dr. l. telisinghe - who

PICO4 – preliminary results V1.7- 16th April 2014 1

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


2) Chemoprophylaxis – of contacts of cases of meningitis is not recommended during epidemics. In non-

epidemic 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.


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.


Results

Systematic review search

Figure 1: Search for systematic reviews (undertaken by LT, TW and JS)

*n=27(39.7%) had no abstracts; SR=systematic review

Records identified through

database search N=906

Records remaining after

duplicates removed n=718

Number of duplicates removed

n=188

Number of records excluded

following abstract screen n=128 Abstracts screened n=196

For full text screen n=68+12=80


following title screen n=522

Full texts screened n=64

Titles screened n=718

Unable to find articles n=16 3rd

review by RJS

Additional articles reviewed

based on reference search

n=12

Number of articles considered

n=4

Excluded

Not SR (i.e. reviews only) n=58

Older version of SR n=2


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 in- and

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 Effectiveness of chemoprophylaxis

Unclear

Yes 2 independent

data extractors

Yes Cochrane, HTA and

national research register (UK); Medline; EMBASE; CAB heath

Mesh terms for NM; chemoprophylaxis; abx; HH; outbreak; tx;

control Reference search Contacted experts

Unclear Does not specify

Did not exclude based on language, date,

country

No List of

excluded studies not provided

Yes

No No formal

quality assessment presented. However,

information is provided on the included studies, which

enables the reader to assess quality.

No Quality aspects

of studies (including lack of controlling for

confounders) taken into account when interpreting

results in the discussion

Yes

No

No

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

Medline; EMBASE; Cochrane; Global Health

Mesh terms: NM; tx; outbreak; HH; chemoprophylaxis; abx

Reference search Contacted experts

Unclear

Does not specify

No

List of excluded studies not provided

Yes

No

No

Quality aspects of studies (including lack

of controlling for confounders) taken into

account when interpreting results in the discussion

Yes

No

Yes

RISK OF BIAS = NOT LOW (the risk of bias was considered as not low as duplicate study selection and data extraction was not performed)


Systematic review A priori study design

Duplicate study

selection and data extraction

Comprehensive literature search

Publication status not used

as inclusion criterion*

List of in- and

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 Effectiveness of

vaccination in addition to chemoprophylaxis to prevent IMD

among HH contacts

Unclear

Yes Only 1 person reviewed titles

and abstracts. 2 people reviewed full

texts

Yes Medline; EMBASE

MESH terms: NM; contact; HH; chemoprophylaxis

Reference lists searched Experts contacted

Unclear Does not specify

No List of excluded

studies not provided

Yes

No No formal quality

assessment presented. Results table does however

include information which enables the reader to

assess quality.

No Quality aspects of

studies (including lack of controlling for

confounders) taken into account when interpreting

results in the discussion

Yes

No

No

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 2 people

reviewed titles, abstracts and full texts

Yes Cochrane, Medline,

EMBASE, LILACS MESH terms: MD;

chemoprophylaxis; abx;

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

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.


Primary study search

Figure 2: Search for primary articles (undertaken by LT, TW and JS)

‡Grey literature included from 2002 onwards; *45(63.4%) had no abstract;

Chemoprophylaxis – from 2004 onwards; Vaccination – no date limit

Records identified through

database search‡ N=2936

Records remaining after

duplicates removed n=2381

Number of duplicates removed

n=555


following abstract screen

n=562

Abstracts screened n=627

For full text screen*

n=65+12=77


following title screen n=1754

Full texts screened** n=77

Titles screened n=2381

Additional articles reviewed

based on reference search

n=12

Articles included n=2

1=chemoprophylaxis; 1=vaccines

Excluded

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

Date from -

to

Index cases

(N)

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)

Stefanoff*

2008 Cohort

Endemic; Poland;

National (surveillance

data)

2003 to 2006

635 -

person living in the same HH as the case

in the 7 days before onset of illness in the

case

1905

at least

2 months

Rifampicin

no antibiotics 629 1

(>30 days) 1276

3 (≤30 days)

Samuelsson 2000

Cohort

Endemic (3-4/100,000);

