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BMJ  2004;328:1339 (5 June),
doi:10.1136/bmj.328.7452.1339

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Paper

Effectiveness of antibiotics in preventing meningococcal disease after
a case: systematic review
Bernadette Purcell,
specialist registrar1, Susanne
Samuelsson, consultant
epidemiologist2, Susan J M
Hahné, European Programme for Intervention Epidemiology
training fellow3, Ingrid
Ehrhard, consultant
microbiologist4, Sigrid
Heuberger, consultant
microbiologist5, Ivonne
Camaroni, European Programme for Intervention Epidemiology
training fellow3, André
Charlett, head6, James
M Stuart, consultant
epidemiologist1

1 Communicable Disease Surveillance Centre
South West, Gloucester GL10 3RF, 2 Statens Serum Institut,
Copenhagen, Denmark 2300, 3 Communicable Disease Surveillance
Centre, Cardiff, Wales CF4 3QX, 4 Landesuntersuchungsanstalt
für das Gesundheits und Veterinärwesen, Dresden, Germany 01099,
5 National Reference Centre for Meningococci, Graz, Austria
A-8010, 6 Public Health Laboratory Service Statistics Unit,
Colindale, London NW9 5EQ

Correspondence to: J Stuart james.stuart{at}hpa.org.uk

Abstract

Top
Abstract
Introduction
Methods
Results
Discussion
References

Objective
To summarise the evidence for the role of antibiotics in
preventing further cases of meningococcal disease through
chemoprophylaxis given to the index patient, household
contacts, and children in day care settings after a single
case.

Design Systematic review.

Methods Studies were identified by searching Embase
(1983-2003), Medline (1965-2003), and CAB Health (1973-2003)
and by contacting the World Health Organization and the
European meningococcal disease surveillance network and
examining references of identified papers. The review included
all studies with at least 10 cases in which outcomes were
compared between treated and untreated groups.

Main outcome measure Subsequent cases of meningococcal
disease 1-30 days after onset of disease in the index
patient.

Results Four observational studies and one small trial met
the inclusion criteria. Meta-analysis of studies on
chemoprophylaxis given to household contacts showed a
significant reduction in risk (risk ratio 0.11, 95% confidence
interval 0.02 to 0.58). The number needed to treat to prevent a
case was estimated as 218 (121 to 1135). Primary outcome data
were not available in studies of chemoprophylaxis given to the
index patient: when prophylaxis had not been given, rate of
carriage after discharge from hospital was estimated as 3% (0
to 6), probably an underestimate of the true rate. No studies
of chemoprophylaxis in day care settings were identified that
met the inclusion criteria.

Conclusion There have been no high quality experimental
trials looking at control policies for meningococcal disease.
The best available evidence is from retrospective studies. The
risk of meningococcal disease in household contacts of a
patient can be reduced by an estimated 89% if they take
antibiotics known to eradicate meningococcal carriage.
Chemoprophylaxis should be recommended for the index patient
and all household contacts.

Introduction

Top
Abstract
Introduction
Methods
Results
Discussion
References

The
severity of meningococcal disease and its tendency to cause
clusters, mainly among household contacts of an index patient,
means strategies to reduce the risk of further cases are of
high priority. However, the lack of evidence for strategies
to control meningococcal disease is a well recognised obstacle
in the development of coherent policies1
and is reflected in the variation in approach across
Europe.2

Chemoprophylactic treatment to eradicate nasopharyngeal carriage
and to interrupt further transmission has been a key approach
to control for more than 50 years.3
Most European countries recommend a short course of rifampicin
or ciprofloxacin for all household contacts—taken here to mean
those people living in the same household or having an
equivalent degree of contact with the index patient. This
approach is biologically plausible. The effect of rifampicin in
preventing subsequent cases of meningitis caused by
Haemophilus influenzae has, indeed, been demonstrated in
a randomised placebo-controlled trial.4
However, the effectiveness of chemoprophylaxis for
meningococcal disease has never been demonstrated in
experimental research, and evidence cited in support has been
limited to one observational study.5
Failures of this approach have been reported,6-8
and there is evidence of overprescribing.9
A different policy is recommended in Norway, where household
members below 15 years of age are treated as though they have
early meningococcal disease. They are kept at home and given
oral penicillin for seven days, the period of maximum
risk.

Some national policies also recommend chemoprophylaxis to the
index case before discharge from hospital, on the premise that
the pathogenic strain may otherwise be reintroduced by the
index patient into the household. However, contradictory
findings regarding carriage of the pathogenic meningococcal
strain after full antibiotic treatment of the index patient are
reflected in different recommendations. For example, policy in
Denmark, Norway, and Sweden does not recommend prophylaxis for
the index patient, whereas it is recommended in the United
Kingdom, Canada, the United States, Spain, and Germany.

