Systematic review of the effect of antibiotics and/or vaccination in
preventing subsequent disease among household contacts
of cases of meningococcal disease
Report for the WHO Meningitis Guideline Revision
May 2014
Dr. L. Telisinghe
Current position: The WHO control of epidemic meningococcal disease; practical guidelines 2nd edition
1998 (http://www.who.int/csr/resources/publications/meningitis/WHO_EMC_BAC_98_3_EN/en/) states that
1) Vaccination – mass vaccination campaigns can halt epidemics
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2) Chemoprophylaxis – of contacts of cases of meningitis is not recommended during epidemics. In nonepidemic settings, chemoprophylaxis is recommended to close contacts of a case including household
contacts.
However, recently during a large outbreak of serogroup W meningococcal meningitis in the Gambia, ciprofloxacin
was administered as chemoprophylaxis to close contacts of cases of meningococcal disease. In addition with
the use of the serogroup A polysaccharide-tetanus toxoid conjugated vaccine, the scale and frequency of
serogroup A meningococcal disease outbreaks in the meningitis belt is likely to decrease. Given these, the
WHO recommendation for the use of chemoprophylaxis and vaccination for the region needs to be reviewed and
updated, to ensure up to date, evidence based practice in the region.
Recommendation question: Should prophylaxis (antibiotics and/or vaccination) be recommended for
household contacts of cases of meningococcal meningitis in epidemic and non-epidemic settings?
PICO question: Among household contacts of a case, what is the risk of meningococcal meningitis during
the month after disease onset among close contacts given and not given prophylaxis?
Populations: Household contacts of cases of meningococcal meningitis
Intervention: Prophylaxis to household contacts
Comparator: No prophylaxis to household contacts
Outcome: Attack rate among household contacts within one month after disease onset in index case
Aim:
To determine the effect of antibiotics and/or vaccination, in preventing subsequent meningococcal
disease in household contacts of cases of meningococcal meningitis, in epidemic and non-epidemic settings.
Objectives:
1) Conduct a systematic review of the literature using an appropriate search strategy.
2) Determine a combined estimate of the effect of appropriate antibiotics on the risk of subsequent
meningococcal disease among household contacts of cases of meningococcal disease at 30 days and 1 year
following the index case.
3) Determine a combined estimate of the effect of appropriate vaccination on the risk of subsequent
meningococcal disease among household contacts of cases of meningococcal disease at 30 days and 1 year
following the index case.
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4) Determine a combined estimate of the effect of appropriate antibiotics and vaccination on the risk of
subsequent meningococcal disease among household contacts of cases of meningococcal disease at 30 days
and 1 year following the index case.
5) Determine the number needed to treat with antibiotics, vaccination, and, antibiotics and vaccination to prevent
one subsequent case of meningococcal disease among household contacts of cases of meningococcal disease
at 30 days and 1 year.
6) Explore drug resistance in isolates of Neisseria meningitidis from subsequent cases of meningococcal disease
given chemoprophylaxis.
7) Explore the proportion of household contacts given prophylaxis (both antibiotics and vaccination), who
develop side effects due to prophylaxis.
Methods:
See protocol v1.6; 7th March 2014 for details of the study methods. Where methods differ from
proposed methods in the protocol – this is indicated in the document.
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Results
Systematic review search
Figure 1: Search for systematic reviews (undertaken by LT, TW and JS)
Records identified through
database search N=906
Additional articles reviewed
based on reference search
n=12
Records remaining after
duplicates removed n=718
Number of duplicates removed
n=188
Titles screened n=718
Number of records excluded
following title screen n=522
Abstracts screened n=196
Number of records excluded
following abstract screen n=128
For full text screen n=68+12=80
Unable to find articles n=16 3rd
review by RJS
Excluded
Full texts screened n=64
Not SR (i.e. reviews only)
n=58
Older version of SR n=2
Number of articles considered
n=4
*n=27(39.7%) had no abstracts; SR=systematic review
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Table 1: Methodological quality assessment of systematic reviews using the AMSTAR tool
Systematic review
A priori study
design
Duplicate
study
selection and
data
extraction
Comprehensive
literature search
Publication
status not used
as inclusion
criterion*
List of inand
excluded
studies
Characteristics of
included studies
provided
Study quality
assessed and
documented
Quality
assessment
used in
conclusions
Appropriate
methods to
combine
findings
Likelihood of
publication bias
assessed
Conflict of
interest
stated
Purcell 2004
Unclear
Yes
Yes
Unclear
No
Yes
No
No
Yes
No
No
2 independent
data extractors
Cochrane, HTA and
national research
register (UK); Medline;
EMBASE; CAB heath
Does not specify
List of
excluded
studies not
provided
No formal
quality
assessment
presented.