Denmark; National

(surveillance data)

Oct-95 to Apr-

97 172 -

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

802

>24 hours (upper

limit not

clear)

ciprofloxacin no antibiotics 724 0 72 2

(≤30 days)

Scholten 1993

Cohort

Endemic

(4/100,000), Netherlands;

National (surveillance

data)

Apr-89 to Apr-

90 502

mostly B; C; A

HH member living in

the same house as the case in the week

before hospitalization of the case

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)

Kristiansen

1992 Time series

Endemic (1986:

6.7/100,000);

Norway; Telemark

(surveillance data)

Jan-84

to Dec-89

13

8B;

4C; 1Y

441

(during 1987-1989)

rifampicin if harbouring

disease

causing strain and penicillin in <15years (1987-1989)

penicillin if <15

years only (1984-1987)

441 0

16**

MDSG 1976

Cohort

Endemic (0.23/100,000);

USA;

27 states & Washington DC

period 1; 17 states &

Washington DC in period 2

Nov-73 to mar-

74 & Jan-75 to Apr-

75

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

no antibiotics or

antibiotics other than sulfonamide,

minocycline or rifampicin

693 0 1179 5

(≤30 days)

Kaiser 1974

Randomised

trial

Outbreak USA;

Dade country,

Florida

Apr-70 to Dec-

70

N/A C People who slept/ate in the same dwelling

as the case

54 9

months rifampicin none specified 35 0 19 0

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


Table 3: Vaccination – description of study considered (primary article)

Author Year

Design

Setting Country Region

Date from -

to

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)

Greenwood

1978

Epidemic

Nigeria, Zaria

Mar-77

to May-77

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 Intervention

group (n/N) Comparator group (n/N)

Risk ratio

95% confidence interval

% Weight

Stefanoff 2008 0/629 3/1276 0.29 0.01 - 5.60 17.54 Samuelsson 2000 0/724 2/72 0.02 0.00 - 0.42 34.45 Scholten 1993 0/276 4/826 0.33 0.02 - 6.14 17.12 MDSG 1976 0/693 5/1179 0.16 0.01 - 2.79 30.89 M-H pooled RR (fixed effect) 0/2322 14/3353 0.16 0.04 - 0.64 100.00 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

Table 5: Meta-analysis of included studies – risk difference of meningococcal disease among household contacts given and not given chemoprophylaxis at ≤30days Study Intervention


Risk difference


% Weight

Stefanoff 2008 0/629 3/1276 -0.002 -0.006 to 0.001 37.28 Samuelsson 2000 0/724 2/72 -0.028 -0.070 to 0.014 5.79 Scholten 1993 0/276 4/826 -0.005 -0.012 to 0.002 18.31 MDSG 1976 0/693 5/1179 -0.004 -0.009 to 0.000 38.62 M-H pooled risk difference 0/2322 14/3353 -0.005 -0.009 to -0.001 100.00 NNT 200 111 to 1000 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

Overall (I-squared = 0.0%, p = 0.531)

Stefanoff 2008

Scholten 1993

Samuelsson 2000

Study

MDSG 1976

0.16 (0.04, 0.64)

Risk

0.29 (0.01, 5.60)

0.33 (0.02, 6.14)

0.02 (0.00, 0.42)

Ratio (95% CI)

0.15 (0.01, 2.79)

0/2322

Events,

0/629

0/276

0/724

Treatment

0/693

14/3353

Events,

3/1276

4/826

2/72

Control

5/1179

100.00

%

17.54

17.12

34.45

Weight

30.89

0.16 (0.04, 0.64)

Risk

0.29 (0.01, 5.60)

0.33 (0.02, 6.14)

0.02 (0.00, 0.42)

Ratio (95% CI)

0.15 (0.01, 2.79)

