical significance was lost under the
random-effect model (fixed-effect: MD -2.13 days, 95% CI -2.46 to -1.80; random-effects: MD -4.04, 95% CI -8.66 to 0.58). I2 for
this outcome was high (81%). When duration of fever alone was assessed between antibiotics and placebo in a single trial (79 patients),
no significant difference existed (6.9 versus 6.6 days; MD 0.30, 95% CI -1.26 to 1.86). Two trials with 332 patients in relatively
severe and possibly late leptospirosis, resulted in trends towards increased dialysis when penicillin was used rather than placebo, but
the estimate of effect was small and did not reach statistical significance (42/163 (25.8%) versus 31/169 (18.4%); OR 1.54, 95% CI
0.91 to 2.60). When one antibiotic was assessed against another antibiotic, there were no statistically significant results. For mortality
in particular, these comparisons included cephalosporin versus penicillin (2 trials, 6/176 (3.4%) versus 9/175 (5.2%); fixed-effect: OR
0.65, 95% CI 0.23 to 1.87, I2 = 16%), doxycycline versus penicillin (1 trial, 2/81 (2.5%) versus 4/89 (4.5); OR 0.54, 95% CI 0.10
to 3.02), cephalosporin versus doxycycline (1 trial, 1/88 (1.1%) versus 2/81 (2.5%); OR 0.45, 95% CI 0.04 to 5.10). There were no
adverse events of therapy which reached statistical significance.
Authors’ conclusions
Insufficient evidence is available to advocate for or against the use of antibiotics in the therapy for leptospirosis. Among survivors who
were hospitalised for leptospirosis, use of antibiotics for leptospirosis may have decreased the duration of clinical illness by two to four
days, though this result was not statistically significant. When electing to treat with an antibiotic, selection of penicillin, doxycycline, or
cephalosporin does not seem to impact mortality nor duration of fever. The benefit of antibiotic therapy in the treatment of leptospirosis
remains unclear, particularly for severe disease. Further clinical research is needed to include broader panels of therapy tested against
placebo.
PLAIN LANGUAGE SUMMARY
Antibiotics for the treatment of leptospirosis
Leptospirosis is a common disease both in the developed and developing world. It is caused by a bacteria spread by the urine of animals.
People travelling, agricultural field workers, hunters, homeless, and others with close animal contact are groups that, in particular, can
get leptospirosis. Like many common infections, most people infected with this disease do not feel sick. When people do feel sick, in
some instances up to 1 out of every 10 people have died. Whether or not antibiotics should be used, and if used which antibiotic should
be used have been matters for debate for many years. This review identified and assessed seven clinical trials that tested antibiotics in
patients sick with leptospirosis. Four of these trials compared intravenous penicillin to a placebo. Three of the trials looked at differences
between different antibiotics. All trials had high risk of systematic errors (bias) and of random errors (play of chance). When looked at
together, these trials do not answer the basic questions about whether or not antibiotics should be used. Part of the reason for this is
that there is a wide range of severity among people ill with the disease. Additional randomised clinical trials are needed. Nonetheless,
these trials suggest that antibiotics administered to patients who are sick with leptospirosis may make patients feel better two days
earlier than they otherwise would have improved. However, it is also possible that when patients are severely ill, penicillin therapy
might increase the risk of death or dialysis in comparison to those who receive no antibiotics. Other antibiotics have not been tested
in this way. Despite the lack of evidence, if a clinician chooses to treat leptospirosis with an antibiotic, there does not seem to be any
difference between the appropriate use of intravenous penicillin, intravenous cephalosporin, doxycyline, or azithromycin. But, for this
they have not been tested to the same extent as intravenous penicillin.
BACKGROUND
sis) predominantly in the Americas, Carribean, and Asia (Pappas
Leptospira species have a wide geographic distribution in nature 2008). While World Health Organization (WHO) guidelines ad-
and are recognised as causing zoonotic clinical disease (leptospiro-
mit that both morbidity and mortality in leptospirosis are variably troops and eco-tourists, potentially exposed to Leptospira infec-
determined, the guidelines strongly promote the use of targeted tion.
antibiotic therapy as soon as leptospirosis is considered a lead-
ing element of the differential diagnosis in an ill patient (WHO
2003). This is despite recognition that benefits of therapy histor-
Types of interventions
ically have been unclear (Bharti 2003). Point of care diagnosis for
leptospirosis is not in use. While clinical scoring exists, serologic Administration of antibiotic expressly given for the treatment of
assays, ideally with acute and convalescent sera and culture em- leptospirosis versus placebo, no intervention, or another antibiotic.
ploying specialised media, are required. We did not exclude studies based upon type of antibiotic, dose,
dose interval, route of administration, or timing of dose, though
Deaths occur in outbreaks most commonly from renal failure these factors were relevant for pooling. We allowed co-interven-
and pulmonary haemorrhage. Proportions of symptomatic disease tions when equally administered to all trial groups.
among exposed persons have ranged from 26% to 40% in small
studies among immune naive populations (Russell 2003; Sejvar
2003; Hadad 2006). Mortality among symptomatic patients also
may be high. After the 2005 flooding in Guyana, one group re- Types of outcome measures
ported six deaths among 40 clinical presentations to a referral cen- We evaluated selected trials for the following outcome measures:
tre (Liverpool 2008).
We sought to better define the role of antibiotic therapy in patients
with Ieptospirosis and update a previously published Cochrane Primary outcomes
systematic review (Guidugli 2000). That review pooled three tri-
• Overall mortality.
als and demonstrated no statistically significant benefit for either
• Leptospirosis mortality (confirmed by laboratory diagnosis).
mortality or number of days hospitalised when doxycycline and
• Hospitalisation (regardless of cause).
penicillin were compared with placebo.
• Leptospirosis hospitalisation (confirmed by laboratory
diagnosis).
• Among those with hospitalisation for leptospirosis
OBJECTIVES confirmed by laboratory diagnosis, ventilator requirement.
To assess the beneficial and harmful effects of antibiotics for the • Among those with hospitalisation for leptospirosis
treatment of leptospirosis. confirmed by laboratory diagnosis, dialysis requirement.
METHODS Secondary outcomes
• Days lost from work or travel.

Criteria for considering studies for this review confirmed by laboratory diagnosis and ventilated, number of
days on mechanical ventilation.
Types of studies confirmed by laboratory diagnosis and dialyzed, number of days
We considered for inclusion all randomised clinical trials study- on dialysis.
ing antibiotics for the treatment of leptospirosis regardless of year, • Adherence to assigned intervention.
language, form of publication, blinding, or comparator (Higgins • All adverse events. An adverse event defined as any
2011). In order to assess potential harm, we searched for contrib- untoward medical occurrence in a patient in any trial group,
utory cohort studies, case-control studies, and quasi-randomised regardless of association with the intervention, but that results in
studies. a dose reduction, discontinuation of treatment, or registration as
an adverse event (ICH-GCP 1996). We characterised events into
the following strata:
Types of participants ◦ Minor not requiring intervention.
All infected patients were included, though we anticipated that ◦ Minor requiring intervention.
most participants would be victims of seasonal flooding, agricul- ◦ Requiring hospitalisation or resulting in long-term
tural workers in endemic regions, veterinarians, and other high- disability.
risk occupations as well as high-risk activity travellers, such as ◦ Death (ICH-E3 1995).