However,
information is
provided on the
included
studies, which
enables the
reader to
assess quality.
Quality aspects
of studies
(including lack
of controlling
for
confounders)
taken into
account when
interpreting
results in the
discussion
Effectiveness of
chemoprophylaxis
Mesh terms for
NM;
chemoprophylaxis;
abx; HH; outbreak; tx;
control
Did not exclude
based on
language, date,
country
Reference search
Contacted experts
RISK OF BIAS = LOW (while study quality assessment was not formerly used in conclusions, this was not considered to be a critical criterion as there was duplicate study selection and data extraction and a comprehensive literature search
performed, with studies not excluded based on language, country or date. Therefore the risk of bias assessment was considered low)
ECDC 2010
Guidelines: Public
health management
of sporadic cases of
invasive
meningococcal
disease and their
contacts
Yes
No
Yes
Unclear
No
Medline; EMBASE;
Cochrane; Global
Health
Does not specify
List of
excluded
studies not
provided
Mesh terms:
NM; tx; outbreak; HH;
chemoprophylaxis; abx
Yes
Reference search
Contacted experts
RISK OF BIAS = NOT LOW (the risk of bias was considered as not low as duplicate study selection and data extraction was not performed)
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No
No
Quality
aspects of
studies
(including lack
of controlling
for
confounders)
taken into
account when
interpreting
results in the
discussion
Yes
No
Yes
Systematic review
A priori study
design
Duplicate
study
selection and
data
extraction
Comprehensive
literature search
Publication
status not used
as inclusion
criterion*
List of inand
excluded
studies
Characteristics of
included studies
provided
Study quality
assessed and
documented
Quality
assessment
used in
conclusions
Appropriate
methods to
combine
findings
Likelihood of
publication bias
assessed
Conflict of
interest
stated
Hoek 2008
Unclear
Yes
Yes
Unclear
No
Yes
No
No
Yes
No
No
Only 1 person
reviewed titles
and abstracts.
Medline; EMBASE
Does not specify
List of
excluded
studies not
provided
No formal
quality
assessment
presented.
Results table
does however
include
information
which enables
the reader to
assess quality.
Quality
aspects of
studies
(including lack
of controlling
for
confounders)
taken into
account when
interpreting
results in the
discussion
Yes
Yes
Yes
Effectiveness of
vaccination in
addition to
chemoprophylaxis
to prevent IMD
among HH contacts
2 people
reviewed full
texts
MESH terms:
NM; contact; HH;
chemoprophylaxis
Reference lists
searched
Experts contacted
RISK OF BIAS = LOW (quality assessment used to formulate study conclusions not considered to be a critical criterion. Therefore the risk of bias assessment was considered as low)
HOWEVER – CAUTION WITH RESULTS AS ONLY 2 DATABASES WERE SEARCHED
STUDY QUESTION DOES NOT ANSWER THE FULL QUESTION REGARDING VACCINATION PROPOSED BY PICO4
Zalmanovici
2013
Effectiveness of
abx in preventing
secondary cases of
MD
Yes
Yes
Yes
2 people
reviewed titles,
abstracts and
full texts
Cochrane, Medline,
EMBASE, LILACS
Yes
Yes
Yes
Yes
Yes
MESH terms:
MD;
chemoprophylaxis;
abx;
RISK OF BIAS = LOW
ONLY CONSIDERED RANDOMISED CONTROLLED TRIALS OR QUASI RANDOMISED CONTROLLED TRIALS– NO STUDIES IDENTIFIED
*question reversed; IMD=invasive meningococcal disease; HH=household; abx=antibiotics; tx=transmission; NM=Neisseria meningitides; MD=meningococcal disease;
Low risk of bias = comprehensive literature review performed + methods to combine studies appropriate + quality of the included studies used to formulate conclusions
Purcell 2004 was chosen as the starting point for the systematic review on chemoprophylaxis as this review had a low risk of bias (although the study quality assessment was not used to formulate
study conclusions this was not considered a critical criterion. A comprehensive literature review was undertaken, included randomised and non-randomised studies, with duplicate data extraction).