There are no uniform recommendations as to how contacts should
be managed in day care settings (children aged 0-6 years). The
national control policies of the United Kingdom and Denmark
recommend chemoprophylaxis only after the second case in a day
care setting, whereas other countries such as Ireland, Sweden,
Spain, and Germany recommend chemoprophylaxis after a single
case.

There is a new impetus to improve coordination of infectious
disease control across countries in the European Union.10
A prerequisite for better coordination is a shared
understanding of the evidence on which recommendations for
disease prevention and control are based. To further this aim
the European Monitoring Group on Meningococci formed a working
group to conduct a systematic review of interventions for
meningococcal disease where there was greatest variation
between countries. Here we have evaluated the effectiveness of
giving chemoprophylaxis to the index patient and to contacts in
households and childcare settings.

Methods

Top
Abstract
Introduction
Methods
Results
Discussion
References

Study
inclusion and characteristics
We included all studies that had
clear intervention and non-intervention groups, including
experimental (randomised and non-randomised trials),
observational studies, and case series with a minimum of 10
cases. We excluded case reports and opinions of authorities or
committees. We did not restrict by date, country, or language
of publication. We included in the intervention group those
people who were given prophylactic antibiotic regimens
considered effective in eradicating meningococcal carriage (for
example, for adults, rifampicin 600 mg orally twice a day for
two days, ciprofloxacin 500 mg orally single dose, ceftriaxone
250 mg intramuscular single dose). Those not given prophylactic
antibiotics or given antibiotics considered ineffective at
eradicating carriage (for example, penicillin) were included in
the non-intervention group.

The primary outcome was specified a priori as the rate of
subsequent cases 1-30 days after an index case, where a
subsequent case was defined as another case among household
contacts of the index patient (or for the day care analysis as
another case in the same day care setting). We included only
those studies that described at least one month of follow up
after the index case. The other main outcome of interest was
the rate of nasopharyngeal carriage of the pathogenic organism
in the index patient on discharge from hospital.

Search strategy
We searched the Cochrane register
of trials and systematic reviews, the database of abstracts of
reviews of effectiveness, the health technology assessment and
the national research register in England and Wales, Medline
1966-2003, Embase 1983-2003, and CAB Health 1973-2003. The text
word terms and MESH headings used were: meningococcal
infections, Neisseria meningitidis, chemoprevention,
prophylaxis, chemoprophylaxis, antibiotics, drug therapy,
primary health care, patient care management, community health
services, communicable disease control, disease outbreaks,
disease transmission, cluster, outbreak, carrier state, cases,
household. We checked bibliographies of existing reviews and
the identified studies. We contacted the Cochrane Acute
Respiratory Infections group, the World Health Organization,
and the European Monitoring Group on Meningococci.

Data extraction and synthesis
The full texts of all
potentially relevant articles were obtained and two reviewers
independently checked the data. If more than one paper with the
same data was identified only that which contained the
definitive data was included. A third reviewer from the group
was available to resolve any disagreements.

Statistical methods
The meta-analyses were
performed with the "meta" command in Stata (StataCorp, College
Station, TX).11
Combined estimates of the risk ratio and the absolute risk
reduction (or risk difference) were obtained by assuming that
the treatment effects from the different studies had a
distribution (random effect) rather than a common treatment
effect (fixed effect). In those studies where there were no
cases in either the treated or untreated groups we added 0.5 to
all four cells. When there were no cases in the intervention
and control groups, we did not estimate risk ratios and the
study was excluded from the pooled risk ratio. We used the
DerSimonian and Laird approach, in which an estimate of
variation within studies is combined with an estimate of
variation between studies.

To estimate the pooled relative risk we used the natural logarithm
and back transformed results to obtain an estimated relative
risk. The number needed to treat was the reciprocal of the
estimated absolute risk reduction. We used a fixed effect
approach with an inverse variance method to pool the carriage
rates. The effects were pooled in the same manner in the two
groups. We tested statistical heterogeneity with 2 tests,
with pre-specified potential sources of heterogeneity.

Results

Top
Abstract
Introduction
Methods
Results
Discussion
References

The
search identified 2606 papers. After reviewing titles and
abstracts we retrieved 102 as potentially relevant. Of these,
five studies met the criteria for this review. Of the excluded
reports, many were descriptive accounts of outbreaks and case
reports, some addressed a different set of questions or did
not evaluate an intervention, and others did not report the
outcomes of primary interest or had no comparison group. We
did not identify any studies of day care and nursery schools
that met our criteria.

Evidence of benefit from chemoprophylaxis to household
contacts
Five studies satisfied our inclusion criteria, four
retrospective cohort studies and one small trial.5
12-15
In total they involved 1249 sporadic cases of meningococcal
disease and about 4271 household contacts. The only
experimental study was a small randomised trial within a larger
seroepidemiological survey.12
Fifty four contacts from 11 affected households were randomised
to receive rifampicin (35) or no treatment (19). No subsequent
cases occurred in either group after nine months (table
1).

