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Diagnose en surveillance van infectieuze aanDoeningen
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risk & Prevention HPv
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Write in your agendaNext seminar
21/11/2013
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Evolutionary changes in antimicrobial resistance of
invasive Neisseria meningitidis isolates
Recent trends
Dr. Bertrand Sophie, Dr. Mattheus Wesley, Ig. Carion Françoise and Dr. Vanhoof Raymond.
Bacterial Diseases Division
Rue Juliette Wytsmanstraat 14 | 1050 Brussels | BelgiumT +32 2 642 51 11 | F +32 2 642 50 01 | email: [email protected] | www.iph.fgov.be
1
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidis
• Gram-negative organism (diplococcal form)
• Asymptomatic carriers (colonises the nasopharynx)
• Exclusive human pathogen
• Transmission via droplet secretion and close contact
• Invasive meningococcal diseases : meningitis, septicaemia
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidisInvasive meningococcal diseases
• Fulminant septicaemia (coma, purpura fulminans)
• Case-fatality rate (10%)
• Sequelae (neurological, amputations)
• High incidence among infants
Net societal costs per case (estimations 2002) :
UK = 12.513€ /case BMJ 2002;324:1-6Québec = 14.070 € /case Vaccine 2002;20:2840-2844
2
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
• Exists since 1971
• Officially recognised by INAMI/RISIV in 2010
• Surveillance and detection of outbreak(s) :detection of new serogroups (vaccine pressure)
detection of new phenotypes (capsule switching)
detection of antibiotic resistances
Neisseria meningitidisBelgium : The National Reference Centre
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidisTyping Methods
• « classical » typing
3
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
• Molecular typing
Neisseria meningitidisTyping Methods
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidisDistribution of serogroups B and C in Belgium (1991-2011)
0
50
100
150
200
250
300
350
400
90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11
Cas
es
Total B C
4
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidisDistribution of serogroups B and C in Belgium (1991-2011)
0
50
100
150
200
250
300
350
40090 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11
Cas
es
Total B C
Serogroup Cvaccination
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
• Prompt treatment• Prevention: rifampicin or ciprofloxacin• Penicillin G : drug of choice for IMD
Neisseria meningitidisTreatment of IMD
5
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Antimicrobial susceptibility testing for 1,933 strainsCtx, Chl and CipAll susceptible
Rif-R1,932 strains susceptible
Penicillin1,637 are PenS(Susceptible)273 are PenI(Intermediate)23 are PenR(Resistant)
296 / 1,933 PenNS= 15,3 %
Neisseria meningitidisSurveillance 2000 to 2010 in Belgium
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidisDistribution of the MIC for penicillin G, 2000
6
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidisDistribution of the MIC for penicillin G, 2000 and 2006
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidisDistribution of the MIC for penicillin G, 2000, 2006 and 2010
7
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidisEvolution of MIC50 (expressed in µg/ml) in PenS and PenNS isolates
0.012 0.016 0.023 0.032 0.047 0.064 0.094 0.125 0.19 0.25 0.38 0.520002001200220032004200520062007200820092010
1 MIC50: Minimal Inhibitory Concentration for 50% of the isolates; values are shaded
YearMIC501 values and number of isolates at indicated concentration
PENS PENI PENR
PENNS
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidisPenicillin G susceptibility linked to penA alleles
8
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidisDistribution of the penA allele among the Non Susceptible population and relation between the penA allele and the average MIC value.
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidisDistribution of the most frequent penA alleles in the PenNSisolates, between 2000 and 2010
0%
20%
40%
60%
80%
100%
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
penA1
penA12
penA14
penA9
penA13
others
9
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidisDistribution of penA alleles in the different serogroups
penA1penA12penA14penA9penA13
B C Others
penA1penA12penA14penA9penA13
penA1penA12penA14penA9penA13
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidisDistribution of the most frequent penA alleles in the PenNSisolates, between 2000 and 2010
0%
20%
40%
60%
80%
100%
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
penA1
penA12
penA14
penA9
penA13
others
Serogroup Cvaccination
10
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
• N. meningitidis remains susceptible to antibiotics
• Susceptibility to penicillin decreases
• Pen S population is less sensitive
• Decreased susceptibility to penicillin G is linked
to alterations of the penA gene
• The penA allele is predictive
Neisseria meningitidisConclusions
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Neisseria meningitidisTo read more ...
11
Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends
Thank you for your attention!
Treatment and new vaccines formeningococcusI. De SchutterUZ Brussel, Pediatric Pulmonology, CF-Clinic and PediatricInfectious Diseases
1
2
Meningococcal disease: Clinical syndromes
43%
48%
meningitis bacteremia pneumoniaarthritis otitis media epiglottitis
http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/mening.pdf
3
Meningococcal disease: outcome
Case fatality rate:Invasive menigococcal disease: 9-12%Menigococcemia: up to 40%
sequelae: 20% of survivorsHearing lossNeurological damageLoss of a limb
http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/mening.pdf
1
4
Meningococcal disease: treatment
Bacterial meningitis (pathogen unidentified)3rd generation cephalosporine ± ampicillin*Dexamethasone (controversial)
N. meningitidis identified – susceptibility pending1st choice: 3rd generation cephalosporineAlternative: Aztreonam or FQ2
N. meningitidis identified – susceptibility proven1st choice: Penicilline G
* In case of: child <3months or risk factor (alcoholism, debilitatingilness, impaired cellular immunity,…)
Sanford guide Belgian/Luxembourg Ed 2010-2011
5
Prophylaxis
Rationale: prevention through elimination of carriership in close contacts
Risk secundary case in household members: 2-4/1000 (= 500-800x risk in general population)1,2
Who should get chemoprophylaxis?2
Patient: at discharge from the hospital (unless he was treated with an agent that eliminates carriership, i.e; ceftriaxone or ciprofloxacine)Close contacts:
Close contacts (contact period 7d prior to disease in index patient)- Household members- Persons that shared a room (overnight) with the index patient- Intensive face to face contact during >4h (indoors)Anyone directly exposed to the patient’s oral secretions (healthcareworkers)Indiv. seated next to index case on a long travel (>4h) (to beconsidered for chemoprophylaxis)
1http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/mening.pdf2 Handboek Richtlijnen Infectieziektenbestrijding Vlaanderen Ed. 20113 Sanford guide Belgian/Luxembourg Ed 2010-2011
1
6
Prophylaxis: which antibiotic?
500mg 1x10mg/kg
1x
10mg/kg
1xazithromycin
250mg IM 1xceftriaxone
1g 2x/d5 daysspiramycin
15 mg/kg(max 500mg)
1x
Children> 5y
FQ2ciprofloxacin
rifampicin
500mg 1x
600mg 2x/d
2 days
10mg/kg 2x/d
2 days
5mg/kg 2x/d
2 days
PregnancyAdo’s & adults
Children< 5y
neonates
Sanford guide Belgian/Luxembourg Ed 2010-2011
7
Meningococcal infections: evolution1991-2011
Vaccination Men C
- 88%
WIV annual report 2011
1
8
Current vaccination schedule (Flanders)
X14 jaar
XXXXX(X)12 jaar
X10 jaar
X6 jaar
XX15 maand
XX12 maand
(X)XX4 maand
XX3 maand
XXX2 maand
TdpaHPVHBVIPV-DTPa
MenCMBRRota**Pnc-13IPV-
DTPa-Hib-HBV
leeftijd
9
Meningococcal vaccines- timelines
MenA CV- Africa
MenCCVMenPSV4
2001 20101970-80’s
MenBV
?