As no prior systematic review which adequately addressed the PICO question on vaccination was identified, the search was conducted without a date limit to determine the effect of vaccination on
subsequent cases of meningococcal disease.
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Primary study search
Figure 2: Search for primary articles (undertaken by LT, TW and JS)
Records identified through
database search‡ N=2936
Additional articles reviewed
based on reference search
n=12
Records remaining after
duplicates removed n=2381
Number of duplicates removed
n=555
Titles screened n=2381
Number of records excluded
following title screen n=1754
Abstracts screened n=627
Number of records excluded
following abstract screen
n=562
For full text screen*
n=65+12=77
Excluded
Full texts screened** n=77
Articles included n=2
1=chemoprophylaxis; 1=vaccines
‡Grey
literature included from 2002 onwards; *45(63.4%) had no abstract;
Chemoprophylaxis – from 2004 onwards; Vaccination – no date limit
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No relevant information for PICO
n = 72
(Includes studies/reviews of
vaccine/antibiotic effectiveness in
non-household setting; outbreak
reports; antibody response
studies; carriage studies;
acceptability studies; economic
evaluations)
Information on clusters only n=2
In Purcell review n=1
Table 2: Chemoprophylaxis: description of studies considered (from Purcell 2004 + primary articles identified since 2004)
Author
Year
Design
Setting
Country
Region
Stefanoff*
2008
Cohort
Endemic;
Poland;
National
(surveillance
data)
2003 to
2006
Samuelsson
2000
Cohort
Endemic
(3-4/100,000);
Denmark;
National
(surveillance
data)
Oct-95
to Apr97
Scholten
1993
Cohort
Endemic
(4/100,000),
Netherlands;
National
(surveillance
data)
Apr-89
to Apr90
Kristiansen
1992
Time series
MDSG
1976
Cohort
Kaiser
1974
Randomised
trial
Endemic
(1986:
6.7/100,000);
Norway;
Telemark
(surveillance
data)
Endemic
(0.23/100,000);
USA;
27 states &
Washington DC
period 1; 17
states &
Washington DC
in period 2
Outbreak
USA;
Dade country,
Florida
Date
from to
Jan-84
to Dec89
Index
cases
(N)
635
Serogp
of
cases
-
172
-
502
mostly
B;
C;
A
Household contact
definition
person living in the
same HH as the case
in the 7 days before
onset of illness in the
case
person sleeping in the
same HH/room or
kissing/saliva
exchanging contact
with the case in the 10
days before onset of
illness in the case
HH member living in
the same house as the
case in the week
before hospitalization
of the case
Number
of
contacts
1905
Total
follow
up time
at least
2
months
Intervention
Rifampicin
Comparator
Exposed
(N)
Exposed
subsequent
cases (n)
Unexposed
(N)
Unexposed
subsequent
cases (n)
no antibiotics
629
1
(>30 days)
1276
3
(≤30 days)
802
>24
hours
(upper
limit not
clear)
ciprofloxacin
no antibiotics
724
0
72
2
(≤30 days)
1102
At least
30 days
rifampicin or
minocycline
no antibiotics or
antibiotics other
than rifampicin or
minocycline
276
1
(>30 days)
826
4
(≤30 days)
441
(during
19871989)
rifampicin if
harbouring
disease
causing strain
and penicillin
in <15years
(1987-1989)
penicillin if <15
years only
(1984-1987)
441
0
no antibiotics or
antibiotics other
than sulfonamide,
minocycline or
rifampicin
693
0
1179
5
(≤30 days)
none specified
35
0
19
0
13
8B;
4C;
1Y
Nov-73
to mar74 &
Jan-75
to Apr75
512
(324
serogr)
45%B;
32%C;
18%Y;
2%A
person that lived in the
same HH/dorm room
with a case in the
week prior to onset of
illness in the case
1872
30 days
rifampicin,
sulphonamide
or
minocycline
Apr-70
to Dec70
N/A
C
People who slept/ate
in the same dwelling
as the case
54
9
months
rifampicin
16**
HH=household; Serogp=serogroup; MDSG=meningococcal disease surveillance group; info=information. *Data obtained from study authors. **Text of article: 11 bacteriologically verified and 4 clinically suspected cases. Table in article shows 12 bacteriologically verified and
4 clinically suspected cases