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Table 1 Effectiveness of
antibiotics to contacts after case of meningococcal disease:
study characteristics

The largest and most frequently cited study used enhanced
surveillance of a case series in 27 US states between 1973 and
1974.5
This paper partly duplicated earlier findings.16
They found an attack rate of 4.2/1000 among untreated household
contacts and no cases among treated contacts (table
2). This difference suggests that chemoprophylaxis is
effective (relative risk 0.15, 95% confidence interval 0.01 to
2.79) but not significant.

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Table 2 Estimate of effect of
chemoprophylaxis given to household contacts after sporadic
case of meningococcal disease

In a survey of meningococcal disease in the Netherlands from
April 1989-May 1990,14
a secondary objective was to assess the attack rate among
household contacts and document the uptake of chemoprophylaxis.
Although it was not official policy to give chemoprophylaxis in
the Netherlands during the study period, 55% (627 people from
220 families) of close contacts had received antibiotics. There
were 502 primary cases reported during the study period.
Information was available on 1130 household contacts in 75%
(378) of these cases, and on antibiotics for 98% (1102) of
these contacts. In the 30 day period after occurrence of the
index case, there were four subsequent cases among 826 contacts
that did not receive adequate chemoprophylaxis (including two
in people who received penicillin) and no cases among 276 who
had "optimal" treatment (0.33, 0.02 to 6.14, table
2).

In a study to evaluate the efficiency of the implementation
of prophylactic measures in Denmark,15
there were no cases among 724 treated contacts and two among 72
who were not treated (0.02, 0.00 to 0.42, table
2). The two subsequent cases were in friends of the index
patients who had slept in the same room as their respective
index case. No further information was available on 56% of
cases (table
1).

Kristiansen's study, among the 165 000 inhabitants of Telemark
in Norway, examined whether a policy of targeted prophylaxis
with rifampicin for contacts carrying the meningococcal strain
that caused the disease could limit the spread of infection
more efficiently than treatment with penicillin alone to
household members aged under 15 years.13
No subsequent cases occurred among 441 potential contacts
screened and treated with rifampicin compared with 15 (11
confirmed) cases in 1984-87, when only penicillin was given.
Although this study suggests benefit from the targeted
intervention, we could not measure risk reduction as the number
of contacts was not available for the earlier time period. The
follow up period was much longer and the contact definitions
were much broader than the definitions used for our
review.

Summary effect estimates for chemoprophylaxis versus no
treatment
Three studies, in the United States, Denmark, and
the Netherlands, had sufficiently similar characteristics
(clinical homogeneity) for inclusion in the
meta-analysis.5
14
15
We did not include Kaiser's study12
as there were no events in treatment or intervention
group.

The summary risk ratio was 0.11 (0.02 to 0.58; figure).
This implies that chemoprophylaxis given to household contacts
after a case of meningococcal disease reduces the risk of
subsequent cases by 89%. Results of tests for heterogeneity
were not significant (P = 0.39). The pooled absolute risk
reduction was 46/10 000 (9/10 000 to 83/10 000), and the number
needed to treat to prevent a case was estimated as 218 (121 to
1135).

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version (18K):
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Effect of chemoprophylaxis given to
household contacts after a case of meningococcal disease on
risk of subsequent cases: pooled risk ratio

Evidence for use of chemoprophylaxis in index patients before
discharge from hospital
We found no studies comparing index
patients given chemoprophylaxis with those who were not. Four
studies assessed persistent meningogcoccal carriage on
discharge from hospital in patients who had not received
chemoprophylaxis. Alvez et al showed that three of 48 children
(aged 3 months to 13 years) who were treated with 300 000
units/kg/day of penicillin G sodium intravenously for at least
10 days were carriers of Neisseria meningitidis on
discharge.17
In the study of Abramson and Spika meningococci were cultured
from the upper respiratory tract in one of 14 patients
discharged after completion of intravenous therapy, initially
with ampicillin or chloramphenicol then benzyl penicillin.18
Four patients had positive cultures one week after the end of
treatment. The household contacts of the patients, but not the
patients themselves, had received chemoprophylaxis with
rifampicin. Barroso found two of 51 patients had positive
nasopharyngeal swabs after the end of their treatment,19
though the exact timing of the swabs in relation to hospital
discharge (eight hours after the end of treatment to six days
after discharge) is not clear. The patients had been treated
with ampicillin, penicillin, or chloramphenicol. Weis found no
carriers among 47 patients on discharge.20
Although this study did not specify the antibiotic treatment
used, benzyl penicillin was then the standard treatment for
meningococcal disease in Denmark (S Samuelsson, personal
communication).