MenCV4
1
10
Characteristics of the immune response evoked bydifferent vaccine types
√xHerd immunity
√xReduction of carriage
√xBooster effect
√xImmune memory / long term protection
√xT-cell dependent
√√B-cell dependent
√xImmunogenicity in <2y olds
Protein conjugatevaccines
Polysaccharidevaccines
Property
Adapted from Nohynek et al. PIDJ 2009;28(10):S127-S132
11
1 x>11j(<12m) β
CRM 197Men A PS 10 μgMen C PS 5 μg
Men W135 PS 5 μg Men Y PS 5 μg
CVMenveo®
1 x>12mTetanus toxoidMen A PS 5 μgMen C PS 5 μg
Men W135 PS 5 μg Men Y PS 5 μg
CVNimenrix®
3-18m: 3x >18m: 1x
All ages **/Men A PS 50 μgMen C PS 50 μg
Men W135 PS 50 μg Men Y PS 50 μg
PSVMencevax®*
<12m: 3 x >12m: 1 x
> 2mCRM 197 (AL-hydroxide)
Men C PS 10 μgCVMenjugate-kit®
<12m: 2 + 1 >12m: 1 x
> 2mCRM 197(AL-
phosphate)
Men C PS 10 μgCVMeningitec®
<12m: 2 + 1 >12m: 1x
> 2mTetanustoxoid(AL-hydroxide)
Men C PS 10 μgCVNeisVac-C®
Dosing(1= 0,5ml)
LisencingCarrier-proteïn
Ag componentsTypeVaccine
*Recommended for use in travelers to the “meningitis belt ” or contacts of Men A or Men C cases ; ** poorly immunogenic in < 2y oldsβ Green book UK: Recommended for travelers <12m
1
12
Men B vaccines: development
Difficulties encountered in development of Men B vaccines
Polysaccharide capsule resembles structure of foetalneural cell adhesion molecules
poorly immunogenicRisk for autoimmune disease?
Men B strains are highly heterogeneous
Solutions?Outer membrane vesicles (OMV) vaccines – monovalentOuter membrane vesicles (OMV) vaccines – multivalentMulticomponent vaccines (recombinant protein vaccines)
Dull PM et al. Vaccine 2012; 30S:b18-b25Ladhani SN et al. Vaccine 2012; 30:3710-16
13
Monovalent Outer membrane vesicles(OMV) vaccines - Trials
1-21y: 51%1-4y: -23%5-21y: 69%
1-21y1995Chile
(Boslego J et al. Vaccine 1995)
B:4:P1,15
B:4:P1,15
B:15:P1.7,16
vaccine
83%10-14y1987-88Cuba
(Sierra GV Et al. NIPH Ann 1991)
>48m: 74%24-47m: 47%<24m: -37%
3m-6y1989-91Brasil
(de Moraes JC et al. Lancet 1992)
57.2%11-16y1989-91Norway
(Bjune G et al. Lancet 1991)
efficacyAge groupperiodcountry
Management for epidemic outbreaksMain limitations:
- Strain specific respons no immunity to heterologousstrains
- Immunity of short duration (particularly in infants)
1
14
Multivalent OMV vaccines
Expression of multiple PorA- Ag (rDNA technology) (2-, 6-, 9-valent)
The Netherlands & UK (6-valent)2 trials (age: 8w - 8y)16-100% sign. Antibacterical Ab response (dependent onPorA variant)Fast lowering of Ab levels- no longterm protection
Coverage to upto ~75% circulating Men B strainsSingle protein (PorA) component
Sufficiently broad coverage?changing epidemiology?
Sadarangani M et al. Lancet Infect Dis 2010; 10:112-24
15
Multicomponent vaccine development
4CMenB: Bexsero®-Novartis3 subcapsular MenB Ag + OMV (PorA P1.4)
- Factor H binding protein (FHbp variant 1.1) (fusion with GNA2091)- neisserial adhesin A (NadA variant 3.1)- Neisseria heparin binding antigen (NHBA variant 1.2) (fusion with
GNA1030)Phase II trials (UK): schedule 3 +1
Well toleratedImmunogenic in infantsEvidence of immune memory
Phase III trials (3630 infants): schedule 3 + 1Confirmation of phase II findingsNo clinical significant interaction with routine vaccines
Estimated vaccine coverage based on MATS: Europe: 73-87%Application for EMA Marketing authorization, for use in children ≥ 2m, ado’s and adults – approval awaited
Serruto D. et al. Vaccine 2012; 30S:B87-97
1
16
Multicomponent vaccine development
rLP2086 vaccine - PfizerTwo fHbp variants
rLP2086 fromsubfamily ArLP2086 fromsubfamily B
Phase I studiesVaccine well toleratedBactericidal Ab againstall fHbp variants
Phase II trialsresults awaited
OMV based vaccine – WRAIR3 genetically modified OMV’s
6 PorA variants3 PorB variants2 fHbp variantsOpcANadA
Phase I trialsInduces bactericidal Ab response in humans
16th International Pathogenic Neisseria Conference 2008
Vipond C. et al. Vaccine 2012;30S:B10-17
13-valent vaccine
17
Other possible vaccine candidates(not all mentioned)
Avoidance of PorA –dependentstrain restriction
Serum Ab response: 8-31%
(adults)
X(antisera do mediateopsonophagocytosis)
N lactamina OMV-vaccine
Nasal IgA:√Serum Ab
response: 43-75%
Intranasal OMV-vaccines
Studies done-results awaited√
Transferrin-binding proteins
Highly conservedprotein =>
crossprotection?x√Protein NspA
advantagesSerum
bactericidal Ab humans
Serum bactericidal Ab
mice
Vaccine type/component
Sadarangani M et al. Lancet Infect Dis 2010; 10:112-24
1
18
Conclusions
major advances in past 20y bring us closer to universal prevention of meningococcal disease
Meningococcal vaccination is routine in some countriesIntroduction of CV against Men C => important decreasein Men C diseaseAvailability of low cost CV against Men A for AfricaAvailability of 4-valent CV against Men ACW135YAvailability and use of monovalent OMV vaccines forcontrole of hyperendemic clonal Men B diseasesNear future: broadly cross-protective Men B vaccines?
Antimicrobial Resistance in Humans and Animals:
Time for Action
Herman GoossensVaccine & Infectious Disease Institute
University of AntwerpBelgium
1
27 democratic European countries23 languages> 490 million people united in diversityMember States remain sovereignPartial delegation of sovereignty to common EU institutionsCouncil, Parliament & Commission in EU decision processes
What is the European Union?
2
OutlinePolitical initiativesSurveillance- Humans- Animals
Targets and interventionsAwarenessResearch- Joint programing- IMI- Horizon 2020
3
Political Initiatives
4
First Steps Towards a European Antibiotic Policy
Economic & Social Committee on Resistance to Antibiotics as a Threat to
September 1998: EU Conference on the Microbial Threat, Copenhagen & Copenhagen
Recommendations
Scientific Steering Committee on Antimicrobial
5
Many EU Presidencies on AMR
Belgium (July - December 2001):- Expert conference, coincided with Health Council meeting of Ministers in Brussels on November 15 18 November 2001-Sweden (July-December 2009):- Innovative Incentives for Effective Antibacterials
REACT meeting in September 2010.Belgium (July - December 2010):- European Strategies to Monitor and ControlInfection, Antibiotic Use and Resistance in Health-care Facilities , Brussels 8 10 November 2010Denmark (January June 2011)- Antimicrobial Resistance in Humans and
Animals: Time for Action Copenhagen 14 15 March 2011.