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Table 3: Vaccination – description of study considered (primary article)
Author
Year
Design
Greenwood
1978
Setting
Country
Region
Epidemic
Nigeria, Zaria
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Date
from to
Mar-77
to
May-77
Serogp
of
cases
Household contact
definition
Number
of
contacts
Total
follow up
time
Intervention
Comparator
Exposed
(N)
Exposed
subsequent
cases (n)
Unexposed
(N)
Unexposed
subsequent
cases (n)
A
Small compound –
all people; large
compound – close
family; Koranic
school – all
Average size of
compounds and
Koranic school - 17
1043
Until the
end of the
epidemic
Meriuex (A&C
vaccine)
Tetanus toxoid
520
0 definite; 1
probable
523
5 definite; 4
probable
Chemoprophylaxis at ≤30days
Studies excluded from the meta-analysis
 Kaiser 1974 – no cases in exposed and unexposed groups
 Kristiansen 1992 – no contact data during 1984-1987
Table 4: Meta-analysis of included studies – risk of subsequent meningococcal disease among household
contacts given and not given chemoprophylaxis at ≤30days
Study
Stefanoff 2008
Samuelsson 2000
Scholten 1993
MDSG 1976
M-H pooled RR (fixed effect)
Intervention
group (n/N)
0/629
0/724
0/276
0/693
0/2322
Comparator
group (n/N)
3/1276
2/72
4/826
5/1179
14/3353
Risk
ratio
0.29
0.02
0.33
0.16
0.16
95% confidence
interval
0.01 - 5.60
0.00 - 0.42
0.02 - 6.14
0.01 - 2.79
0.04 - 0.64
% Weight
17.54
34.45
17.12
30.89
100.00
n=number of subsequent cases; N=number of contacts
Chi squared test for heterogeneity p=0.543;I2 (variation in RR attributable to heterogeneity)=0.0%; Test of RR=1: p=0.008
Figure 3: Forest plot of the risk of subsequent cases of meningococcal disease among household contacts given
and not given chemoprophylaxis at ≤30days
Risk
Events,
Events,
%
Study
Ratio (95% CI)
Treatment
Control
Weight
Stefanoff 2008
0.29 (0.01, 5.60)
0/629
3/1276
17.54
Samuelsson 2000
0.02 (0.00, 0.42)
0/724
2/72
34.45
Scholten 1993
0.33 (0.02, 6.14)
0/276
4/826
17.12
MDSG 1976
0.15 (0.01, 2.79)
0/693
5/1179
30.89
Overall (I-squared = 0.0%, p = 0.531)
0.16 (0.04, 0.64)
0/2322
14/3353
100.00
.001
.01
.04
.16
Favours chemoprophylaxis
.64 1
2
6
Favours no chemoprophylaxis
Risk Ratio
Table 5: Meta-analysis of included studies – risk difference of meningococcal disease among household contacts
given and not given chemoprophylaxis at ≤30days
Study
Stefanoff 2008
Samuelsson 2000
Scholten 1993
MDSG 1976
M-H pooled risk difference
NNT
Intervention
group (n/N)
0/629
0/724
0/276
0/693
0/2322
Comparator
group (n/N)
3/1276
2/72
4/826
5/1179
14/3353
Risk
difference
-0.002
-0.028
-0.005
-0.004
-0.005
200
95% confidence
interval
-0.006 to 0.001
-0.070 to 0.014
-0.012 to 0.002
-0.009 to 0.000
-0.009 to -0.001
111 to 1000
% Weight
37.28
5.79
18.31
38.62
100.00
n=number of subsequent cases; N=number of contacts; NNT=number needed to treat; Chi squared test for heterogeneity p=0.34; I2=10.3%; Test of RD=0:
p=0.005
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Chemoprophylaxis at ≤1year
Studies excluded from the meta-analysis
 Kaiser 1974 – no cases in exposed and unexposed groups
 Kristiansen 1992 – no contact data during 1984-1987
 MDSG 1976 – follow up for only 30days
Table 6: Meta-analysis of included studies – risk of subsequent meningococcal disease among household
contacts given and not given chemoprophylaxis at ≤1year*
Study
Stefanoff 2008
Samuelsson 2000
Scholten 1993
M-H pooled RR (fixed effect)
Intervention
group (n/N)
1/629
0/724
1/276
2/1629
Comparator
group (n/N)
3/1276
2/72
4/826
9/2174
Risk
ratio
0.68
0.02
0.75
0.34
95% confidence
interval
0.07 - 6.49
0.00 - 0.42
0.08 - 6.67
0.11 - 1.06
% Weight
23.23
53.27
23.50
100.00
n=number of subsequent cases; N=number of contacts;
Chi squared test for heterogeneity p=0.12;I2 (variation in RR attributable to heterogeneity)=52.4%; Test of RR=1: p=0.06
*The total duration of follow-up of the entire cohort is unclear in the included studies. Therefore denominators may be inaccurate.