Search methods for identification of studies • Study design
We performed electronic and manual searches.
◦ Inclusion and exclusion criteria.
◦ Sample size (premise, calculation).
Electronic searches ◦ Outcome measures.
We searched The Cochrane Hepato-Biliary Group Controlled Tri- ◦ Randomisation and how randomised participants were
als Register (Gluud 2011), the Cochrane Central Register of Con- allocated across groups.
trolled Trials (CENTRAL) in The Cochrane Library, MEDLINE, ◦ Definitions of outcomes, in particular clinical and
EMBASE, and Science Citation Index Expanded (Royle 2003). laboratory diagnosis.
Search strategies with the time span of the searches are given in ◦ Assigned interventions and control.
Appendix 1. Once we selected a trial for inclusion, we used its ◦ Who was blinded and how concealment was
bibliography to search for candidate trials. In MEDLINE, we used accomplished.
the ’Related links’ feature to search the 25 most related publica- ◦ Dichotomous: If not selected for inclusion for analysis
tions to each selected study. of benefit, should it be abstracted to inform analysis of harms? (if
yes, abstract).
◦ Dichotomous: If not selected for inclusion for analysis
Searching other resources of benefit, should it be abstracted to inform the discussion? (if
We attempted contact with the authors of included trials in press yes, abstract).
within the previous 20 years. We provided a draft of this review in
order to afford them an opportunity to supplement study infor- • Participant demographics
mation to better inform study description or incorporated data.
Such correspondences were sent on 15 May 2011. ◦ Age.
◦ Sex.
◦ Nature of exposure (agricultural worker, eco-tourist,
Data collection and analysis etc).
We followed the instructions in The Cochrane Handbook for Sys-

• Results
tematic Reviews of Interventions (Higgins 2011) and the Cochrane
Hepato-Biliary Group Module (Gluud 2011) for data collection
◦ Observed outcomes as published and augmented by
and analysis.
author query.
◦ Follow-up.
Selection of studies ◦ Completion rates by trial arms.
◦ Type of analysis (intention-to-treat sought).
Both authors independently reviewed the entire list of candidate
studies obtained by databases search for compliance with the se-
lection requirements. The authors did not have disagreement on
inclusion of individual trials; however, they, if necessary, had avail- Assessment of risk of bias in included studies
able arbitration through The Cochrane Hepato-Biliary Group Ed-
We followed the instructions given in the Cochrane Handbook
itorial Team Office.
for Systematic Reviews of Interventions (Higgins 2011) and the
Cochrane Hepato-Biliary Group Module (Gluud 2011). Due to
Data extraction and management the risk of biased overestimation of intervention effects in ran-
domised trials with inadequate methodological quality (Schulz
We abstracted each selected study with two independent abstrac-
1995; Moher 1998; Kjaergard 2001; Wood 2008), we looked at
tions.
the influence of methodological quality of the trials on the results
As available, we extracted the following information from each
by evaluating the risk of bias domains described below. When in-
selected study:
formation was not available in the published trial, we contacted
• Study and publication identifiers
the authors in an attempt to assess each trial fully. Explicit method-
◦ Database index number, first author, journal, year of ologic grading criteria are recommended standard in the Cochrane
publication, and language. Hepato-Biliary Group Module (Gluud 2011).
◦ Location, period of intervention, duration participants Allocation sequence generation
were followed. - Low risk of bias: sequence generation was achieved using com-
◦ Funding source. puter random number generation or a random number table.

Drawing lots, tossing a coin, shuffling cards, and throwing dice of bias, each trial was assessed in particular for funding and aca-
are adequate if performed by an independent adjudicator. demic biases.
- Uncertain risk of bias: the trial is described as randomised, but - Low risk of bias: the trial appears to be free of other components
the method of sequence generation was not specified. that could put it at risk of bias. Funding - sources clearly delin-
- High risk of bias: the sequence generation method is not, or eated and non-commercial; Academic - searchable literature from
may not be, random. Quasi-randomised studies, those using dates, the study group which demonstrated balanced conclusions on the
names, or admittance numbers in order to allocate patients are topic of publication.
inadequate and will be excluded for the assessment of benefits but - Uncertain risk of bias: the trial may or may not be free of other
not for harms. components that could put it at risk of bias. Funding - not disclosed
or incomplete; Academic - not discernible due to lack of searchable
Allocation concealment literature.
- Low risk of bias: allocation was controlled by a central and inde- - High risk of bias: there are other factors in the trial that could
pendent randomisation unit, sequentially numbered, opaque and put it at risk of bias, eg, for-profit involvement, authors have con-
sealed envelopes or similar, so that intervention allocations could ducted trials on the same topic etc. Funding - commercial sponsors
not have been foreseen in advance of, or during, enrolment. particularly if lacking statement on level of participation in study
- Uncertain risk of bias: the trial was described as randomised, but execution by sponsors; Academic - searchable literature from the
the method used to conceal the allocation was not described so study group which demonstrated persistently themed conclusions
that intervention allocations may have been foreseen in advance on the topic of publication.
of, or during, enrolment. We abstracted selected studies independently of each other and
- High risk of bias: if the allocation sequence was known to the without masking of the trial names. Mediation was not necessary.
investigators who assigned participants, or if the study was quasi- We used an abstraction form detailing information for global bias
randomised. Quasi-randomised studies will be excluded for the risk assessment and potential subgroup analyses.
assessment of benefits but not for harms. We assessed selection and observation biases by abstracting core
trial methodologies to include inclusion and exclusion criteria,
Blinding randomisation, blinding, outcome definitions, and follow-up. We
- Low risk of bias: the trial was described as blinded, the parties used each trial’s enrolling definitions, duration of participant fol-
that were blinded, and the method of blinding was described so lowing, and surveillance methods in order to assess lead and lag-
that knowledge of allocation was adequately prevented during the time biases.
trial. Trials assessed as having ’low risk of bias’ in all individual domains
- Uncertain risk of bias: the trial was described as blinded, but were considered ’trials with low risk of bias’. Trials assessed as
the method of blinding was not described so that knowledge of having ’uncertain risk of bias’ or ’high risk of bias’ in one or more
allocation was possible during the trial. of the specified individual domains were considered trials with
- High risk of bias, the trial was not blinded so that the allocation ’high risk of bias’.
was known during the trial.
Incomplete outcome data
- Low risk of bias: the numbers and reasons for dropouts and Dealing with missing data
withdrawals in all intervention groups were described, or if it was
Analyses were planned for the primary categorical outcome mea-
specified that there were no dropouts or withdrawals.
sures with five potential scenarios to the intention-to-treat analy-
- Uncertain risk of bias: the report gave the impression that there
ses as able from the available published and author supplemented
had been no dropouts or withdrawals, but this was not specifically
data (Hollis 1999). These scenarios are described in the Cochrane
stated.
Hepato-Biliary Group Module (Gluud 2011) and are defined as
- High risk of bias: the number or reasons for dropouts and with-
the following:
drawals were not described.
◦ Carry-forward analysis: for all participants with
Selective outcome reporting
missing data, regardless of group, the last reported observed
- Low risk of bias: death and dialysis are reported on.
response will be used.
- Uncertain risk of bias: either death or dialysis is not reported on,
◦ Poor outcome analysis: assumes that all of the
or are not reported fully, or it is unclear whether data on these
participants with missing data (from either group) had the
outcomes were recorded or not.
outcome of interest.
- High risk of bias: either death or dialysis is not reported on; data
◦ Good outcome analysis: assumes that none of the
on these outcomes were likely to have been recorded.
participants with missing data (from either group) had the
Other bias
outcome of interest.
While each study was assessed qualitatively for unexpected sources
◦ Extreme-case favouring antibiotic therapy: assumes