Other: Sweden (2003), Slovenia (2008), France (2008), Czech Republic (2009)
6
ESAC: European Surveillance of Antimicrobial Consumption
Launched in November 2001 (Belgian EU Presidency)ESAC is an international network of surveillance systems, aiming to maintain a continuous, comprehensive and comparable database on antimicrobial consumption for all Member States, candidate countries and EFTA-EEA countries Coordinator: Herman Goossens (UA)Funding organisation: DG SANCO of EC (2001-2007) and ECDC (2007-2011)Transfer to ECDC (Stockholm) in July 2011New acronym: ESAC-Net
7
Council Recommendations on the Prudent Use of Antimicrobial Agents, 15
November 2001
8
European Centre for Disease Prevention and Control (ECDC) and European Medicines Agency (EMA) pipeline analysis:
- Very few antibacterial compounds in late stage clinical development
- Gram negative infections particularly critical
London School of Economics report on incentives, - Push incentives (research funding, tax incentives, PDPs)- Pull incentives (regularory adjustments, awards, patents,
advance market commitments, pricing and reimbursements)- Combination Push/Pull (Orphan Drug incentives, Call
Option for Antibiotics, Special Designation for priority Antibiotics)
Need for a new business model for new drugs that decouples profit from use
Swedish EU Presidency Conference: "Innovative Incentives for Effective
Antibiotics", September 2009
9
Source: EMEA, 2009. http://ecdc.europa.eu/en/publications/Publications/0909_TER_The_Bacterial_Challenge_Time_to_React.pdf
The Antibiotic Pipeline
13 agents against Gram-positive bacteria 6 agents against Gram-negative bacteria
10
Trans Atlantic Task Force on Antimicrobial Resistance - TATFAR
EU-US Summit Washington 3 November 2009
The EU-US Summit Declaration called
transatlantic task force on urgent antimicrobial resistance issues focused on appropriate therapeutic use of antimicrobial drugs in the medical and veterinary communities, prevention of both healthcare- and community-associated drug-resistant infections, and strategies for improving the pipeline of new antimicrobial drugs, which could be better addressed by intensified
11
TATFAR Objectives
Increase the mutual understanding of US and EU activities and programmes relating to antimicrobial issues
Deepen the transatlantic dialogue
Provide opportunities to learn from each other
Promote information exchange, coordination and co-operation between the US and the EU
12
TATFAR Members
United States Department of Health and Human Services
Office of Global Health Affairs (OGHA)
Centers for Disease Control and Prevention (CDC)
Food and Drug Administration (FDA)
National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID/NIH)
European Commission: EC-Directorate General for Health and Consumers EC-Directorate General for Research and InnovationEuropean Centre for Disease Prevention and Control (ECDC)European Medicines Agency (EMA)European Food Safety Authority (EFSA)
Council of the European Union:Represented by the TRIO Presidency (Spain, Belgium, Hungary)
USA EU
13
TATFAR report
The TATFAR report was made public on 22 Sept 2011Full report available at: http://www.ecdc.europa.eu/en/activities/diseaseprogrammes/TATFAR/Documents/210911_TATFAR_Report.pdfEndorsed by the US Secretary of Health and Human Services, Kathleen Sebelius, and EU Commissioner for Health, John DalliTATFAR has identified a set of 17 recommendations in key areas where future cooperation would prove fruitful
14Conclusions14
WORKSHOP 1: How to begin, how to implement and how to sustain a national (and local) hand hygiene campaign
WORKSHOP 2: Indicators of hospital infection control and antimicrobial management
WORKSHOP 3: To roll-out a common European methodology for Point Prevalence Surveys on AM and HAI in acute care hospitals
WORKSHOP 4: Infection prevention and prudent use of antimicrobial agents in long-term care facilities
Belgian EU Presidency Workshop:November 8-10, 2010 in Brussels
15
Expert-Proposed European Strategies
Initiate or continue hand hygiene campaigns and use hand hygiene as a quality indicator Collection and monitoring of structure-of-care quality indicators and indicators of good practice (e.g. consumption of alcohol solution)ECDC Point Prevalence Surveys on HAI and AB Use (completed in all Member States by November 2012; repeated at least once every 5 years)National LTCF resident safety programmes, external audits of LTCF and monitoring
Goossens, Lancet Infect Dis 2011, April 7th
16
Danish EU Presidency Workshop:
Combating Antimicrobial Resistance: Time for Joint Action
March 14-15, 2012 in Copenhagen
17
Antimicrobial use in Animals: An example of effect of intervention by
reducing veterinarians profit from drug sale (Denmark)
New veterinary regulation on medicines adopted in 1995
Profit ontherapeuticsreduced
Reduction of total usage of prescribed veterinary medicine by 30-40%
Data: VetStat
18
Relation between use of antibiotics as growth promotion and of vancomycin resistant E. faecium in pigs
Modified from DANMAP 2007, 2008
Data as basis for action
Ban of Avoparcin
Stop use of Tylosin as growth promoter
19
20
Surveillance
21
EU Public Health Funding of Surveillance
EARSS = European Antimicrobial Resistance Surveillance System
Endorsed by European Parliament and the Council Legislation 2119/98/EC and Commission Decision 2000/96/EC
Moved to ECDC in 2010 (EARS-Net)
ESAC = European Surveillance of Antimicrobial Use
Endorsed by Council Recommendation of the 15th November 2001 on the prudent use of antimicrobial agents in human medicine (2002/77/EC).
Moved to ECDC in 2011 (ESAC-Net)
22
Correlation Between Penicillin Use and Prevalence of Penicillin-
resistant S. pneumoniae
Consumption of Penicillin (J01C) in DID, AC 2000
181614121086420
Peni
cilli
n-re
sist
ant S
. pne
umon
iae
(%)
50
40
30
20
10
0
UK SW
SI
PT
PL
NL
LU ITIE
HU
HR
FR
FI
ES
DKDE
CZ
BE
AT
Organism year of isolation [source of
information]
Antibiotic resistance
Antibiotic use -ATC group
(year of data)
No. of countrie
s
Spearman correlation (r)(confidence
interval)
P-value
S. pneumoniae2001[7]
Penicillin Penicillin J01C(2000)
19 0.84(0.62-0.94)
<0.001
Goossens et al., Lancet 2005; 365: 579-87
23
Le Point, January 2006
24
Outpatient Antibiotic Use in DID in 33 European Countries in 2009.
DID and PID data available
Adriaenssens et al. JAC 2011 66: vi79-87.
25
Outpatient Antibiotic Use in PID in 17 European Countries in 2009.
Country IT GR RU BG LT HR IE PT BE SI CZ AT FI DK EE NL SERanking PID 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Ranking DID 2 1 15 8 7 5 6 4 3 13 9 12 10 11 17 16 14
DDD/package 2.6 7.3 3.0 5.7 6.6 7.4 8.6 9.0 10.9 6.8 8.1 8.1 9.5 9.3 6.5 7.4 11.8
Adriaenssens et al. JAC 2011; 66: vi79-87.
1000 DDD 333 packages 90 packages
26
Point Prevalence Surveysin Hospitals
Entire hospitalIn each in-patient ward:- Collecting the number of patients present at 8 am- Collecting information about the treated patients, only
Treated patients:- Demographic data (age/gender)- Prescription (drug, dose, route of administration)- Indication/Diagnosis- Basic quality indicators (e.g. policy compliant)
19 pre-defined diagnosis groups by anatomical site
Indication for therapy: community and hospital acquired infection or (medical/surgical) prophylaxis
27
Web-Based Data Entry
28
ECDC PPS23 countries, 66 hospitalsProtocol:
Light: 16 hospitalsStandard: 50 hospitals
19,888 patientsHAI: 7.1%Antimicrobial use: 34.6%
Most frequent types of HAI
Zarb et al, EuroSurveillance Nov 2012
22%
12%
17%
19%
22%
0% 10% 20%
Other HAI
Bloodstream infections (BSI)
Urinary tract infections (UTI)
Surgical site infections (SSI)
Pneumonia (PN)/ Lowerrespiratory tract (LRTI)
29
Prevalence (%) of HAI by hospital
0%
5%
10%
15%
20%
25%
11
13
15
20
38
59
58
34
27
63
49
30
50 2
62
14
51
61
40
37 7
48
55
41
16
18
17
46
33
24
57
21
12
36
56
19
39
43
60 5
53
22
42 4
29
45
23
28
32
44
52
35 6
54 8
47 3 1
26
31 9
25
10
Hospital number
% p
atie
nts
wit
h H
AI
Mean prevalence: 7.1% [0%-23%]
30
Use of Results at European Level
Hypothetical figures!