0/2322

Events,

0/629

0/276

0/724

Treatment

0/693

Favours chemoprophylaxis Favours no chemoprophylaxis

1.001 .01 .04 .16 .64 2 6

Risk Ratio


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 Intervention


Risk ratio


% Weight

Stefanoff 2008 1/629 3/1276 0.68 0.07 - 6.49 23.23 Samuelsson 2000 0/724 2/72 0.02 0.00 - 0.42 53.27 Scholten 1993 1/276 4/826 0.75 0.08 - 6.67 23.50 M-H pooled RR (fixed effect) 2/1629 9/2174 0.34 0.11 - 1.06 100.00 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

Table 7: Meta-analysis of included studies – risk difference of meningococcal disease among household contacts given and not given chemoprophylaxis at ≤1year* Study Intervention


Risk difference


% Weight

Stefanoff 2008 1/629 3/1276 -0.001 -0.005 to 0.003 60.74 Samuelsson 2000 0/724 2/72 -0.028 -0.070 to 0.014 9.44 Scholten 1993 1/276 4/826 -0.001 -0.010 to 0.007 29.82 M-H pooled risk difference 2/1629 9/2174 -0.003 -0.009 to 0.002 100.00 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.

Overall (I-squared = 52.4%, p = 0.122)

name

samuelsson

Scholten

stefanoff

0.34 (0.11, 1.06)

Ratio (95% CI)

0.02 (0.00, 0.42)

0.75 (0.08, 6.67)

0.68 (0.07, 6.49)

Risk

2/1629

Treatment

0/724

1/276

1/629

Events,

9/2174

Control

2/72

4/826

3/1276

Events,

100.00

Weight

53.27

23.50

23.23

%

0.34 (0.11, 1.06)

Ratio (95% CI)

0.02 (0.00, 0.42)

0.75 (0.08, 6.67)

0.68 (0.07, 6.49)

Risk

2/1629

Treatment

0/724

1/276

1/629

Events,

Favours chemoprophylaxis Favours no chemoprophylaxis

1.001 .01 .11 .34 2 6

Risk Ratio


Table 8: Chemoprophylaxis - risk of bias assessment for observational studies Item Stefanoff 2008 Samuelsson 2000 Scholten 1993 MDSG 1976 Kristiansen 1992

Study design Cohort

(national) Cohort

(national) Cohort

(national) Cohort

Cohort (time series in

one county)

Allocation of intervention Treatment decision

specific to area Treatment decision specific

to area Treatment decision

specific to area Treatment decision

specific to area 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 Fatal cases excluded

Control group from a different time period to

intervention group but from

the same area.

Outcomes Objective sources used to ascertain outcome + ? + - + Adequate duration of follow up for outcome ascertainment

? ? + + +

Losses to follow up/no information ? 32% 25% ? ?

Comments 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.

Analysis Adequate control for confounders - - - - - Comments


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


Vaccination

Table 10: Risk of subsequent meningococcal disease among household contacts who were and were not vaccinated Study Intervention


Risk ratio 95% confidence interval

p -value

Greenwood 1978 Definite only 0/520 5/523 0.09 0.01-1.65 0.11 Definite & probable 1/520 9/523 0.11 0.01-0.88 0.04 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 Justification

Selection bias Random sequence generation Unclear risk of bias Alternative compounds allocated

to intervention and comparator group. Unclear if allocation could have been predicted in advance

Allocation concealment

Unclear risk of bias

Not specified

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 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

Attrition bias Incomplete outcome data Low risk of bias Study does not appear to have

any missing data for outcomes

Reporting bias Selective reporting Unclear risk of bias 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


Table 12: Details of studies assessing resistance development to rifampicin

Munford 1974 Guttler 1971 Blakebrough 1980 Simmons 2000 Deal 1969 Kaiser 1974

Main serogroup B/C B/C A B B C

Resistant serogroup C C A

Follow-up (weeks) 2 5 7 6 days 2-3 3-4

Rifampin dose 600mgX2 for 2days 600mgX1 for 4days 600mgX2 for 2days 600mgX2 for 2days 600mgX1 for 4days 600mgX1 for 4days

Population Families+children

(Brazil) Army recruits

(USA) Household+children

(Nigeria) Household+children

(New Zealand) Students

(USA) Household+children

(USA)

Resistance testing method Agar dilution Agar dilution Agar dilution E test Plate dilution Plate dilution