that none of the participants with missing data from the Sensitivity analysis
antibiotic group had the outcome of interest, whereas all of those
We performed sensitivity analyses for pre-defined outcomes when
from the control group had the outcome of interest.
sufficient applicable trials were available.
◦ Extreme-case favouring control: assumes that all of the
Pre-planned analyses were (but ultimately not relevant in this re-
participants with missing data from the antibiotic group had the
view because of a lack of overlap of outcomes for analysis and sub-
outcome of interest, whereas none from the control group had
group):
the outcome of interest.
• Trials with low risk of bias compared to trials with high risk
of bias.
Assessment of heterogeneity • By presence of adequate methodological components
compared with unclear or inadequate components.
Heterogeneity was assessed using the Chi-square test and I-square
• By presence or absence of blinding.
statistic.
• By presentation forum (abstracts versus peer-reviewed
journal).
Data synthesis • By specificity of inclusion criteria.
• Iterative removal of trials from the meta-analysis to isolate
We attempted to assess each outcome on an intention-to-treat
sources of heterogeneity.
basis, though some trials failed to report the necessary data for this.
• Given sufficient number of selected trials (more than 10),
Trial context and methods were assessed to determine if pooling
we planned to perform funnel plot asymmetry analysis of trial
of their data was appropriate.
size against antibiotic treatment in order to assess small-trial
We used Cochrane’s Review Manager 5.1 software (RevMan 2011)
effects suggesting bias (Egger 1997).
to calculate individual trial estimates where appropriate generate
meta-analyses of trials’ estimates of effect as well as to perform sta-
bility analysis when indicated. When pooling of data was appro-
priate, we performed both fixed-effect and random-effects mod-
elling. We reported the fixed-effect result when there was no dif-
ference between them. Otherwise, we reported both results. Trials RESULTS
that assessed an antibiotic against placebo were analysed separately
from trials that assessed one antibiotic regimen with another one.
Subgroup analysis and investigation of heterogeneity Description of studies

Two subgroup categorisations appeared relevant after initial eval- See: Characteristics of included studies; Characteristics of excluded
uation of included trials: severe versus not-severe leptospirosis and studies.
troops or travellers versus endemic populations. However, these
subgroups when sufficiently distinguishable did not overlap sub-
stantively providing data (events) to inform trial objectives.
Results of the search
Where considerable heterogeneity was present (I2 > 50%), we eval-
uated trial differences such as patient population and trial defini- Record yields from each of the components of the search strategy
tions. and subsequent vetting of results is delineated in Figure 1.

Figure 1. Study flow diagram.

studies were from the 1950s. Two studies provided information
Included studies
relevant to adverse events of therapy. Their contributions are dis-
Seven trials met inclusion criteria and were incorporated ( cussed in that section.
Characteristics of included studies). Four of these were from the
last decade and three from the 1980s. One of the trials evaluated
Risk of bias in included studies
troops in a training area while the others assessed interventions in
resident populations. A determination of unclear bias was more common in older rather
than newer trials. The presence of sufficient evidence to identify
high risk of bias was present most frequently related to blinding.
Excluded studies Specific comments on risk of bias are provided (Characteristics
Five studies were excluded. Their details are provided ( of included studies), as is a summary of study performance with
Characteristics of excluded studies). Reasons for exclusion ranged regards to bias (Figure 2; Figure 3). Each of the seven included
from use of retrospective data and mixed infections to no disclo- trials were at unclear or high risk for at least one bias domain and
sure of definition for a patient’s disease. Four of the five excluded thus they fell into the group of trials with high risk of bias.
Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.

Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.

One trial excluded three patients for problems obtaining post dis-
charge following (Suputtamongkol 2004), one patient in the ce- compared with doxycycline; cephalosporin compared with doxy-
fotaxime group and two in the penicillin group. Data for death cycline. Inclusion criteria for these trials required laboratory con-
are given in the text under both the poor outcome scenario (which firmation of leptospirosis, though the laboratory definition varied.
also is the extreme case scenario favouring doxycycline against Low number of outcomes and qualitative vice quantitative descrip-
penicillin and cefotaxime) and good outcome scenario (which also tion of ventilator and dialysis requirements prevented assessment
is the extreme case scenario favouring penicillin and cefotaxime of the impact of therapy on these primary outcomes. None of the
against doxycycline). Data in the figures and tables reflect the poor trials assessed attempted to intervene on hospitalisation through
outcome scenario. They were not considered for other outcomes. antimicrobial therapy.
Carry forward analysis was not relevant to this situation. Antibiotics versus placebo
While all four trials that compared antibiotics with placebo did re-
Allocation
port mortality (McClain 1984; Edwards 1988; Watt 1988; Costa
Generation of allocation sequence was described adequately in five 2003), there were no deaths in two of them (McClain 1984; Watt
trials and allocation concealment adequately in four out of the 1988). Since odds ratio calculations cannot employ zero-event tri-
seven included trials. als, only two trials contributed to this estimate (Edwards 1988;
Costa 2003). The calculated fixed-effect OR (1.56, 95% CI 0.70
to 3.46) (Analysis 1.1), while not achieving statistical significance,
Blinding is in the direction that favours placebo (skewed rightward). How-
All seven included trials were either at high or unclear risk for bias ever, the estimate is driven by the larger trial (Costa 2003), and
related to blinding. Blinding methodology either was not reported the directions of effect in the two trials are opposite. Consistent
or not performed across trials. with this, the random-effects OR (1.16; 95% CI 0.23 to 5.95) is
smaller and less skewed. The heterogeneity suggested by this ran-
dom-effects and fixed-effect difference had an I2 of 50% though
Incomplete outcome data as event count was low in Edwards 1988; this under-represents
Attrition was well delineated or minimised in three of the seven the differences between the two trials regarding mortality. In con-
trials. In the single trial assessing azithromycin versus doxycycline trast to Costa 2003, the experimental penicillin group in Edwards
for the treatment of leptospirosis, nearly a third of randomised 1988 was favoured with 1 versus 3 deaths though it did not reach
patients were either not able to be assessed for post-discharge out- statistical significance.
come or unable to be categorised as having leptospirosis or scrub Only one trial reported days of hospitalisation without significant
typhus, or neither due to lack of suitable convalescent sera (Phimda effect (8.9 versus 8.8 days) (MD 0.10 days, 95% CI -0.83 to 1.03)
2007). Carry-forward analysis was not employed, however, the (Analysis 1.2) (Costa 2003). Days of clinical illness were decreased
other four scenarios for dealing with missing data are represented incorporating data from two of the trials (McClain 1984; Watt
with their relevant results. 1988). This reached statistical significance under fixed-effect mod-
elling; however, under random-effects modelling, the statistical
significance was lost (fixed-effect: MD -2.13 days, 95% CI -2.46
Selective reporting to -1.80; random-effects: MD -4.04 days, 95% CI -8.66 to 0.58)
(Analysis 1.3). I2 for ratio of true heterogeneity in the outcome
Two out of seven of the trials robustly reported on relevant out-
days of clinical illness was high (81%). The two incorporated trials
comes (Costa 2003; Panaphut 2003) while in the other trials it was
varied in several ways. One included presumably immune troops
less clear but possible that all intended observations were reported.
in a carefully monitored setting, while the other assessed relatively
severe disease among an endemic population.There was no differ-
Other potential sources of bias ence in days of fever (MD 0.30, 95% CI -1.26 to 1.86) (Analysis
1.5) (Edwards 1988). Three trials reported that therapy markedly
Only one trial was demonstrably free of academic and funding decreased subsequent isolation of leptospires from urine, though
biases (Costa 2003). sufficient data were not available to incorporate this outcome in
our analysis (McClain 1984; Edwards 1988; Watt 1988).
Effects of interventions Cephalosporin versus penicillin
This comparison was explored in two trials (Panaphut 2003;
Five main comparator groups existed among included trials: an-
Suputtamongkol 2004). Death and days of fever were assessable
tibiotics compared with placebo; cephalosporin compared with
across the trials, though for both outcomes the size of the estimate
penicillin; doxycycline compared with penicillin; azithromycin