31
European Surveillance of Veterinary Antimicrobial Consumption
(ESVAC)
Initial investigation (September 09 December 09)
Pilot project (2009-2011) Development and implementation of protocol and data collection form (template) to obtain harmonized dataCollecting data accordingly from MS willing to participate
ESVAC is managed by the European Medicines Agency (EMA)
32
EMA-ESVACAntibiotic Use in Animals in Europe
www.belvetsac.ugent.be
Data 2007
Grave et al. JAC, 65:2037-40, 2010
33www.belvetsac.ugent.be
Antibiotic Use in Animals in Belgium and the Netherlands
0
50
100
150
200
250
2007 2008 2009 2010 2011
mg
act
ive c
om
po
un
d/
kg
b
iom
ass
The Netherlands
Belgium
Lineair (The Netherlands)Lineair (Belgium)
3434
35
35 40% E. coli resistant for ceftiofur 60% of broilers carrier of ESBL
Belgian broilers
Persoons et al., 2010
36
68 6848
30 26 2412 6 6 6 4 2 2 2
020406080
100Percentage
Pig
Herds
Frequency of Use of Antimicrobial Compounds in Belgian Fattening Pig Herds
(n=50) in 2010
Callens et al. Prev Vet Med , 106:53-62, 2012
37
Targets and Interventions
38
39
40
Scottish ESAC 2009 PPS
Hospitals included: 31Patients included: 8,732Treated patients: 28%Areas of good practice:- Greater use of narrow spectrum antimicrobials
compared to the rest of Europe
Areas where improvement is required:- Indication documented: 76% (target: 95%)- Compliance with NHS Board guidelines: 58% (target:
95%)- Surgical prophylaxis greater than one day: 30%- Cephalosporins for surgical prophylaxis: 40%
William Malcolm, Health Protection Scotland, Report March 2010
41
Results Scotland Empirical Prescribing
National compliance 83% and 4/14 NHS boards achieved target2011 - need to focus on improvement
42
Awareness
43
Belgian National Public Campaigns
When: since November 2000, annually during winter seasonOrganised by: BAPCOC (Belgian Antibiotic Policy Coordination Committee)Budget:- 400,000 EUR/annual campaign
Interventions targeting the public:- Ads on TV, radio and newspaper- Information booklets- Folders- Posters- Internet campaigns: www.antibiotics-info.be
44
Outpatient Antibiotic Use in Belgium in Packages per 1,000 Inhabitants
per Day July - June
46
Outpatient Antibiotic Use in Belgium in DDD per 1,000 Inhabitants
per Day July - June
47
Trends of the Relative Outpatient Use of Antibiotic Subgroups in
Belgium (1997-2009).
48
49
Slogans & logos
50
Images from National Campaigns on Prudent Use of Antibiotics
51
52Earnshaw S, et al. Euro Surveill 2009;14(30) &http://antibiotic.ecdc.europa.eu
2008 - Materials for general public- 32 countries participated
2009- Materials for primary care
prescribers- Website translated in all EU
languages, three TV spots developed
- 34 countries participated
2010- Materials for hospital prescribers- 36 countries participated
2011-2012- Consolidation
EAAD, 2008-2012
53
47%49%
4%
n=476
Print Online Newsagency
Number of clippings 476
Reach (print) 51,334,208Circulation (print) 17,152,770Visits (online) 54,241,600
Key Figures
Coverage in the Course of Time
EAAD 2010Media coverage
Media Type Media Distribution
53
33%
17%
48%
2%
n=476
local regional national international
CW 40 CW 41 CW 42 CW 43 CW 44 CW 45 CW 46 CW 47 CW 48 CW 49 CW 50 CW 51
Newsagency 0 0 0 0 0 0 20 0 0 0 0 0
Online 0 0 0 1 0 2 219 6 4 1 2 0
Print 1 0 1 2 3 9 122 55 12 9 6 1
0
100
200
300
400Peak Week 46
15.11 16.11 17.11 18.11 19.11 20.11 21.11
Newsagency 2 6 10 2 0 0 0
Online 6 70 74 40 24 4 1
Print 2 12 25 52 26 4 1
0
20
40
60
80
100
120
54
Eurobarometer Opinion Poll, November-December 2009
Antibiotics kill viruses. True or false?% respondents with correct answer
73%)
Special -Dec. 2009.
61 73%
41 60%
31 40%
21 30%
14 20%
55
The United States and Canada joined in 2010
Hong Kong joined in 2011
Australia joined in 2012
56
Research
57
EU Research Project Funding
FP5 (1999-2002)100+ million for 80 mainly
smaller projects on antimicrobial resistance
FP6 (2003-06)186 million for fewer, larger
and more focused projects
FP7 (2007-13)273 million by 2012;
antimicrobial resistance is a key priority
More than560 million
In 2013, research into antimicrobial resistance will be a priority area!
58
Public Funding for Research (Source : ERA Key Figures 2007, EC)
0
10000
20000
30000
40000
50000
60000
70000
80000
90000
100000
Ger
man
y
Fran
ce UK
Italy
Spai
n
EU C
omm
unity
Net
herla
nds
Swed
en
Belg
ium
Finl
and
Aust
ria
Den
mar
k
Portu
gal
Irela
nd
Pola
nd
Gre
ece
Cze
ch re
p.
Hun
gary
RO
man
ia
Slov
enia
Slov
akia
Bulg
aria
Luxe
mbo
urg
Lith
uani
a
Esto
nia
Cyp
rus
Latv
ia
Mal
ta
Chi
na
Japa
n
Uni
ted
Stat
es
Mio
Eur
o
Research Funding in the EU and US
EU27 + ECTransnational Collaboration
in EU 27: 10 to 15 %SINCE 1999: APPROXIMATELY 350
MILLION EURO ON AMR (1/3 IC; 1/3 ABU; 1/3 NEW TARGETS)
Competitive Federal Funding
in US : 85 to 90 %VERY LITTLE ON AMR?
59
Joint Programming
The overall aim of Joint Programming is to align national research efforts in order to make better use of Europe's precious public R&D resources and to tackle common European challenges more effectively in a few key areas.
It may involve collaboration between existing national programmes or the setting up of entirely new ones.
60
Joint Programming on AMR
Countries: BE, CH, CZ, DE, DK, ES, FI, FR, GR, IT, NL, NO, PL, RO, SE, TK, UK
Management Board (funding organisations)
Scientific Advisory Board (experts)
Strategic Research Agenda 2020 and beyond (DL date: December 2013)
Calls for proposals
Complements EU level funding
61
Members of the SAB
Herman Goossens (Chair) Antoine Andremont Fernando BaqueroMarc BontenYehuda CarmeliNiels Frimodt-MøllerBruno Gonzalez-Zorn Hajo GrundmannStephan HarbarthBirgitta Henriques NormarkPatrice Nordmann Arnfinn SundsfjordTim Walsh Paul Williams
62
Mission Statementof the SRA
The JPI on AMR will develop integrated approaches to pursue unique world-class research on AMR that will be translated into new prevention and intervention strategies that improve the public health and wellbeing of populations, and delivers economic and societal benefit throughout Europe and beyond.
63
Innovative Medicines Initiative:the Largest Public-Private
Partnership n Life Sciences R&D
2 Billion Euro
1 Billion 1 Billion
Public PrivatePartnership
EFPIA = European Federation of Pharmacological Industries and Associations
64
New Drugs 4 Bad Bugs (ND4BB)COMBACTE
Combating Bacterial Resistance in Europe
65
The future of COMBACTECLIN-, LAB- and STAT-Net
The EORTC is both multinational and multidisciplinary, and the EORTC Network comprises over 300 hospitals and cancer centers in over 30 countries which include some 2,500 collaborators from all disciplines involved in cancer treatment and research.