Number treated with rifampicin 67 147 48 82 15 13

Number of treatment failures 6 13 11 4 2 1

Initial MICs of isolates (µg/ml) <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=100-

200 3=3.2; 1=6.4 <2 <1 <0.12

Comments

No resistance in rifampin-

minocycline combination arm; 7 resistant isolates

detected out of 37 tested

75 isolates tested 11 isolates tested 7 isolates tested 4 isolates tested

Proportion of isolates with raised MICs

18.9% 76.0% 36.4% - - -

(Data received from Professor Paul and Professor Leibovici, authors of the Cochrane Review Zalmanovici et al. Antibiotics for preventing meningococcal infections 2013)


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


GRADE profile

Question: Should chemoprophylaxis be used for subsequent meningococcal disease among household contacts of cases of meningococcal disease?

Quality assessment Summary of findings

Importance No of patients Effect

Quality No of studies

Design Limitations Inconsistency Indirectness Imprecision Other considerations Chemoprofylaxis control Relative (95% CI)

Absolute

Subsequent case of meningococcal disease (30 days) (follow-up 30 days; clinical judgement or PCR/culture)

4 observational studies

serious1 no serious inconsistency

serious2 serious3 none

0/2322 (0%) 14/3353 (0.42%)

RR 0.16 (0.04 to

0.64)

4 fewer per 1000 (from 2

fewer to 4 fewer)

VERY LOW

CRITICAL

Subsequent case of meningococcal disease (1 year) (follow-up 1 year; clinical judgement or PCR/culture)

3 observational studies


serious2 serious3 none

2/1629 (0.1%) 9/2174 (0.4%)

RR 0.34 (0.11 to

1.06)


fewer to 0 more)

OOO VERY LOW

CRITICAL

Resistance to antibiotics (follow-up 14+ days)

3 randomised trials

serious4 serious5 no serious indirectness

serious3 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.

- - - - OOO VERY LOW

CRITICAL

Adverse effects: rifampicin vs ceftriaxone (follow-up 6+ days)

1 randomised trials


no serious indirectness

serious3 none

129/440 (29.3%) 88/416 (21.2%)

RR 1.39 (1.10 to

1.75)

83 more per 1000 (from 21 more to 159

more)

OO LOW

IMPORTANT

Adverse effects: rifampicin vs ciprofloxacin (follow-up 2 weeks)

2 randomised trials



very serious3,6

none

13/861 (1.5%) 15/737 (2%)

RR 0.75 (0.36 to

1.56)


fewer to 11 more)

OOO VERY LOW

IMPORTANT

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

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


Question: Should vaccination be used for subsequent meningococcal disease among household contacts of cases of meningococcal disease?


Importance Number of patients Effect

Quality No of studies

Design Limitations Inconsistency Indirectness Imprecision Other

considerations An appropriate

vaccine control

Relative (95% CI)

Absolute

Subsequent definite meningococcal disease (clinical features, culture, antibody and antigen test)

1 trial serious1 no serious inconsistency


serious2 None 0/520 (0%)

5/523 (0.96%)

RR 0.09 (0.01 to 1.65)

9 fewer per 1000 (from 9 fewer to 6 more)

LOW

CRITICAL

Adverse effects

0 - - - - - None - - - -

IMPORTANT 1 Unclear risk of selection, performance and detection bias; 2 Optimal Information Size (OIS) not met; No=Number

Question: Should chemoprophylaxis and vaccination be used for subsequent meningococcal disease among household contacts of cases of meningococcal disease?


Importance Number of patients Effect

Quality No of studies Design Limitations Inconsistency Indirectness Imprecision Other considerations Chemoprophylaxis and vaccination control

Relative (95% CI)

Absolute

Subsequent case of meningococcal disease at ≤30days

0 - - - - - none - - - -

CRITICAL

Subsequent case of meningococcal disease at ≤1 year

0 - - - - - none - - - -

CRITICAL

Resistance to antibiotics

0 - - - - - none - - - -

CRITICAL

Adverse effects

0 - - - - - none - - - -

IMPORTANT

No=number


Conclusions:

There is limited evidence on the effect of chemoprophylaxis (4 observational studies) and vaccination (1 quasi-

randomised 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


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.