of effect was small and did not reach statistical significance (MD 265 µmol/L) in 33% of patients in the penicillin group and 28%
-0.03 days, 95% CI -0.09 to 0.03) (Analysis 2.2). of patients in the placebo group. It was not possible from the
Results for death did not vary substantively with missing data available data to assess whether risk of dialysis explained the trend
analysis (poor outcome scenario: OR 0.65, 95% CI 0.23 to 1.87; towards increased death nor to appreciate to what extent this 5%
good outcome scenario: OR 0.72, 95% CI 0.23 to 2.21; extreme difference in initial renal involvement explained the trend towards
case scenario favouring cephalosporin: OR 0.56, 95% CI 0.19 to dialysis. Edwards 1988 et al reported that they employed an early
1.64; extreme case scenario favouring penicillin: OR 0.84, 95% peritoneal dialysis strategy in renal failure within their trial. Con-
CI 0.28 to 2.58) (Analysis 2.1). While I2 was low in the analysis sequently, their data was included in the analysis with Costa 2003
of death representing a low risk for heterogeneity, risk was high (Analysis 1.4). Heterogeneity between these two studies was low
for days of fever with an I2 of 94%. for this outcome, I2 of 0 and a result tending to favour the control
While both of these trials explored severe leptospirosis, their def- group (OR 1.54, 95% CI 0.91 to 2.60). Due to the possibility that
initions of such as well as their populations differed. Pooling of the professed Edwards 1988 early dialysis strategy was unevenly
these results may not be valid. applied, missing data analysis favouring the extreme case scenarios
Doxycycline versus penicillin were employed to test the potential impact on their trial. In neither
This comparison was explored ina single trial (Suputtamongkol case was statistical significance achieved (extreme case favouring
2004). There was no appreciable difference in either death (poor penicillin: OR 0.39, 95% CI 0.01 to 14.86, I2 84% (used random-
outcome scenario: OR 0.54, 95% CI 0.10 to 3.02; good outcome effects modelling); extreme case favouring control: OR 3.92, 95%
scenario: OR 1.10, 95% CI 0.15 to 8.00) (Analysis 3.1) or days CI 0.40 to 38.43; I2 63% (used random-effects modelling)). One
of fever within this trial (MD 0.00 days, 95% CI -0.25 to 0.25) excluded trial asserted that no difference was present in frequency
(Analysis 3.2). or severity of renal injury in treated as compared with untreated
Azithromycin versus doxycycline patients (Hall 1951), though it investigated a heterogenous group
This comparison also was explored in a single trial (Phimda 2007). of therapies. Edwards 1988 reported a single Jarisch-Herxheimer
Among the subset of patients who had confirmed leptospirosis reaction in a patient three hours after administration of penicillin.
time to defervescence was not significantly different between the This trial also reported iritis though it occurred in two instances in
two groups, median 45 hours (range 8 to 118) in the doxycycline the placebo group and in only one instance in the therapy group.
group, 40 hours (range 8 to 136) in the azithromycin group. Data A trial of azithromycin versus doxycycline for treatment of all com-
were not available to analyse mean difference. The authors re- ers suspected of either leptospirosis or scrub typhus demonstrated
ported the fraction of participants with leptospirosis who became two cessations of therapy for adverse events in the doxycycline
afebrile within 48 hours of initiation of therapy (Analysis 4.1). group (one patient with rash and the other with severe vomiting),
Odds of becoming afebrile quickly were similar in the two inter- but none in the azithromycin group (Phimda 2007). Proportions
vention groups (OR 1.51, 95% CI 0.57 to 4.00). Severe outcomes of adverse events also were higher in the doxycycline group, occur-
were not observed. ring in 28% versus 11% of patients. Thirty-seven of the 40 events
Cephalosporin versus doxycycline in the doxycycline group were mild to moderate gastrointestinal
This comparison was explored in a single trial (Suputtamongkol complaints, while one complaint of rash in the doxycycline group
2004). There was no appreciable difference in death (poor out- and two in the azithromycin group were reported. Two events of
come scenario: OR 0.45, 95% CI 0.04 to 5.1; good outcome sce- dizziness were reported only in the doxycycline group. The trial by
nario: OR 0.18, 95% CI 0.01 to 3.80) (Analysis 5.1). Phimda 2007 et al did not contribute information related to dial-
Adverse events ysis requirements. An included trial also assessed gastrointestinal
No adverse events were reported as attributed to cephalosporin complaints related to doxycycline (McClain 1984). No cessations
therapy. In the discussion of Costa 2003, the authors commented of therapy due to adverse events were reported by McClain 1984
that 4% of patients who died did so in the first three days of their et al. While the trial did not provide comparative proportions of
enrolment with a trend towards earlier death when it did occur adverse events, it reported mean duration of gastrointestinal com-
in the group receiving penicillin. As above noted, the trend for plaints among enrollees in both groups of the trial. Those in the
increased death in the intervention group did not reach statistical placebo group reported a mean 2.1 +/- 0.5 days of gastrointestinal
significance and was diminished when incorporating random-ef- upset in contrast to 1.1 +/- 0.3 days in the doxycycline group.
fects modelling in the setting of study heterogeneity. This was the
only trial to report dialysis rates, a pre-defined primary outcome
of interest in this review. Again, statistical significance was not
reached, but in that trial the estimate of effect favoured the placebo DISCUSSION
group with regards to need for dialysis. The baseline characteristics
table in that trial revealed a differential rate of severe renal failure
with serum creatinine levels greater than 3 mg/dL (approximately Summary of main results