66
Setting sail for Horizon 2020
Europe needs cutting edge research and innovationEssential to ensure competitiveness, growth and jobsVital to tackle pressing societal challenges 3% of GDP invested in R&D: headline target of Europe 2020
67
Horizon 2020 Timeline
From 30/11 Parliament and Council negotiations on the basis of the Commission proposalsOngoing Parliament and Council negotiations on EU budget 2014-20 (including Horizon 2020)By end 2013 Adoption of legislative acts by Parliament and Council on Horizon 2020 January 2014 Horizon 2020 starts; launch of first calls
68
International K.O. Mouse Consortium
International Cancer Genomics Consortium
Continued International Cooperation
International Human Metagenome Consortium
International Human Epigenome Consortium
International Rare Disease Research
Consortium
Int. Initiative for Traumatic Brain Injury
Research
© rtguest/Fotolia.com
69
Why is Europe (Partially) Successful in Controlling AMR?
Bottom up Member States initiatives (e.g. rotating European presidencies) resulting in top down political support and commitment at European level (e.g. Council recommendations);Successful surveillance programmes on antimicrobial use and resistanceStrong leadership with close link between opinion leaders, policy makers and politicians Support of AMR research projects by the EC, providing evidence for public health interventionsEuropean antibiotic awareness day (EAAD), built on success stories of countries;
Carbapenemase producing Enterobacteriaceae: A global major public health threat ?
Y. Glupczynski
National Reference Center for multidrug-resistant EnterobacteriaceaeCHU Mont-Godinne, Yvoir, Belgium
MONT-GODINNE
Escalating antimicrobial resistance in Enterobacteriaceae
• Enterobacteriaceae = large family of bacteria (+/- 60 genera) human/animal commensals (intestine), environment (water/soil, sewage), pathogens (strict or opportunistic)
Principal species: Serratia, Citrobacter, Enterobacter, Proteus, Morganella, K. pneumoniae, E. coli (75-90% of non complicated UTIs)
Involved in health-care associated infections (e.a. K. pneumoniae, Enterobacter sp)
β-lactam agents: have been used widely for treatment of infections caused by Enterobacteriaceae since the 70-80’sWorldwide emergence of community-acquired ESBL+ strains since the early 2000’sCarbapenems: last resort antimicrobial agents for the treatment of ESBL+ infectionSince 1993: Emergence of first carbapenem-R isolates due to production of carbapenemasesTherapeutic dead-end (Almost no reserve/new drugs in the pipelines)Use of colistine (nephrotoxicity), tigecycline (inconstant activity, bacteriostatic), sometimesaztreonam (depends on type of carbapenemase, and absence of other concomitant resistance mechanisms)
Carbapenemases-Enterobacteriaceae
Reservoirs
With courtesyFrom P. Nordmann
Class BGroup 3
AmpC TEM/SHVCTX-M, KPC
OXASPM, GIM, SIM
CephsInhib-R
Pens, CephsInhib-S
Pens (Oxa++)Inhib-R/S
CarbapenemsInhib-R
K Bush, curr. Opin. Invest. Drugs 3-1284 (200
Cephalosporinases Penicillinases, ESBLs, Carbapenemases Carbapenemases
• Plasmid encoded (mobile through various genetic elements: transposons, integrons)• R to carbapenems (variable level of R) and to most other ß-lactams• Variable susceptibility to beta-lactamases inhibitors (depending on carbapenemase type)• Often co-resistant to other classes of antibiotics (aminoglycosides, trimethoprim, quinolones)
Serine ß-lactamases
Metallo-enzymes
What are carbapenemases ?
Class CGroup 1
Class DGroup 2d
Class AGroup 2
IMP, VIM, NDM
Classification of the differentcarbapenemases in Enterobacteriaceae
With courtesy from P. Nordmann
Acquired carbapenemases
• IMP- and VIM- types are integron associatedOXA-48 and KPC are IS and transposon associated
Association of carbapenemase-encoding geneswith various genetic mobile elements and different
plasmids
KPC
VIM
IMP
NDM
OXA-48 type
Transposons
integrons
Truncated IS
KPC-2 + SHV-12 + SHV-11 + OXA-9 + TEM-1 + aminoglycosides + quinolones…Colistine / Tigecycline / Fosfomycin) often remain the only active agents)
CPE often associated with several othermechanisms of resistance
KPC type
Ranges of carbapenem MICs observed in clinical isolates producing acquired
carbapenemases
MICs (mg/L)
Organism/enzyme type Imipenem Meropenem Ertapenem
Pseudomonas aeruginosa / MBLPseudomonas aeruginosa / KPCAcinetobacter baumanii / MBL
2- >64>642- >64
2- >64>322- >64
---
Acinetobacter baumannii / OXA 1- >64 1- >64 -
Enterobacteriaceae / MBL 0.5- >64 0.25- >64 0.5- >32
Enterobacteriaceae / KPC 0.5- >64 1- 64 0.5- >64
Enterobacteriaceae / OXA-48 1- >64 0.5-64 4->64
Adapted from V. Miriagou et al. Clin Microb Infect 2010; 16:112-122and from P. Nordmann; Arch Ped 2010; 17: S156-S162
Increased mortality with Infections caused by KPC producers
• A high invasive-device score was a predictor of CRE isolation (P=0.02).• The mortality in the CRE group was 33%, compared to 9% among controls (P =0.043)• Delay in effective therapy was found to increase the length of hospitalization amongsurvivors (34+/-3.2 days versus 26.5 +/- 5.4 days; P 00.2)
Why are carbas in the top chart of ß-lactamases?
•Case patients were more likely than control patients to die during hospitalization (48% vs 20%; P < .001) die from infection (38% vs 12%; P < .001).
• The timely administration of antibiotics with in vitro activityagainst CR-KP was not associated with patient survival.
KPC: Klebsiella Pneumoniae Carbapenemase
Source: Patrice Nordmann, Thierry Naas, and Laurent Poirel . Global Spread of Carbapenemase producingEnterobacteriaceae. Emerging Infectious Diseases , October 2011: Vol. 17, No. 10, pp. 1791-1798.
Mortality rate: > 50%
OXA-48 : OXAcillinase
Source: Patrice Nordmann, Thierry Naas, and Laurent Poirel . Global Spread of Carbapenemase producingEnterobacteriaceae. Emerging Infectious Diseases , October 2011: Vol. 17, No. 10, pp. 1791-1798.
CPE in Europe and different types of carbapenemases by country
(epidemiological scale of nationwide expansion)
R. Canton et al. Clin Microbiol Infect 2012; 18: 413–431
OXA-48 carbapenemase (Class D)
Plasmid-mediated resistanceMostly in Klebsiella spp. (E. coli)
Turkey, India, North AfricaUK, France, Belgium (since 2010)
Variable level of resistance to carbapenems(meropenem MICs <0.5->128)
Susceptible to 3-4 gen cephs when not Associated with other mechanisms
Resistance to penicillins (temocillinincl.); no effect of BL inhibitors
Difficult to detect (low-level R, algorithms of Expert systems not adapted)
CLSI <2010 CLSI 2010 EUCAST 2010
S R S R S RImipenem <4 >16 <1 >4 <2 >8Meropenem <4 >16 <1 >4 <2 >8Ertapenem <2 >4 <0.25 >1 <0.5 >1Doripenem NA NA <1 >4 <1 >4
Carbapenem breakpoints in Enterobacteriaceae
Disk diffusion suceptibility of CPE isolates to meropenem (CLSI guidelines 2012)
0
2
4
6
8
10
12
6 9 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 32 33 34 35 38
Meropenem disk inhibition diameter (mm)
n is
olat
es
VIM
KPC
OXA-48
No CPE
50% of the OXA-48 CPE isolated received by the NRCare susceptible to meropenem ‘zone by CLSI interpretive criteria
Combined tests for detection and recognition of type of carbapenemases
MER: meropenem aloneDPA: +dipicolinic acid 1,000 μgBOR: + boronic acid 600 μgCLX: + cloxacillin 750 μg
β-lactamase Inhibited byEDTA/DPA Boronic acid Cloxacillin
MBL Y N NKPC/class A carbapenemases
N Y N
OXA-48 N N NESBL N N NAmpC N Y Y
Detection of carbapenemase producersas colonizers of the intestinal flora
Gold standard: molecular biology +++
Multiplex PCR; IMP, VIM, KPC, OXA-48, NDM….
