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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.

PICO4 – preliminary resultsV1.7- 16th April 2014 1

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.


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=128Abstracts screened n=196

For full text screen n=68+12=80

Number of records excluded following title screen n=522

Full texts screened n=64

Titles screened n=718

Unable to find articles n=16 3rd review by RJSAdditional articles reviewed based on reference search n=12

Number of articles considered n=4

ExcludedNot SR (i.e. reviews only)

n=58

Older version of SR n=2

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


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 2004Effectiveness of chemoprophylaxis

Unclear Yes

2 independent data extractors

Yes

Cochrane, HTA and national research register (UK); Medline; EMBASE; CAB heath

Mesh terms forNM; chemoprophylaxis; abx; HH; outbreak; tx; control

Reference searchContacted 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 2010Guidelines: 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 searchContacted 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)

Hoek 2008Effectiveness of vaccination in

Unclear Yes

Only 1 person

Yes

Medline; EMBASE

Unclear

Does not specify

No

List of

Yes No

No formal

No

Quality

Yes No No


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

addition to chemoprophylaxis to prevent IMD among HH contacts

reviewed titles and abstracts.

2 people reviewed full texts

MESH terms:NM; contact; HH; chemoprophylaxis

Reference lists searchedExperts contacted

excluded studies not provided

quality assessment presented.Results table does however include information which enables the reader to assess quality.

aspects of studies (including lack of controlling for confounders) taken into account when interpreting results in the discussion

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 SEARCHEDSTUDY QUESTION DOES NOT ANSWER THE FULL QUESTION REGARDING VACCINATION PROPOSED BY PICO4

Zalmanovici 2013Effectiveness 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 = LOWONLY 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.


Records identified through database search‡ N=2936

Records remaining after duplicates removed n=2381 Number of duplicates removed n=555

Number of records excluded following abstract screen n=562Abstracts screened n=627

For full text screen* n=65+12=77

Number of records excluded 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=21=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

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


Table 2: Chemoprophylaxis: description of studies considered (from Purcell 2004 + primary articles identified since 2004)AuthorYear

Design

SettingCountryRegion

Date from -

to

Index cases

(N)

Serogp of

casesHousehold contact

definitionNumber

of contacts

Total follow

up timeIntervention 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)

Samuelsson2000

Cohort

Endemic(3-4/100,000);

Denmark;National

(surveillance data)

Oct-95 to Apr-

97172 -

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)

Scholten1993

Cohort

Endemic (4/100,000),Netherlands;

National (surveillance

data)

Apr-89 to Apr-

90502

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)

Kristiansen1992

Time series

Endemic(1986:

6.7/100,000);Norway;Telemark

(surveillance data)

Jan-84 to Dec-

89 138B;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**

MDSG1976

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)

Kaiser1974

Randomised trial

OutbreakUSA;

Dade country,Florida

Apr-70 to Dec-

70N/A C

People who slept/ate in the same dwelling

as the case54 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)


AuthorYear

Design

SettingCountryRegion

Date from -

to

Serogp of

casesHousehold contact

definitionNumber

of contacts

Total follow up

timeIntervention Comparator Exposed

(N)Exposed

subsequent cases (n)

Unexposed (N)

Unexposed subsequent

cases (n)

Greenwood 1978 Epidemic

Nigeria, Zaria

Mar-77 to

May-77A

Small compound – all people; large

compound – close family; Koranic

school – allAverage size of compounds and

Koranic school - 17

1043Until 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 ≤30daysStudy Interventio

n 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 17.54Samuelsson 2000 0/724 2/72 0.02 0.00 - 0.42 34.45Scholten 1993 0/276 4/826 0.33 0.02 - 6.14 17.12MDSG 1976 0/693 5/1179 0.16 0.01 - 2.79 30.89M-H pooled RR (fixed effect) 0/2322 14/3353 0.16 0.04 - 0.64 100.00n=number of subsequent cases; N=number of contactsChi 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

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

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

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

Risk difference


% Weight

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


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 Interventio

n group (n/N)

Comparator group (n/N)

Risk ratio


% Weight

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

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


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




Comments

SelectionCohort 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.

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

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

CommentsData 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.

AnalysisAdequate control for confounders - - - - -Comments


Table 9: Chemoprophylaxis - risk of bias assessment for trials (Kaiser 1974)Domain Judgement JustificationSelection biasRandom sequence generation Low risk of bias Allocation by dice throwAllocation concealment Unclear risk of bias Not stated

Performance biasBlinding Low Not specified, but it is unlikely that

blinding would have influenced the outcome.

Detection biasBlinding 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 biasIncomplete outcome data Unclear risk of bias Not stated

Reporting biasSelective 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 vaccinatedStudy Intervention


Risk ratio 95% confidence interval

p -value

Greenwood 1978Definite only 0/520 5/523 0.09 0.01-1.65 0.11Definite & probable 1/520 9/523 0.11 0.01-0.88 0.04n=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 studyDomain Judgement JustificationSelection biasRandom 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 biasBlinding Low Not specified, but it is unlikely that

blinding would have influenced the outcome.

Detection biasBlinding 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 biasIncomplete outcome data Low risk of bias Study does not appear to have

any missing data for outcomes

Reporting biasSelective 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 CResistant serogroup C C AFollow-up (weeks) 2 5 7 6 days 2-3 3-4Rifampin 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 dilutionNumber treated with rifampicin 67 147 48 82 15 13Number 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

ImportanceNo of patients EffectQualityNo of

studies Design Limitations Inconsistency Indirectness Imprecision Other considerations Chemoprofylaxi

s control Relative(95% CI) Absolute

Subsequent case of meningococcal disease (30 days) (follow-up 30 days; clinical judgement or PCR/culture)4 observational

studiesserious1 no serious

inconsistencyserious2 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

studiesserious1 no serious

inconsistencyserious2 serious3 none

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

RR 0.34 (0.11 to 1.06)


fewer to 0 more)

OOOVERY LOW

CRITICAL

Resistance to antibiotics (follow-up 14+ days)3 randomised

trialsserious4 serious5 no serious

indirectnessserious3 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.

- - - -OOOVERY LOW

CRITICAL

Adverse effects: rifampicin vs ceftriaxone (follow-up 6+ days)1 randomised

trialsserious4 no serious

inconsistencyno 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)

OOLOW

IMPORTANT

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

trialsserious4 no serious


very serious3,6

none

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

RR 0.75 (0.36 to 1.56)


fewer to 11 more)

OOOVERY 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?


ImportanceNumber of patients EffectQualityNo of

studiesDesig

nLimitation

s 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


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 effects0 - - - - - None - - - - IMPORTAN

T1 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?


ImportanceNumber of patients EffectQualityNo of studies Design Limitations Inconsistency Indirectness Imprecision Other considerations Chemoprophylaxis and vaccination control Relative

(95% CI) Absolute

Subsequent case of meningococcal disease at ≤30days0 - - - - - none - - - - CRITICALSubsequent case of meningococcal disease at ≤1 year0 - - - - - none - - - - CRITICALResistance to antibiotics0 - - - - - none - - - - CRITICALAdverse effects0 - - - - - none - - - - IMPORTANTNo=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.ecdc.europa.eu/en/publications/publications/1010_gui_meningococcal_guidance.pdf

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

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

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