The only result to achieve statistical significance (valid estimate of selections. These three trials with Edwards 1988 contributed all
effect across its 95% CI or P < 0.05), approximately a two-day re- of the mortality events. The trial of troops did not seem to have
duction in the number of days of clinical illness amongst patients significant baseline severity though it was not detailed in the report
on antibiotic therapy in contrast with placebo, lost statistical sig- (McClain 1984). Duration of illness at presentation also varied
nificance when assessed with random-effects modelling indicated across trials. Though, one trial had a high rate of exclusion due
by the apparent study heterogeneity. The effect may be greater for to death within 24 hours and another reported that most patients
severe disease. Neither a choice of antibiotics versus placebo nor had more than five days of symptoms, both suggesting later disease
cephalosporin versus penicillin statistically significantly impacted (Watt 1988; Costa 2003).
patient mortality. Differences in assessable outcomes between dif- Despite a lack of evidence of the utility of antibiotic therapy for
ferent antibiotic choices were small. Some authors asserted that leptospirosis, penicillin, cephalosporins, and doxycycline are com-
earlier therapy resulted in improved results, but supporting data monly employed therapies in the management of leptospirosis.
were not reported. Despite its higher cost, interest in azithromycin against Leptosira
Doxycycline-associated gastrointestinal complaints dominated the spp. is increasing due to its broad activity against confounding
adverse events in a single excluded study. While this was not mir- pathogens, low mean inhibitory concentration (MIC), and fewer
rored in the relevant included trials, it is consistent with findings mild adverse events (Phimda 2007; Ressner 2008).
on a review of antibiotic use for prophylaxis against leptospirosis Penicillin has been tested against placebo for the treatment of se-
(Brett-Major 2009). Dialysis was more common among penicillin vere leptospirosis. However, benefits were uneven across the pa-
recipients than those who received placebo (Costa 2003; Edwards tient populations and the nature of adverse events from therapy in
1988). The result did not reach statistical significance. While some severe disease is not clear. This makes a robust risk-benefit analysis
authors argue that a threshold of P < 0.1 may be more appropriate difficult. Further placebo controlled trials are needed.
in this type of analysis in order to account for the effect of unre-
ported data and publication bias on sensitivity (Leandro 2005),
the P value for this analysis result was 0.11 and the convention Quality of the evidence
remains P < 0.05. Additionally, this finding may be confounded
by an increased proportion of baseline severe renal dysfunction in The potential for bias in the trials was high and may reflect the
the penicillin group (Costa 2003). long period of time across which both the included and excluded
trials were conducted, consequently the literature practices of their
times. The most problematic issues were blinding and disclosure of
Overall completeness and applicability of the roles of commercial partners. Blinding was particularly difficult
evidence to accomplish in these trials because antibacterial agents against
gram negative pathogens were available to treatment teams when
Multiple databases without language restrictions were explored in not employing a cephalosporin for the trial intervention. The lack
the generation of this review. While an explicit test for publication of a placebo for these anti-gram negative pathogen agents such as
bias was relevant only for the outcome days of clinical illness for gentamicin increased variability in the trials and possibly intro-
antibiotics versus placebo, it was inconclusive. duced confounding, though use was generally well distributed be-
Several interesting observational studies and clinical trials have tween groups. The potential for misclassification of patients dur-
been executed on the treatment of leptospirosis over the past 60 ing intake into these types of trials is high. Edwards 1988, for
years. Nonetheless, the breadth of literature remains pleomorphic. instance, used clinical criteria for dengue as an exclusion criteria.
Four of the seven included trials in this review purported to assess However, clinical confusion between leptospirosis and dengue can
therapy in severe leptospirosis. However, in most cases clear defini- be high (LaRocque 2005).
tions of severity were not provided and the most severe presenting
patients - those with anuria, obtundation - excluded. In one trial,
roughly 90% of patients exhibited jaundice at baseline while severe
renal failure was present in 33% and 28% of the penicillin and
Potential biases in the review process
placebo groups, respectively, with more mild renal failure present Random errors are particularly problematic in reviews in which
in over 90% (Costa 2003). Another trial reported baseline jaun- few trials are contributing events to individual outcomes. Only
dice in 43% and 47% of the cephalosporin and penicillin groups, one author of two of the trials responded to this review when a
respectively, and approximately 80% with some renal failure in draft of this manuscript was sent 15 May 2011, Dr. Yupin Suputta-
both groups (Panaphut 2003). Some renal failure was present in mongkol. His clarification was very helpful for two of the reviewed
41%, 28%, 40% of the penicillin, doxycycline, cefotaxime groups trials (Suputtamongkol 2004; Phimda 2007). While only three
with 32%, 25%, and 35% prevalences of jaundice, respectively additional candidate references were identified on serial electronic
(Suputtamongkol 2004). In this trial doxycycline was favoured literature searches between initiation and repeat of the search, some
with patients of lower severity of illness against other antibiotic relevant pre-MEDLINE studies later excluded were identified only

by bibliographic or hard copy Cochrane Hepato-Biliary Group file Implications for research
review. As in any such review, relevant literature might have been
Further placebo controlled trials exploring antibiotic therapy for
missed. Publication bias towards those trials which show affirma-
carefully staged leptospirosis is needed. The question of whether
tive results is a well recognised concern. However, several negative
or not antibiotics should be used in leptospirosis remains open,
trials for most outcomes were present in both the included and
as does the optimal timing and severity in which to employ such
excluded trials.
therapy. Potential trials could include a wider array of tested agents
tried against placebo for therapy against leptospirosis. Careful
planning in such trials should be done for disease severity, targeted
outcomes such as minimisation of lost work days, prevention of
Agreements and disagreements with other hospitalisation, dialysis, and in areas where pulmonary manifes-
studies or reviews tations are dominant, ventilation as well as death. If antibiotics
confer true risk in leptospirosis therapy, their assessment might
The breadth of available data has evolved since the previous itera- include factorial research designs which simultaneously assess ad-
tion of this review (Costa 2003; Panaphut 2003; Suputtamongkol junctive therapies which might mitigate their effect. In the future,
2004; Phimda 2007). That review identified 12 relevant records trials ought to be conducted with less risk of systematic errors (bias)
meriting full-text evaluation and incorporated five trials (Guidugli and less risk of random errors (play of chance) and ought to be
2000). Like the earlier review, this review did not reveal evidence reported according to the CONSORT guidelines (www.consort-
compelling the use of antibiotic therapy for leptospirosis. statement.org).
ACKNOWLEDGEMENTS
AUTHORS’ CONCLUSIONS We thank the authors of the previous Cochrane review on this
topic for their work assessing the available literature on antibiotic
therapy for leptospirosis - F Guidugli, AA Castro, and AN Atal-
Implications for practice lah. Support from the Cochrane Hepato-Bilary Group remains
Insufficient evidence is available to advocate for or against the use outstanding from both the Trials Search Co-ordinator, Ms. Sarah
of antibiotics in the therapy for leptospirosis. Among survivors Klingenberg, and Dimitrinka Nikolova, Managing Editor.
who were hospitalised for leptospirosis, use of antibiotics for lep-
Protocol
tospirosis may have decreased the duration of clinical illness by
two to four days though this result was not statistically significant. Peer Reviewers: Vanja Giljaca, Croatia; Goran Poropat, Croatia.
Relatively severe and possibly late leptospirosis patients may have
Contact Editor: Christian Gluud, Denmark.
increased dialysis when penicillin is used rather than placebo, but
this result was driven by a single trial, the estimate of effect was Review
small and it did not reach statistical significance. If a clinician
Peer Reviewers: Vanja Giljaca, Croatia; Goran Poropat, Croatia.
chooses to utilize antibiotic therapy, there is no evidence to suggest
that selection of penicillin, doxycycline, or cephalosporin impacts Contact Editor: Ronald Koretz, United States; Christian Gluud,
mortality or duration of fever. Denmark.
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Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Costa 2003
Methods Prospective, single site, randomised, clinical trial.
Participants All comers to a regional hospital with four days of symptoms and a WHO leptospirosis
score of at least 26, predominantly men in the 3rd to 5th decade of life. 247 of 253
patients had a positive macroscopic slide agglutination test for leptospirosis, 45 a micro-
agglutination test (MAT) and 17 a positive blood culture for Leptospira.
Interventions PCN 1 million units parentally every four hours for seven days against no targeted
antimicrobial therapy
Outcomes Death, length of hospitalisation, and dialysis.
Notes Approximately 94% of their patients in both groups had icterus suggesting that this rep-
resented a trial of therapeutic efficacy in late disease. Multiple biomarkers were collected
at days 0, 3, and 7 from admission. Authors reported no difference between groups but
did not discuss changes over time
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Unclear risk P 142, “each patient... and was randomly
bias) assigned to... .” though no description of
method of randomisation to include se-
quence generation was provided
Allocation concealment (selection bias) Unclear risk Not discerned.
Blinding (performance bias and detection High risk P 143, “Even though in the present study
bias) the treating physicians were not blind to
All outcomes the patient assignment”
Incomplete outcome data (attrition bias) Unclear risk Not discerned.