NDM-1, KPC, AmpC and ESBL Check-MDR CT101*
NDM-1 KPC, OXA-48, VIM, IMP and ESBL Check-MDR CT102*
Molecular tests: commercial tests
(Naas et al. AAC, 2010; JCM, 2011)
Mass spectrometry (MALDITOF)
Carbapenem hydrolysis: « Carba NP test »
Nordmann P, Poirel L, Dortet L. Rapid detetion of Carbapenemase-producing Enterobacteriaceae.
•Carbapenem hydrolysis pH change color change
•2 hours (incubation at 37°C)•Sensitivity 100%, specificity 100%•Low cost
Possible strategies for the use ofthe Carba NP test for detection of carbapenemases
- Rapid (<2h), simple and inexpensivetest
- Direct from colonies on the antibiogramculture plate
- From colonies of a selective screeningplate (18-24 h before AST results)
-> Results > 24 h earlier than AST
Potential interest:-Screening in outbreak setting-Epidemiologic surveillance
(selection of isolates to be sent for Confirmation and characterization of CPE)
Nordmann et al., EID; 18(9) 2012
Year Evolution2007 Sporadic cases of CPE in 2008
September 2008
Imported through transfert (Greece):
K. pneumoniae,type VIM-1
June 2010 Imported (Pakistan & Balkan countries):
E. coli,type NDM-1
Since 2010 Rapid emergence of carbapenem-resistant isolates (I/R) aux and/orcarbapenemase producing Enterobacteriaceae species.
Early reports of CPE in Belgium (2008-2010)
23
Risk Assessment Group (13/10/2011)
[email protected] (1/1/2012)
Confirmation de CPE (CNR) et signalement de cas à l’Institut Scientifique
de Santé Publique (ISP)
Recommandations pour établissements de soins &
guidelines
Résistance aux carbapénèmes
Etudes: épidémiologie
des CPE (prévalence,
incidence dans différents
secteurs de soins)CNR + ISP
Réalisation d’études
complémentaires
National alerts of Public Health authorities and actions
Centre National de Référence (CNR)
24
Number of CPE cases: 1/1 /2012 - 31/10/2012
25
June OctoberNr laboratories reporting ≥ 1 CPE cases: 32 56 Nr episodes of CPE 66
Distribution of bacterial species and types of carbapenemases involved:1/1 – 31/10/2012
SOUCHES DE CPE CONFIRMEES
Type de carbapénémase Cas de CPE
Type d’entérobactérie OXA-48 KPC-2 VIM-1 NDM GES IMI OXA-48 + VIM
nombre %
Klebsiella pneumoniae 242 32 4 1 1 280 73.5
Escherichia coli 25 1 2 28 7.4
Enterobacter cloacae 18 0 7 2 1 28 7.4
Citrobacter freundii 13 4 1 18 4.7
Klebsiella oxytoca 11 2 3 16 4.2
Enterobacter aerogenes 2 2 0.5
Serratia marcescens 1 1 0.3
Hafnia alvei 1 1 0.3
Morganella morganii 1 1 0.3
Providencia rettgeri 1 1 0.3
Plusieurs entérobactéries 5 5 1.3
n. total de souches 318 35 19 6 1 1 1 381
% 83.5% 9.2% 5.0% 1.6% 0.3% 0.3% 0.3% 100%
OXA-48 KPC-2 VIM-1 NDM TOTAL*Nombre de patients 318 35 19 6 381Age moyen (min-max)
76.4 a. (1-101)
73.4 a. (24-88)
62.1 a. (31-92)
53.3 a. (19-81)
75 a. (1-101)Sex ratio (H/F) 0.84 1.4 1.6 5 0.92
Indications /contexte pour le prélèvement (données pour 375 patients)Contexte de dépistage
58.3% 17.7% 44.4% 83.3% 54.7%Contexte clinique 41.7% 82.3% 55.6% 16.7% 45.3%Site anatomique prélevé (échantillons cliniques seulement) (données pour 169 patients)Urines 59.2% 50.0% 60.0% 57.4%Respiratoire 18.5% 28.6% 10.0% 19.5%Plaies, pus 10.0% 7.1% 8.9%Sang (hémoculture) 3.9% 3.6% 10.0% 1/6 4.7%Plusieurs sites 5.4% 3.6% 4.7%Autres sites 3.1% 7.1% 20.0% 4.7%Statut infectieux des patients CPE+ (données pour 366 patients)Colonisation 63.2% 34.4% 55.6% 83.3% 60.7%Infection 36.8% 65.6% 44.4% 16.7% 39.3%
Characteristics of CPE+ Patients
* Total: incluant les patients positifs pour GES, IMI, OXA+VIM 27
OXA-48 KPC-2 VIM-1 NDM TOTAL*Nr of patients 318 35 19 6 381Hospitalisé ou ambulant (at time of detection of CPE) (data for 374 patients)Hospitalized–Ambulatory
91.4% -8.6% 90.9% -9.1% 94.4% - 5.6% 100% - 0% 91.7% -8.3%
Hospital unit (at time of detection of CPE) (data for 338 patients)ICU, burn, oncology 19.9% 46.7% 82.4% 16.7% 25.7%Geriatrics 42.6% 13.3% 37.0%Medicine 21.3% 33.3% 33.3% 21.3%Surgery 9.9% 3.3% 17.7% 33.3% 10.1%Others, several 6.4% 3.3% 16.7% 5.9%Patients CPE+ with hospitalisation in Belgium- Foreign countries (data for 216 patients)Hospitalization/stay abroad countries
7.3% 30% 16.7% 66.7% 13%
Recent stay in Belgian hospital / NH
56.4% 40% 41.7% 16.7% 51.4%
No previous stay in hospital / NH
36.4% 30% 41.7% 16.7% 35.7%
Traitement récent avec des anti-infectieux (data for 120 patients) Recent AB exposure 83.9% 86.4% 100% 66.7% 84.2%
Characteristics of CPE +
* Total: including patients positive for GES, IMI, OXA+VIM carbapenemases28
CPE + Patients :Link with hospitalization / stay in foreign countries (n=28)
29
Infected: 44%Colonized: 56%
Countries Nr OXA-48 KPC-2 VIM-1 NDM OXA+VIMGreece 6 5 1Turkey 6 5 1Egypt 3 1 1 1India 3 3Italy 3 3Morocco 3 3Senegal 1 1Thailand 1 1Tunisia 1 1Vietnam 1 1TOTAL 28 12 9 2 4 1
30
Number CPE cases:31/10/2012 (n=381 cas) ,
Association with foreign countries(n=28 cases)
5 labos, lien avec étranger4 (66.7%)
1
2
6
1 1
2
KPC-2(n=35)
VIM-1(n=19)
OXA-48(n=318)
16 labos, lien avec étranger: 9 (25.7%)
NDM-1(n=6)
1
15
1 7
2
2
1
1
11 labos, lien avec étranger: 2 (10.5%)
1
5
1 3 1
1
45 labos, lien avec étranger: 12 (3.8%)
OXA-48(n=318)
31
OXA-48: Evolution from 1/1 to 31/10/2012
< 10 cas
10 à 49 cas
≥50 cas
Nombre de cas cumulés:
32
KPC-2: Evolution from 1/1 to 31/10/2012
6/10 cases linked to hospitalization
in countries abroad 1/16 cas linked to
abroad countries:7 hospitals
< 10 cas
10 à 49 cas
≥50 cas
Nombre de cas cumulés:
2H
4H
Interim guidelines - High Council of Health• Level 1: basic- Admission screening (all wards): patients transfered from hospitals from
foreign countries- If strain suspect: send to NRC (confirmation) + case reporting (IPH)
meanwhile: - standard precautions (all patients in the unit)- isolation of suspect case + contact precautions- list potential contacts + communicate if transfered
• Level 2: ≥ 1 secondary case (infected/colonised) with epidemiologic link in the unit:
- Multidisciplinary outbreak management team- List up and collect epidemiological data (all colonised/infected cases)- Screening all contacts + routine 1/week all patients in the unit + admission
screening in high risk units- Send strains to NRC (confirmation) + case reporting (IPH)- AB-policy: general policy + treatment of CPE infections- Control implementation of standard and additional precautions in the unit(s)- Limit transfer of cases (other wards, other hospital, nursing home,..)