References:(1-12)

1. World Health Organization. Control of epidemic meningococcal disease; WHO practical gudielines 1998. Available from: http://www.who.int/csr/resources/publications/meningitis/WHO_EMC_BAC_98_3_EN/en/index.html. 2. Hossain MJ, Roca A, Mackenzie GA, Jasseh M, Hossain MI, Muhammad S, et al. Serogroup W135 meningococcal disease, The Gambia, 2012. Emerging infectious diseases. 2013;19(9):1507-10. PubMed PMID: 23965435. Pubmed Central PMCID: 3810914. 3. Purcell B, Samuelsson S, Hahne SJ, Ehrhard I, Heuberger S, Camaroni I, et al. Effectiveness of antibiotics in preventing meningococcal disease after a case: systematic review. Bmj. 2004 Jun 5;328(7452):1339. PubMed PMID: 15178612. Pubmed Central PMCID: 420283. 4. European Centre for Disease prevention and Control. Public health management of sporadic cases of invasive meningococcal disease and their contacts 2010. Available from: http://www.ecdc.europa.eu/en/publications/publications/1010_gui_meningococcal_guidance.pdf. 5. Hoek MR, Christensen H, Hellenbrand W, Stefanoff P, Howitz M, Stuart JM. Effectiveness of vaccinating household contacts in addition to chemoprophylaxis after a case of meningococcal disease: a systematic review. Epidemiology and infection. 2008 Nov;136(11):1441-7. PubMed PMID: 18559124. Pubmed Central PMCID: 2870749. 6. Zalmanovici Trestioreanu A, Fraser A, Gafter-Gvili A, Paul M, Leibovici L. Antibiotics for preventing meningococcal infections. The Cochrane database of systematic reviews. 2013 Oct 25;10:CD004785. PubMed PMID: 24163051. 7. Samuelsson S, Hansen ET, Osler M, Jeune B. Prevention of secondary cases of meningococcal disease in Denmark. Epidemiology and infection. 2000 Jun;124(3):433-40. PubMed PMID: 10982067. Pubmed Central PMCID: 2810929. 8. Scholten RJ, Bijlmer HA, Dankert J, Valkenburg HA. [Secondary cases of meningococcal disease in The Netherlands, 1989-1990; a reappraisal of chemoprophylaxis]. Nederlands tijdschrift voor geneeskunde. 1993 Jul 24;137(30):1505-8. PubMed PMID: 8366938. Secundaire gevallen van meningokokkenziekte in Nederland, 1989-1990; chemoprofylaxe opnieuw bezien. 9. Kristiansen BE, Tveten Y, Ask E, Reiten T, Knapskog AB, Steen-Johnsen J, et al. Preventing secondary cases of meningococcal disease by identifying and eradicating disease-causing strains in close contacts of patients. Scandinavian journal of infectious diseases. 1992;24(2):165-73. PubMed PMID: 1641593. 10. Analysis of endemic meningococcal disease by serogroup and evaluation of chemoprophylaxis. The Journal of infectious diseases. 1976 Aug;134(2):201-4. PubMed PMID: 823273. 11. Kaiser AB, Hennekens CH, Saslaw MS, Hayes PS, Bennett JV. Seroepidemiology and chemoprophylaxis disease due to sulfonamide-resistant Neisseria meningitidis in a civillian population. The Journal of infectious diseases. 1974 Sep;130(3):217-24. PubMed PMID: 4213375. 12. Greenwood BM, Hassan-King M, Whittle HC. Prevention of secondary cases of meningococcal disease in household contacts by vaccination. British medical journal. 1978 May 20;1(6123):1317-9. PubMed PMID: 417754. Pubmed Central PMCID: 1604678.

http://www.who.int/csr/resources/publications/meningitis/WHO_EMC_BAC_98_3_EN/en/index.html

http://www.ecdc.europa.eu/en/publications/publications/1010_gui_meningococcal_guidance.pdf

dr. l. telisinghe - who

Documents