Figure 4: Forest plot of the risk of subsequent cases of meningococcal disease among household contacts given
and not given chemoprophylaxis at ≤1year
Risk
Events,
Events,
%
name
Ratio (95% CI)
Treatment
Control
Weight
stefanoff
0.68 (0.07, 6.49)
1/629
3/1276
23.23
samuelsson
0.02 (0.00, 0.42)
0/724
2/72
53.27
Scholten
0.75 (0.08, 6.67)
1/276
4/826
23.50
Overall (I-squared = 52.4%, p = 0.122)
0.34 (0.11, 1.06)
2/1629
9/2174
100.00
.001
.01
.11
.34
Favours chemoprophylaxis
1
2
6
Favours no chemoprophylaxis
Risk Ratio
Table 7: Meta-analysis of included studies – risk difference of meningococcal disease among household contacts
given and not given chemoprophylaxis at ≤1year*
Study
Stefanoff 2008
Samuelsson 2000
Scholten 1993
M-H pooled risk difference
Intervention
group (n/N)
1/629
0/724
1/276
2/1629
Comparator
group (n/N)
3/1276
2/72
4/826
9/2174
Risk
difference
-0.001
-0.028
-0.001
-0.003
95% confidence
interval
-0.005 to 0.003
-0.070 to 0.014
-0.010 to 0.007
-0.009 to 0.002
% Weight
60.74
9.44
29.82
100.00
n=number of subsequent cases; N=number of contacts; Chi squared test for heterogeneity p=0.20; I2=37.9%; Test of RD=0: p=0.21. *The total duration
of follow-up of the entire cohort is unclear in the included studies. Therefore denominators may be inaccurate.
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Table 8: Chemoprophylaxis - risk of bias assessment for observational studies
Item
Study design
Allocation of intervention
Stefanoff 2008
Cohort
(national)
Treatment decision
specific to area
Samuelsson 2000
Cohort
(national)
Treatment decision specific
to area
Scholten 1993
Cohort
(national)
Treatment decision
specific to area
MDSG 1976
Cohort
Treatment decision
specific to area
Kristiansen 1992
Cohort (time series in
one county)
Treatment decision
specific to area
+
-
+
+
+
+
+
+
+
-
-
-
-
-
-
Comments
Selection
Cohort exposed representative of all household contacts
of a case of meningococcal disease
Cohort not given chemoprophylaxis from the same
population as the exposed cohort
Comparability of exposed and unexposed assessed
Baseline demographic details given
Comments
Outcomes
Objective sources used to ascertain outcome
Adequate duration of follow up for outcome
ascertainment
Losses to follow up/no information
Comments
Analysis
Adequate control for confounders
Comments
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Control group from a
different time period to
intervention group but from
the same area.
Fatal cases excluded
+
?
+
-
+
?
?
+
+
+
?
32%
25%
?
?
Data obtained from
author – need to contact
to obtain details
Notification systems used to
identify cases. Households
interviewed. Unclear if
subsequent cases determined by
notification or interview.
172/252 eligible households
participated
378/502 eligible households
included. Valid information
only on 1102/1130 (97.5%) of
included contacts.
Households contacted to
enquire on secondary cases,
at least 30days after
hospitalization of index case.
No information to assess
losses to follow-up
Follow up 7-31months
during the intervention
period. For 84-87 (control
period) some cases were
followed up for at least 300
days.
-
-
-
-
-
Table 9: Chemoprophylaxis - risk of bias assessment for trials (Kaiser 1974)
Domain
Judgement
Justification
Selection bias
Random sequence generation
Low risk of bias
Allocation by dice throw
Allocation concealment
Unclear risk of bias
Not stated
Performance bias
Blinding
Low
Not specified, but it is unlikely that
blinding would have influenced the
outcome.
Detection bias
Blinding of outcome assessment
Low
Unclear if investigators assessing
outcome status of study
participants were blinded.