• Level 3: if additional cases- Cohort nursing staff, admission stop in the unit, avoid/limit transfers
34
Limiting the impact of carbapenemases
• Detect resistance rapidly in the clinical laboratory– Test more than one carbapenem agent (mero, erta)– Use more than one single method (manual + automates)– MIC testing (for clinical purposes)– Phenotypical confirmatory tests (synergy tests with carbapenemase
inhibitors, …)– Reference laboratory support (molecular tests)– Development of new rapid tests
• Identify infected/colonized patients. Essential for:– Appropriate patient management– Rapid implementation of infection control procedures
• Prevents onwards cross-transmission
Recommended control measures for preventing the spread of CPE
• General recommendation– Improved sanitary measures in the outpatient setting (+long term
facilities)
• Strongly suggested– Limitation of patient transfer between healthcare facilities– Active screening of patients transferred from a high-risk institution/country– In-hospital contact precautions and cohorting for already colonized
patients (+dedicated nursing staff in case of outbreak in acute institutions)
• Also recommended, but effectiveness unclear– Application of antibiotic stewardship programmes– Restricted use of any broad-spectrum antibiotics (fluoroquinolones,
broad-spectrum cephalosporins and penicillins, and carbapenems)– Avoid unnecessarily long duration of antibiotic treatment– Promotion of hand hygiene– Environmental surface decontamination– Decolonization of patients with antiseptic bathing– Education of healthcare personnel– Closure or reduced activity of high-risk units (uncontrolled outbreaks)
Recommended control measures for preventing the spread of CPE
Acknowledgements
UCL Mont Godinne• Pierre Bogaerts• Daniel Huang• Caroline Bauraing• Catherine Berhin• Amélie Guisset • Warda Boucharhouf• Roberta Rezende
Hôpital ULB-Erasme • Ariane Deplano• Ricardo De Mendonca• Olivier Denis• Sandrine Roisin• Claire Nonhoff
Hôpital de Bicêtre, Paris• Thierry Naas• Gaelle Cuzon• Laurent Poirel• Patrice Nordmann
Institute of Public Health• Bea Jans• Boudewijn Catry
Belgian Infection controlSociety (BICS)
MONT-GODINNE
Measles outbreak 2011
Europe & Belgium
Prof. Dr. Patrick Goubau
Dr Carole Schirvel
1
Outline
• Introduction• Measles in Europe • Measles in Belgium• Lessons learned in Fédération Wallonie
Bruxelles
Measles Virus ~14 days until rashappears
sneezing, cough, saliva
One genetic serotype – same basic vaccine worldwide
WHO Manual for the laboratory diagnosis of measles and rubella virus infection. WHO/IVB/07.01
www.niaid.nih.gov
R0 = 15-20
coverage 95% MMR 2 doses
2
Clinical PresentationRhinitis, conjunctivitis, Koplik spotsFever & maculopapular rash
Infectious period4 days before to 4 days after rash onset
Complications in wellresourced countries
Otitis media (7-9%)Pneumonia (1-6%)Diarrhea (8%)Blindness, corneal scarring (1%)Acute Encephalitis (1/1000)Subacute Sclerosing Panencephalitis(1/100.000) - always fatalDeath (1-10/10.000)
Plotkin et al. Vaccines
• Committee Established in January 2003 in Belgium• Set up action plan
– Measles: 2004, Rubella: 2006 – updates every 2 years
• Participants– Measles experts (laboratory, epidemiologists)– Representatives of the communities
• Meeting 2 or 3 times a year– Follow-up of the activities & recommendations
WHO European RegionElimination of measles and rubella in by 2015
3
Oral fluid testing developed
• Non-invasive• Less painful• Easy to perform• Safe• Time point of sampling and
conservation very important
Max. 5 days after start rashGenotyping
Max. 7 days after start rashPCR (virusdetection)
7-28 days after start rashIgM
Hutse V et al. 2010, IJID
email:[email protected]://nrchm.wiv-isp.be
• Introduction• Measles in Europe • Measles in Belgium• Lessons learned in Fédération Wallonie
Bruxelles
4
Measles incidence (per million) WHO European Region
Source: WHO EURO
2010
2011
European measles outbreakthreat to children
5
Vulnerable populations
Euvac.net. Measles surveillance annual report 2010
Komitova R, et al. Euro Surveill. 2011;16(15). Parent du Châtelet I et al. Euro Surveill. 2010;15(36)
•Differences in European Region: who these vulnerable population are
•Reasons for not immunization are different
•Tailored approaches needed
6
• Introduction• Measles in Europe • Measles in Belgium• Lessons learned in Fédération Wallonie
Bruxelles
0
100
200
300
400
500
600
700
800
900
1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010
Inci
denc
e of
mea
sles
* 10
0 00
0
MMR1
MMR1
Measles in Belgium
1982-1999: Sentinel network of GPs2002: PediSurv
sentinel network of pediatricians2009: Mandatory reporting
Surveillance
7
Measles cases in Belgium since 2007-2012 (Sept)
In 2007-2008: > 130 measles cases in Orthodox Jewish Families in Antwerp
In 2011 at least 566 cases
In 2012 (Sept): 94 casesLernoutT et al. Euro Surveill. 2009; 14(2) Sabbe M et al. Euro Surveill. 2011;16(16):
0
20
40
60
80
100
120
140
160
J F M A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S
2007 2008 2009 2010 2011 2012
n 6 98 33 40 566 94
Was this outbreak unexpected?Prevalence (%) of seronegativity against measles (<150mIU/ml) (red) per
age group, Belgium, 2006
Theeten et al. Epidemiol Infect. 2011 Apr;139(4):494-504.