All outcomes
Selective reporting (reporting bias) Low risk P 143, Table 2 outcome data for death cal-
culated for same numbers as shown in Ta-
ble 1 Demographics
Other bias Low risk P 144, trial executed using public grants.

Edwards 1988
Methods Prospective, single site, randomised, clinical trial.
Participants All comers for who there was a clinical suspicion of icteric leptospirosis later diagnosed
through culture or convalescent titer rise. They were predominantly men in the fourth
decade of life
Interventions 2 million units of intravenous penicillin every 6 hours for 5 days or saline
Outcomes Time to defervescence, clearance of urine culture, normalisation of laboratory values,

renal failure, and death
Notes This trial targeted severe leptospirosis. Serum biomarkers collected on admission had
high standard deviations though reportedly 7 of 38 and 8 of 41 patients in the penicillin
and placebo groups, respectively, had renal failure on admission
Risk of bias
Random sequence generation (selection Low risk P 388, while the method of randomisation
bias) is not explicitly stated, authors reference a
source with several approaches to randomi-
sation
Blinding (performance bias and detection Unclear risk P. 388, the trial used a saline placebo and
bias) stated that the investigator involved in al-
All outcomes location was not involved in management,
but there is no explicit mention of blinding
Incomplete outcome data (attrition bias) Unclear risk Not discerned.

All outcomes
Selective reporting (reporting bias) Low risk Death was reported. While renal failure and
not dialysis was reported, authors stated
that they employed early peritoneal dialysis
in renal failure so that assertion applied in
the dialysis analysis incorporating missing
data outcome scenarios
Other bias Unclear risk Not discerned.

McClain 1984
Methods Prospective, single site, blinded, randomised, clinical trial
Participants Troops presenting for care with fever and subsequent verified leptospirosis serology or
culture at the Jungle Operations Training Center, Panama. 26 of 29 patients had positive
blood cultures for Leptospira.
Interventions Seven day course of twice daily doxycyline hyclate 100 mg or placebo
Outcomes Assessed clearing of cultures and resolution of fever.
Notes This trial evaluated therapeutic efficacy in early disease.
Risk of bias
Random sequence generation (selection Low risk P. 697, “packets were randomly assigned by
bias) computer to contain doxycycline hyclate or
lactose”
Allocation concealment (selection bias) Low risk P. 696, “assigned sequentially numbered
packets of tablets that were identical in ap-
pearance”
Blinding (performance bias and detection Unclear risk Not discerned.

bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk P. 697, “after discharge, patients were fol-
All outcomes lowed every other day for 1 week and once
a week thereafter for 2 weeks”
Selective reporting (reporting bias) Unclear risk Pre-defined study outcomes inconsistent
with those listed in the Types of Outcomes
section, though death did not occur and
was discernible from the published data
Panaphut 2003
Methods Prospective, single-site, randomised, comparative trial.
Participants Adult patients presenting with severe leptospirosis, predominantly men in the 4th
through 6th decades of life with an average WHO leptospirosis score 23 to 24. Labora-
tory confirmation by titer or culture was required for inclusion in analysis. All 173 had
a positive rapid test for leptospirosis, only 126 were confirmed by MAT

Panaphut 2003 (Continued)
Interventions Antibiotics for seven days or until afebrile for 48 hours: ceftriaxone 1gm parenterally
daily or penicillin 1.5 million units every 6 hours with the addition of gentamicin if also
suspicious for gram negative sepsis
Outcomes Death, duration of fever, and renal failure.
Notes All deaths occurred within five days of hospitalisation - 5 pulmonary haemorrhage, 2
multi-organ failure, 1 severe hyperK, uraemic encephalopathy, 1 ARDS. However, causes
are not delineated by treatment group. It is unclear for how long patients who received
penicillin also received gentamicin. Those patients treated with ceftriaxone had higher
rates of prior treatment with doxycycline and penicillin. Standard deviation on mean
days of fever were not provided so substituted the range of absolute difference
Risk of bias
Random sequence generation (selection Low risk P. 1508, “patients were randomly allocated
bias) into 2 groups by stratified-block randomi-
sation”
Allocation concealment (selection bias) Low risk P. 1508, “each label was enclosed in a sealed,
opaque envelope”
Blinding (performance bias and detection High risk P. 1508, the ceftriaxone and penicillin
bias) groups had different medication adminis-
All outcomes tration regimens, each day versus four times
daily. The addition of gentamicin among
penicillin recipients when gram negative
sepsis had not been excluded increased the
likelihood that observers were aware of
treatment allocation
Incomplete outcome data (attrition bias) Low risk p1509, causes for exclusion from the trial
All outcomes and analyses were clearly enumerated. P
1509-10, “For those who did not return for
follow-up after being discharged from the
hospital, data regarding their physical con-
ditions after discharge were obtained indi-
vidually by direct contact of local health
care personnel. All of the patients [who had
not returned] completely recovered from
the illness.”
Selective reporting (reporting bias) Unclear risk P. 1510, “Ten patients (5 in each group)
died, for an overall case mortality rate, 5.
8%” which is correct for the number of
patients reported to have been included.
While burden of renal failure was reported

Panaphut 2003 (Continued)
as was an overall dialysis rate of more than

10 per cent, dialysis was not discernible in
each trial arm
Other bias Unclear risk P. 1507, Ceftriaxone was provided by Siam