However, it is unlikely that
assessment of this objective
outcome would have been
influenced (and there were no
subsequent cases in the study)
Attrition bias
Incomplete outcome data
Unclear risk of bias
Not stated
Reporting bias
Selective reporting
Unclear risk of bias
Protocol not available to determine
main objectives of study
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Vaccination
Table 10: Risk of subsequent meningococcal disease among household contacts who were and were not
vaccinated
Study
Intervention
group (n/N)
Comparator
group (n/N)
Risk ratio
95% confidence
interval
p -value
0/520
1/520
5/523
9/523
0.09
0.11
0.01-1.65
0.01-0.88
0.11
0.04
Greenwood 1978
Definite only
Definite & probable
n=number of subsequent cases; N=number of contacts; Definite case=proven meningitis and positive culture or antigen test; Probable case (intervention
group) = acute febrile illness but died on the way to hospital with no clinical samples takes; Probable cases (comparator group) = proven meningitis (with
negative cultures and antigen test) or septicaemia and high baseline antibody titre (≥1 in 32) or rise in titre of >4 fold.
Table 11: Risk of bias assessment for vaccination study
Domain
Judgement
Selection bias
Random sequence generation
Unclear risk of bias
Allocation concealment
Performance bias
Blinding
Detection bias
Blinding of outcome assessment
Attrition bias
Incomplete outcome data
Reporting bias
Selective reporting
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Unclear risk of bias
Justification
Alternative compounds allocated
to intervention and comparator
group. Unclear if allocation could
have been predicted in advance
Not specified
Low
Not specified, but it is unlikely that
blinding would have influenced the
outcome.
Low / Unclear risk of bias
Unclear if investigators assessing
outcome status of study
participants were blinded.
However it is unlikely that blinding
would influence the outcome
assessment for definite cases.
For probable cases, the risk of
bias is unclear
Low risk of bias
Unclear risk of bias
Study does not appear to have
any missing data for outcomes
Protocol not available to determine
main objectives of study
Development of resistance to antibiotics used as chemoprophylaxis
Not reported in studies included in this systematic review and meta-analysis.
A systematic review undertaken by the Cochrane Collaboration (Zalmanovici 2013, page 10) reported the
following:
“Eleven trials reported the susceptibility of persistent isolates to at least one of the studied antibiotics
(Blakebrough 1980; Deal 1969a; Deal 1969b; Devine 1971b; Dworzack 1988; Guttler 1971; Kaiser 1974;
Munford 1974; Pugsley 1987; Renkonen 1987; Simmons 2000). No development of resistance was detected for
any antibiotic drug other than rifampin. Six trials assessed resistance development to rifampin (Blakebrough
1980; Deal 1969a; Guttler 1971; Kaiser 1974; Munford 1974; Simmons 2000). In Guttler 1971 rifampin-resistant
isolates requiring minimal inhibitory concentrations (MICs) of 100 to 200 μg/ml of rifampin were seen in 20 of 75
post-treatment isolates, while MICs increased from pre-treatment values of less than 0.25 μg/ml to 2 to 6 μg/ml in
37 additional isolates. All resistant isolates were detected among patients treated with rifampin. In Munford
1974, seven resistant isolates were detected out of 37 isolates among 67 patients treated with rifampin (MICs of
16 to 256 μg/ml). All pre-treatment isolates were susceptible to rifampin and no resistance to rifampin developed
among patients randomised to rifampin in addition to minocycline in this study. The meningococci identified in
these two studies were serogroup B or C and all resistant isolates were identified as group C. One additional
study assessing group A meningococci (Blakebrough 1980) found an increase in rifampin MICs from less than
0.1 μg/ml to 3.2 μg/ml (three isolates) and 6.4 μg/ml (one isolate) post treatment. In all trials seven eradication
failures were assessed for resistance development, which was not found.”