The four studies were included in meta-analysis. Results of
tests for heterogeneity were not significant (P = 0.35). The
pooled estimate from these studies was calculated as 0.03 (0.00
to 0.06, table
3).

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Table 3 Estimated carriage
rate on discharge from hospital in index patients not treated
with chemoprophylaxis. Meta-analysis results

Discussion

Top
Abstract
Introduction
Methods
Results
Discussion
References

We
found that if household contacts of a patient with meningococcal
disease are given prophylaxis with antibiotics that eradicate
meningococcal carriage there are fewer subsequent cases. The
reduction in risk is considerable. We estimate that about 200
household contacts need to be treated to prevent a subsequent
case during the first month. This applies to a strategy of
giving chemoprophylaxis to a network of household contacts but
provides no evidence to support indiscriminate prescribing of
antibiotic prophylaxis to people outside this group.

The main difficulty in interpreting the findings is that they
are obtained from retrospective observational studies. Risk
factors for meningococcal disease, such as young age, male sex,
passive smoking, and lower socioeconomic status, are all
potential confounding factors.21
22
None of the studies took account of these factors in their
analysis. There is evidence that people of lower socioeconomic
status are less likely to receive preventive
interventions.23
If this were the case for meningococcal disease, these
observational studies would overestimate the true benefit of
treatment. On the other hand, adults have a lower baseline risk
of disease and if children were more likely to get prophylaxis
than adults this would underestimate the true effect. The
studies gave no baseline comparisons of age distribution
between treated and untreated groups. If efforts to achieve
follow up had differed in some way between treated and
untreated groups, this would only dilute the observed effect of
treatment, unless the investigators had somehow applied
different stringency of criteria (for instance, for case
definitions) between groups. The risk to untreated household
contacts is highest in the first week after the index case and
declines rapidly thereafter.24
A one month period to measure risk reduction is therefore
reasonable but does not assess whether chemoprophylaxis could
prevent subsequent cases beyond this period.25

Previous studies have suggested that subsequent cases may be
caused by reintroduction of the virulent strain to the
household by the index patient.26
We estimate that about 3% of index patients treated with
penicillin and who have not received chemoprophylaxis will
still be carrying the virulent strain on discharge from
hospital. As carriage may be suppressed but not eradicated by
penicillin treatment so that carriage is less easily detected
on completion of treatment,18
this figure is likely to underestimate the true carriage rate
among index patients. Giving chemoprophylaxis to the index
patient before discharge from hospital should also be
supported, unless they have already been treated with an
antibiotic such as ceftriaxone, which is known to eradicate
carriage.

Studies to estimate the effect of chemoprophylaxis in day care
settings are needed, and the current variation in policy across
European countries is therefore not surprising. As clusters
are unusual in this setting and as policies vary by country,
a multinational study may be needed to provide evidence on
benefit.

This is the first systematic review of evidence for control
policies for meningococcal disease and supports giving a short
course of antibiotics that eradicate carriage to household
contacts and index patients. The consistency of the study
findings, the size of the risk ratio, and the biological
plausibility of this approach lend further weight to our
conclusions. We believe that such a policy should be applied
across Europe and other industrialised countries.

What is already
known on this topic

A lack of evidence for strategies to control
meningococcal disease has resulted in a variation
in approach among countries in Europe

Most countries recommend a short course of
rifampicin or ciprofloxacin for all household
contacts but evidence to support this has previously
been limited to one observational study

There are no uniform recommendations for giving
chemoprophylaxis to the index patient or to
contacts in childcare settings

What this study adds

Evidence from three studies supports the use of
chemoprophylaxis to prevent further cases of
meningococcal disease

The risk of further cases during the first month
is reduced by 89%, and to prevent one case about
200 household contacts need to be treated

After treatment of disease with penicillin and
without giving chemoprophylaxis, at least 3% of
index patients will be carrying the virulent
meningococcal strain on discharge from hospital

There are insufficient studies to estimate the
effect of chemoprophylaxis in childcare settings

Julie Christmas and Potenza Atiogbe helped
with the search strategy and database searches. Maria
Santamaria reviewed the initial dataset. Matthias Egger gave
advice on the methods and earlier drafts.

Contributors: JMS conceived the study. All
authors except AC contributed to the design of the study,
carried out searches, and extracted data. AC performed the
meta-analyses. BP wrote the first draft. All authors were
involved in the writing of the final draft. JMS is guarantor
for this study.

Funding: During part of this study, SJMH
and IC were funded by the European Programme for Intervention
Epidemiology Training (EPIET), which is funded by the European
Commission under the agreement numberSI2.74030 (99CVVF4-003-0).
Two meetings of the working group were supported by Wyeth
Lederle.

Ethical approval: Not required.

References

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Discussion
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(Accepted 1 April 2004)

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