Pharmaceutical. No statement regarding
the role of funding agents was provided
Phimda 2007
Methods Prospective, multi-site, randomised, clinical trial.
Participants Patients over 14 years of age with suspected leptospirosis or scrub typhus as described by
acute fever without clear source of infection and able to tolerate oral antibiotic therapy.
Among all randomised patients (pre-diagnosis), this study had the lowest ratio of men:
women of approximately 2.5:1, predominantly in the 4th decade of life. Laboratory
confirmation by titer or culture was required for inclusion in analysis. 10 patients were
identified by culture, 45 by four-fold rise in convalescent titer and 1 by a single titer of
at least 1:400
Interventions Oral doxycycline 200mg for 1 dose then 100 mg every 12 h for 7 days, or azithromycin
1 g for 1 dose then 500 mg once daily for 2 days
Outcomes The primary outcome for this trial was rate of cure defined by afebrile for 48 hours
Notes This trial was designed as a non-inferiority trial of azithromycin against doxycycline
among febrile patients. Data presented here was provided on correspondence with the
senior author, Dr. Suputtamongkol, who verified for the authors results among those
enrolled patients with laboratory confirmed leptospirosis
Risk of bias
Random sequence generation (selection Low risk P. 3260, “Independent, computer-gener-

bias) ated, simple random allocation sequences
were prepared for each study hospital by
the investigator team in Bangkok.”
Allocation concealment (selection bias) Low risk P. 3260, “These were sealed in an opaque
envelope and numbered. The investigator
in each study hospital assigned study partic-
ipants to their treatment groups after open-
ing the sealed envelope.”
Blinding (performance bias and detection High risk P. 3260, the two intervention options were
bias) dosed differently and were not used in con-
All outcomes junction with placebo

Phimda 2007 (Continued)
Incomplete outcome data (attrition bias) High risk P. 3260, confirmation of leptospirosis de-
All outcomes pended upon analysis of both acute and
convalescent sera. 89 of 296 patients who
were randomised were not assessed at 1 to 2
weeks following discharge. For 23 of these
patients nearer term sera 3 to 5 days follow-
ing admission was available and used for
assessing interval titer
Selective reporting (reporting bias) High risk Pre-defined outcome was time to deferves-
cence and whether outcomes in the Types
of Outcomes section were completely dis-
cerned was not discernible
Suputtamongkol 2004
Methods Prospective, multi-site, randomised, comparative trial.
Participants Adults with less than 15 days of fever and laboratory confirmation of leptospirosis (all
but two with both serology and culture positivity). In contrast to the other trials, roughly
3 of 4 (rather than 9 of 10) of the participants were men. Age ranges included mid-late
adolescents and geriatric patients though median was in the 4th decade of life
Interventions This trial assessed three treatment groups of parenteral induction therapy with penicillin
1.5 million units every six hours, cefotaxime 1gm six hours, or doxycycline loaded with
200 mg then 100 mg twice daily; then, once afebrile and tolerating oral therapy, penicillin
and cefotaxime patients were randomised to either amoxicillin 2 g per day or doxycycline
200 mg per in divided doses, while those who started with doxycycline transitioned to
oral doxycycline therapy. Total course of therapy was 7 days
Outcomes Death and duration of fever.
Notes Two patients in the penicillin group and one in the cefotaxime group were excluded for
uncertain outcomes. They were included in these analyses as deaths. While the researchers
prospectively characterised disease severity at inclusion, outcome data were not stratified
by disease severity. The researchers assert that in multi-variate analysis disease severity
(at least two organs with dysfunction) and not antibiotic choice impact days of fever,
though only level of statistical significance and not strength of effect are provided. As
standard deviation was not provided for the duration of fever, an over-estimate based upon
the range and presuming near normal distribution were used.
Risk of bias

Suputtamongkol 2004 (Continued)
Random sequence generation (selection Low risk P. 1418, “The independent, computer-gen-
bias) erated random allocation sequences were
prepared”
Allocation concealment (selection bias) Low risk P. 1418, “sealed in an opaque envelope, and
the envelopes were numbered.”
Blinding (performance bias and detection High risk P. 1418, each administered regimen dif-
bias) fered and required investigator knowledge
All outcomes of regimen in order to adjust for the possi-
ble presence of gram negative sepsis
Incomplete outcome data (attrition bias) Unclear risk P. 1419 Table 1, while the number of ex-
All outcomes cluded patients due to uncertain outcome
is provided, details and success of the fol-
lowing component of the protocol is not
disclosed
Selective reporting (reporting bias) Unclear risk Death was reported. Dialysis was not dis-
cernible.
Watt 1988
Methods Prospective, single site, randomised, double-blind, placebo clinical trial
Participants Patients over 16 years of age presenting to a national infectious diseases hospital with
suspected leptospirosis and either a positive rapid IgM-based immunosorbent assay or
a positive single serovar microagglutination assay, all later confirmed with multi-serovar
based serologic assays or culture. Only 7 participants had positive Leptospira cultures.
The patients were predominantly men 20 to 40 years of age
Interventions 1,500,000 units of parenteral sodium penicillin G administered four times daily for 7
days or a normal saline placebo
Outcomes Durations of fever and serum creatinine rise.
Notes The trial was intended to focus on more severe disease but anuric patients or those so
severely ill that they could not provide consent were excluded, and no deaths or re-
quirements for dialysis occurred. Second infections were disqualifying, but the screening
algorithm for potential co-endemic diseases was not provided. Patients were categorised
as severely infected if serum creatinine was > 177 µmol/L or the patients were clinically
jaundiced
Risk of bias

Watt 1988 (Continued)
Random sequence generation (selection Unclear risk P. 433, “randomly assigned to receive
bias) sodium penicillin G or placebo,” method
of randomisation not disclosed
Blinding (performance bias and detection Unclear risk Not discerned.

bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk P. 433, “patients were followed up a week
All outcomes and a month after discharge;” p434, all lep-
tospirosis patients completed therapy
Selective reporting (reporting bias) High risk Pre-defined outcome was time to deferves-
cence and serum creatinine and whether
outcomes in the Types of outcomes sec-
tion were completely discerned was not dis-
cernible
ARDS = acute respiratory distress syndrome.

IgM = immunoglobulin M.
h = hour.
g = gram.
µmol/L = micromole.
> = greater than.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Doherty 1955 This retrospective study assessed 115 cases of leptospirosis among Australian troops. The study attempts an analysis
of the impact of increasing dose of penicillin on shortening of the duration of fever. It suggests mild decreases (1
to 2 days) of duration of fever and well describes the fever curve of untreated and treated leptospirosis. It did not
contribute information on adverse events
Fairburn 1956 This study prospectively assessed British troops deployed to an endemic area (Malaya). Ill troops with suspected
leptospirosis all of who were mildly ill were divided among three groups: control, penicillin therapy or chloram-
phenicol therapy. A case definition for leptospirosis was not provided. Confirmation by a serologic method or cul-
ture was reported in 50 of the 83 patients. However, the results could not be explored based upon this confirmation
and serologic categorizations and methods have evolved considerably since study execution. No information on
randomisation was provided. Adverse events of therapy were not discussed