11 studies; variety of setting (most from North America; South America; sub-Saharan Africa [1]; New
Zealand); variety of populations (household contacts, students; army recruits, volunteers)

Antibiotics used: rifampicin, ciprofloxacin, sulphonamides, minocycline, cephalexin, ampicillin, ceftriaxone

Follow up time: 5 to 130days

Primary outcomes: eradication/morbidity
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Table 12: Details of studies assessing resistance development to rifampicin
Munford 1974
B/C
C
2
600mgX2 for 2days
Guttler 1971
B/C
C
5
600mgX1 for 4days
Blakebrough 1980
A
A
7
600mgX2 for 2days
Families+children
(Brazil)
Army recruits
(USA)
Resistance testing method
Number treated with rifampicin
Number of treatment failures
Agar dilution
67
6
Initial MICs of isolates (µg/ml)
Main serogroup
Resistant serogroup
Follow-up (weeks)
Rifampin dose
Simmons 2000
B
Deal 1969
B
Kaiser 1974
C
6 days
600mgX2 for 2days
2-3
600mgX1 for 4days
3-4
600mgX1 for 4days
Household+children
(Nigeria)
Household+children
(New Zealand)
Students
(USA)
Household+children
(USA)
Agar dilution
147
13
Agar dilution
48
11
E test
82
4
Plate dilution
15
2
Plate dilution
13
1
<0.25
<0.25
<0.1
Not reported
<1
<0.12
Final MICs of isolates (µg/ml)
1=16; 1=32; 1=64;
1=125; 1=256
37=2-6; 20=100200
3=3.2; 1=6.4
<2
<1
<0.12
Comments
No resistance in
rifampinminocycline
combination arm; 7
resistant isolates
detected out of 37
tested
75 isolates tested
11 isolates tested
7 isolates tested
4 isolates tested
18.9%
76.0%
36.4%
-
-
Population
Proportion of isolates with raised
MICs
(Data received from Professor Paul and Professor Leibovici, authors of the Cochrane Review Zalmanovici et al. Antibiotics for preventing meningococcal infections 2013)
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-
Adverse effects of antibiotics and/or vaccination used as prophylaxis
Not reported in studies included in this systematic review and meta-analysis.
A systematic review undertaken by the Cochrane Collaboration (Zalmanovici 2013, page 9, 36 and 38) reported the following:
“Eighteen trials provided quantitative data regarding the occurrence of adverse effects. These were all mild in nature and included nausea, diarrhoea, abdominal pain,
headaches, dizziness, skin rash and pain at injection site. One study comparing rifampin to ceftriaxone yielded an overall risk ratio (RR) for any clinical adverse effects of 1.39
(95% confidence interval (CI) 1.10 to 1.75) (Analysis 1.1). Two studies comparing rifampin to ciprofloxacin yielded an overall non-significant RR of 0.75 (95% CI 0.36 to 1.56)
(Analysis 1.2).”




18 trials; variety of settings (North & South America, sub-Saharan Africa [1], North Africa, Asia); variety of populations (household contacts, children, students, army
recruits, volunteers, patients with gonorrhoea)
Antibiotics used: rifampicin, ciprofloxacin, cephalexin, minocycline, sulphadiazine, amoxicillin, coumermycin, azithromycin, spectinomycin, ceftriaxone
Follow up time: 5 to 30days
Primary outcome: eradication/morbidity
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GRADE profile
Question: Should chemoprophylaxis be used for subsequent meningococcal disease among household contacts of cases of meningococcal disease?
Quality assessment
No of
Design
Limitations Inconsistency Indirectness Imprecision
Other considerations
studies
Subsequent case of meningococcal disease (30 days) (follow-up 30 days; clinical judgement or PCR/culture)
4
observational serious1
no serious
serious2
serious3
none
studies
inconsistency
Subsequent case of meningococcal disease (1 year) (follow-up 1 year; clinical judgement or PCR/culture)
3
observational serious1
no serious
serious2
serious3
none
studies
inconsistency
Resistance to antibiotics (follow-up 14+ days)
3
randomised serious4
serious5
trials
no serious
indirectness
Adverse effects: rifampicin vs ceftriaxone (follow-up 6+ days)
1
randomised serious4
no serious
no serious
trials
inconsistency indirectness
serious3
serious3
Adverse effects: rifampicin vs ciprofloxacin (follow-up 2 weeks)
2
randomised serious4
no serious
no serious
very
trials
inconsistency indirectness serious3,6
Summary of findings
Effect
Relative
Chemoprofylaxis control
Absolute
(95% CI)
No of patients
Quality
Importance
0/2322 (0%)
14/3353
(0.42%)
RR 0.16
(0.04 to
0.64)
4 fewer per

1000 (from 2
VERY CRITICAL
fewer to 4
LOW
fewer)
2/1629 (0.1%)
9/2174
(0.4%)
RR 0.34
(0.11 to
1.06)
3 fewer per
1000 (from 4
fewer to 0
more)
OOO
VERY
LOW
CRITICAL
-
-
-
-
OOO
VERY
LOW
CRITICAL
129/440 (29.3%)
88/416
(21.2%)
RR 1.39
(1.10 to
1.75)
Resistance development was not detected for any
antibiotic other than rifampicin. In 3 studies
undertaken in a variety of settings, raised MICs to
rifampicin used developed in 18.9%, 36.4% and
76.0% of the isolates tested.
none
none
83 more per
1000 (from 21 OO
IMPORTANT
more to 159
LOW
more)
5 fewer per
OOO
1000 (from 13
VERY IMPORTANT
fewer to 11
LOW
more)
1 No baseline demographic details provided; no adjustment for confounding in all studies; 2 All studies carried out in US or Western Europe (non-epidemic situations); 3 Optimal Information Size (OIS) not met; 4 All
13/861 (1.5%)
studies high risk of bias; 5 One study in army recruits with very high percentage of rifampicin resistance; 6 CI includes both benefit and harm
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15/737
(2%)
RR 0.75
(0.36 to
1.56)
Question: Should vaccination be used for subsequent meningococcal disease among household contacts of cases of meningococcal disease?
Quality assessment
No of
Other
Design Limitations
Inconsistency
Indirectness
Imprecision
studies
considerations
Subsequent definite meningococcal disease (clinical features, culture, antibody and antigen test)
1
trial
serious1
no serious
no serious
serious2
None
inconsistency
indirectness
Adverse effects
0
None
1 Unclear risk of selection, performance and detection bias; 2 Optimal Information Size (OIS) not met; No=Number
Number of patients
An appropriate
control
vaccine
Summary of findings
Effect
Relative
Absolute
(95% CI)
0/520
(0%)
5/523
(0.96%)
RR 0.09
(0.01 to 1.65)
-
-
-
Quality
Importance
9 fewer per 1000

CRITICAL
(from 9 fewer to 6 more)
LOW
-
IMPORTANT
Question: Should chemoprophylaxis and vaccination be used for subsequent meningococcal disease among household contacts of cases of meningococcal disease?
Summary of findings
Number of patients
Quality assessment
No of studies Design Limitations Inconsistency Indirectness Imprecision
Subsequent case of meningococcal disease at ≤30days
0
Subsequent case of meningococcal disease at ≤1 year
0
Resistance to antibiotics
0
Adverse effects
0
No=number
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Other considerations
Chemoprophylaxis and vaccination
Effect
Importance
Quality
Relative
control
Absolute
(95% CI)
-
none
-
-
-
-
CRITICAL
-
none
-
-
-
-
CRITICAL
-
none
-
-
-
-
CRITICAL
-
none
-
-
-
-
IMPORTANT
Conclusions:
There is limited evidence on the effect of chemoprophylaxis (4 observational studies) and vaccination (1 quasirandomised trial) on the risk of subsequent meningococcal disease among household contacts of a case of
meningococcal disease. Data on risk of meningococcal disease among household contacts, including risk over
time in the African setting would be useful to guide decision making.
Chemoprophylaxis
 All four included studies were from non-epidemic settings in Europe and USA (annual disease incidence
ranging from 0.23 – 4.0 per 100,000 population)
 Data suggests an 84% reduction in the risk of subsequent cases of meningococcal disease among
household contacts given chemoprophylaxis at ≤30days (p=0.008).
 Using the pooled estimate, 200 (95%CI 111-1000) household contacts would need to be treated to
prevent 1 subsequent case of meningococcal disease at ≤30days.
 Data suggests a 66% reduction in the risk of subsequent cases of meningococcal disease among
household contacts given chemoprophylaxis at ≤1 year (P=0.06).
 However, the quality of the evidence (at ≤30days and ≤1year) was very low.
Vaccination

Single trial from Africa

While data suggests a 91% reduction in the risk of subsequent cases of definite meningococcal disease
among household contacts given vaccine, there is insufficient evidence to rule out a chance finding
(p=0.11).

When both definite and probable cases were taken into consideration, the data suggests an 89%
reduction in the risk of subsequent cases of meningococcal disease (p=0.04)
Resistance to antibiotics used as chemoprophylaxis

Not reported on in the studies included in this systematic review.

Evidence from a previous systematic review suggests that resistance only developed when rifampicin
was used (raised MICs were found to 18.9% to 76.0% of isolates tested from 3 studies)
Adverse effects of antibiotics used

Not reported on in the studies included in this systematic review
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
Evidence from a previous systematic review suggests that there is no difference in adverse effects
reported when rifampicin or ciprofloxacin were used, but more adverse effects were found after
rifampicin compared to ceftriaxone.
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1.
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from:
http://www.who.int/csr/resources/publications/meningitis/WHO_EMC_BAC_98_3_EN/en/index.html.
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and
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