(Continued)
Hall 1951 This study reports treatment performance in 67 cases of leptospirosis in Puerto Rico. Chloramphenicol, aureomycin,
penicillin, terramycin, streptomycin, aureomycin and streptomycin, cortisone and aureomycin were employed. The
article implies that these treatment groups were undertaken prospectively and sequentially in block, however it
acknowledges variability in how the treatments were applied. Also it was unclear whether twelve contemporary
controls were used in their analyses. With regards to adverse events, the study asserted that there was no difference
in the frequency or severity of renal injury between treated and untreated patients
Munnich 1972 This is a single arm observational study of an oral ampicillin formulation of ampicillin in the treatment of lep-
tospirosis. The study did not report any adverse events. The observational series appears to have continued with a
related amoxycillin formulation in Chemotherapy 1976;22(6):372-80
Russell 1958 This study prospectively assessed British troops deployed to an endemic area (Malaya). Ill troops with suspected
leptospirosis divided among two groups: ascorbic acid placebo or parenteral oxytetracycline. Definition for lep-
tospirosis in a patient was not provided. Confirmation by a serologic method or culture was reported to have
occurred in all 52 patients. However, the results could not be explored based upon this confirmation, and serologic
categorisations and methods have evolved considerably since study execution. The patients were alternately placed
in each group without randomisation. This test drug is no longer employed in common practice

DATA AND ANALYSES
Comparison 1. Antibiotics versus placebo
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Death 4 403 Odds Ratio (M-H, Random, 95% CI) 1.16 [0.23, 5.95]
2 Days of hospitalisation 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
3 Days of clinical illness 2 71 Mean Difference (IV, Random, 95% CI) -4.04 [-8.66, 0.58]
4 Dialysis employed 2 332 Odds Ratio (M-H, Fixed, 95% CI) 1.54 [0.91, 2.60]
5 Days of fever 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
Comparison 2. Cephalosporin versus penicillin
No. of No. of
1 Death 2 351 Odds Ratio (M-H, Fixed, 95% CI) 0.65 [0.23, 1.87]
2 Days of fever 2 348 Mean Difference (IV, Fixed, 95% CI) -0.03 [-0.09, 0.03]
Comparison 3. Doxycycline versus penicillin
No. of No. of
1 Death 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
2 Days of fever 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
Comparison 4. Azithromycin versus doxycycline
No. of No. of
1 Afebrile within 48 hours of 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
initiation of therapy

Comparison 5. Cephalosporin versus doxycycline
No. of No. of
1 Death 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
HISTORY
Protocol first published: Issue 1, 2010
Review first published: Issue 2, 2012
CONTRIBUTIONS OF AUTHORS
Conceiving the review: [pre-existing]
Designing the review: DMB.
Co-ordinating the review: DMB.
Data collection for the review: DMB.
Developing search strategy: DMB, RC, CHBG Staff.
Undertaking searches: DMB, CHBG Staff.
Screening search results: DMB, RC.
Organising retrieval of papers: DMB.
Screening retrieved papers against inclusion criteria: DMB, RC.
Appraising quality of papers: DMB, RC.
Abstracting data from papers: DMB, RC.
Writing to authors of papers for additional information: DMB.
Providing additional data about papers: DMB by responding authors.
Obtaining and screening data on unpublished studies: for abstracts, DMB.
Data management for the review: DMB.
Entering data into RevMan: DMB.
Analysis of data: DMB, RC.
Interpretation of data: DMB, RC.
Providing a methodological perspective: DMB, RC.
Providing a clinical perspective: DMB, RC.
Providing a policy perspective: DMB, RC.
Providing a consumer perspective: DMB, RC.
Writing the review: DMB, RC.
Providing general advice on the review: CHBG Staff.
Securing funding for the review: NA.
Performing previous work that was the foundation of current study: NA.
DECLARATIONS OF INTEREST
None known.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW
Multiple analyses for missing data were not indicated. Handling of three patient outcomes in a specific case is discussed (Risk of bias
in included studies).
NOTES
This review replaces the review by Guidugli et al (Guidugli 2000).
Additional affiliations.
DMB - Program Director, U.S. Military Tropical Medicine, Navy Medicine Manpower Personnel Training and Education (NAVMED
MPT&E), Bethesda MD; and, Assistant Professor, Divisions of Tropical Public Health and Infectious Diseases, Departments of
Preventive Medicine and Biometrics, and Medicine, Uniformed Services University, Bethesda MD.
RC - Director, Division of Tropical Public Health, Department of Preventive Medicine and Biometrics, Uniformed Services University,
Bethesda MD.
These views are those of the authors and do not necessarily reflect those of Navy Medicine Manpower, Personnel, Training & Education
Command, Departments of the Army or Navy, Uniformed Services University, Department of Defense, or the U.S. Government.
INDEX TERMS
Medical Subject Headings (MeSH)
Anti-Bacterial Agents [∗ therapeutic use]; Cephalosporins [therapeutic use]; Doxycycline [therapeutic use]; Leptospirosis [∗ drug therapy;
mortality]; Penicillins [therapeutic use]; Randomized Controlled Trials as Topic
MeSH check words

Humans


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Antibiotics for leptospirosis (Review)

Brett-Major DM, Coldren R

Antibiotics for leptospirosis (Review)

Antibiotics for leptospirosis (Review) i

Antibiotics for leptospirosis

David M Brett-Major1 , Rodney Coldren2

Editorial group: Cochrane Hepato-Biliary Group.

PLAIN LANGUAGE SUMMARY

Antibiotics for the treatment of leptospirosis

METHODS Secondary outcomes

• Days lost from work or travel.

Antibiotics for leptospirosis (Review) 3

We followed the instructions in The Cochrane Handbook for Sys-

Antibiotics for leptospirosis (Review) 4

Antibiotics for leptospirosis (Review) 5

Subgroup analysis and investigation of heterogeneity Description of studies

Antibiotics for leptospirosis (Review) 6

Antibiotics for leptospirosis (Review) 7

Antibiotics for leptospirosis (Review) 8

Antibiotics for leptospirosis (Review) 9

Antibiotics for leptospirosis (Review) 10

Antibiotics for leptospirosis (Review) 11

Antibiotics for leptospirosis (Review) 12

Antibiotics for leptospirosis (Review) 14

Antibiotics for leptospirosis (Review) 15

Characteristics of included studies [ordered by study ID]

Methods Prospective, single site, randomised, clinical trial.

Outcomes Death, length of hospitalisation, and dialysis.

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk Not discerned.

Incomplete outcome data (attrition bias) Unclear risk Not discerned.

Antibiotics for leptospirosis (Review) 16

Methods Prospective, single site, randomised, clinical trial.

Outcomes Time to defervescence, clearance of urine culture, normalisation of laboratory values,

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk Not discerned.

Incomplete outcome data (attrition bias) Unclear risk Not discerned.

Other bias Unclear risk Not discerned.

Antibiotics for leptospirosis (Review) 17

Methods Prospective, single site, blinded, randomised, clinical trial

Outcomes Assessed clearing of cultures and resolution of fever.

Notes This trial evaluated therapeutic efficacy in early disease.

Bias Authors’ judgement Support for judgement

Blinding (performance bias and detection Unclear risk Not discerned.

Other bias Unclear risk Not discerned.

Methods Prospective, single-site, randomised, comparative trial.

Antibiotics for leptospirosis (Review) 18

Outcomes Death, duration of fever, and renal failure.

Bias Authors’ judgement Support for judgement

Antibiotics for leptospirosis (Review) 19

as was an overall dialysis rate of more than

Other bias Unclear risk P. 1507, Ceftriaxone was provided by Siam

Methods Prospective, multi-site, randomised, clinical trial.

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk P. 3260, “Independent, computer-gener-

Antibiotics for leptospirosis (Review) 20

Other bias Unclear risk Not discerned.

Methods Prospective, multi-site, randomised, comparative trial.

Outcomes Death and duration of fever.