« WHO Elimination targets not met »
National coverage Belgium (2006-2009):MMR 1st dose: 94,5% MMR 2nd dose 83,1%
8
Vaccination status of MMR vaccine of measles
cases by age group, 2011
Measles incidence by age group, 2011
0,0
10,0
20,0
30,0
40,0
50,0
60,0
< 1 1-4 5-9 10-14 15-19 20-29 30+
Age Group (years)
Inci
denc
e/10
0 00
0
0
10
20
30
40
50
60
70
< 1 1-4 5-9 10-14 15-19 20-29 30+
Age Group
N
not vaccinated 1 dose 2 doses
Reasons for non-vaccination?• Most cases were not vaccinated • ⇐ Age < 1 year: n=64 • ⇐ For cases > 1 year, reasons for non-vaccination
(n=195):– Circumstantial 17%– Allergy 2%– Unknown 23%
Advise of homeopathic doctor 7%Anthroposophic beliefs 24%
Parental decision 27%
9
Hospitalisation - Complications• 26% hospitalisations • Hospital duration: range 1 – 14 days (median 4
days)• 31 pulmonary complications, 1 followed by septic
shock• 1 encephalitis • no deaths
Laboratory confirmation – Genotype
MVs/Ghent.BEL/09.11/1/[D4]
MVs/Brussels.BEL/08.11/[D4]
Genotype D4
activities 2011-2012• 24/03/2011 meeting of Committee for elimination of Measles & Rubella (start outbreak in Ghent
50 cases)• 04/04/2011 informative letter to hospital laboratories & hygienists (about 100 cases)• 04/04/2011 press-communication to health care professionals and to general public leading to
several interviews• 06/04/2011 Early Warning and Response System (EWRS) message• 21/04/2011 publication Eurosurveillance (about 150 cases)• 23 to 30/04/2011 European Immunization Week: active communication by communities• 05/2011 two publications in Vlaams Infectieziektenbulletin (about 230 cases)• 5 and 15/05/2011 two parliamentary questions on measles• 18/05/2011 presentation St Pierre• 27/05/2011 2nd EWRS message (adopted measures)• 10/06/2011 extra meeting of Committee (about 380 cases)• 28/06/2011 recommendations of Superior Health Council on immunization• 18/07/2011 informative letter from reference laboratory on testing during outbreak situation• 09/2011 publication in Noso Info (about 480 cases)• 21/09/2011 poster presentation European Society Clinical Virology (about 520 cases)• Monthly updates for Belgium• 17/01/2012 meeting of Committee for elimination of Measles & Rubella• 21/03/2012 EU teleconference: UEFA football championship and Olympic Games • 04/2012 press communication• 21/05/2012 meeting of Committee for elimination of Measles & Rubella
10
• Introduction• Measles in Europe • Measles in Belgium• Lessons learned in Fédération Wallonie
Bruxelles
MMR1 and MMR2
0
200
400
600
800
1000
1200
1400
1982 1984 1986 1988 1990 1992 1994 1996 1998
Inci
denc
e/10
0 00
0
Vlaamse Gemeenschap Communauté française
11
Coverage MMR1 and MMR2
Provac, ULB
Incidence of Measles cases per 1 000 000 population, Belgium, 2011
Brabant Wallon: 127/ million
Hainaut: 83/million
None of provinces < 1measles case/million population
WIV-ISP
12
MMR2 vaccination coverage
Provac, ULB
Measles cases in Fédération Wallonie Bruxelles: where contact?
N=30N=35
N>20 N=9
N=9
N>3
Concentration of susceptible in some sub-population groups “pockets of under-immunised population” but different reasons for non vaccination
13
Public health interventions whenmeasles case is notified
• Notification through MATRA/Telephone• Case confirmed/epidemiological link?• Laboratory confirmation needed?• Define the exposed collectivity (crèche, hospital, work…)• Identify exposed infividuals, ad risk groups with
collection of additional information (age, vaccinationstatus)
• Determine immunization status of close contacts• Proposition of vaccination if appropriate• Discuss possibility of immunoglobulins• Discuss of isolation measures• Communication to schools, parents, medical staff…
Recommandations for Laboratoryconfirmation changed during outbreakElimination context (non-epidemic) :> National Reference Laboratory• Saliva test : IgM/IgG , Viral detection,
Genotyping• Naso-pharyngal : Viral detection, Genotyping
Epidemic context :> Any Laboratory (importance of timeliness) • Serum : Specific IgM and IgG
NRL in case of Babies < 2yrsVaccinatedImmunocompromised and pregnant womenTravelatypical/severe cases
14
Challenges•Commitment needed: Competing priorities for the health system, economic crisis•Increasing momentum of vaccine refusals:
•General complacency in absence of diseas (low risk perception), variablepublic trust•Anti-vaccination movement•Refusal due to religious/philosophicreasons
•Unrecognized pockets of un/underimmunized vulnerable groups
Lessons learned
– Increasing the coverage (> 95%) with two doses of MMR vaccine needed– Need for sero epidemiological studies in order to identify the non-protected groups on time– Need for catch-up campaigns to address identified susceptible population groups/cohorts– Strengthening measles surveillance and vaccine coverage monitoring – Improving the communications – with the general public, with medical specialists and with the most vulnerable
Mumps, an update of the outbreak
in Flanders
28th Seminar on
diagnosis and surveillance
of infectious diseases
Wim Flipse
arts infectieziektebestrijding
Gent
mumps
Clinical criteria Any person with
Fever AND at least one of the following three:
Sudden onset of unilateral or bilateral tender swelling of the parotid or other salivary glands without other apparent cause Orchitis Meningitis
Laboratory Criteria At least one of the following three:
Isolation of mumps virus from a clinical specimen Detection of mumps virus nucleic acid Mumps virus specific antibody response characteristic for acute infection in serum or Saliva
Laboratory results need to be interpreted according to the vaccination status Epidemiological Criteria
An epidemiological link by human to human transmission ECDC
Case definition
A. Possible case Any person meeting the clinical criteria B. Probable case Any person meeting the clinical criteria and with an epidemiological link C. Confirmed case Any person not recently vaccinated and meeting the laboratory criteria In case of recent vaccination: any person with detection of wild-type mumps virus strain ECDC
Epidemic curve mumps in Flanders
0
20
40
60
80
100
120
140
160
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41number of the week
RVL
OV
AN
student parties Ghent
Start notification Flanders
festival Werchter
The facebook page
Blue =our register Red =facebook Purple=both registers Green= estimate according to capture-recapture method
0
50
100
150
200
250
9 10 11 12 13 14 15 16 17 18 19 20
Unknown cases estimated by capture-recapture method
0
10
20
30
40
50
60
70
week 38 week 39 week 40 week 41 week 42 week 43 week 44 week 45 week 46
oost-vlaanderen
west-vlaanderen
vlaams-brabant
limburg
antwerpen
Number of mumps cases by province
164
This year already 1700 cases notified
Distribution of mumpscases bij agegroup and sex
0
50
100
150
200
250
300
0- 9 10-14 15-19 20-24 25-29 30+
MF
years
Questionnaire (preliminary results)
Complaints/symptoms
Complications Vaccination status
Days of illness
Responsrate questionnaire 59%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
fever swellingparotis
unilateralswelling
bilateralswelling
headache fatigue
symptomatology mumpscases
days of illness
Obs Mean Median Mode 0- 9 years 39 6,1 5 3
10-14 years 12 5,4 5 5 15-19 years 89 8,2 8 10 20-24 years 137 8,2 7 7 25-29 years 38 11,6 10 10 30+ years 66 10,5 10 14
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
confirmedcases
hospitaladmission
meningitis orchitis confirmedcases
hospitaladmission
meningitis orchitis
before and after notification
11-6-2012
0
20
40
60
80
100
120
140
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29age
number of cases of mumps by year of age
MBR 2
MBR 1
Vaccinated according to questionnaire agegroup 15-24 years of age
n % N not vaccinated 11 4,7 232 1x MBR 61 26,3 232 2x MBR 156 67,2 232
subset of agegroup 12 to 16 years of age 2x MBR agreement questionnaire versus data Vaccinnet Kappa=0,78 (n=30)
Two years of HPV vaccination Two years of HPV vaccination in Flandersin Flanders
Karel Hoppenbrouwers (KU Leuven)Anouk Vanlander (VWVJ)
Diagnose en Surveillance van Infectieuze Aandoeningen28e seminarie – 22 november 2012
WIV-ISP
Content of the presentation
HPV-infections en HPV-vaccines
HPV vaccination in Flanders
HPV vaccination in Europe
Key factors for success
HPV-infections and pathology
There is an epidemiologic association between HPV-infection and cervical cancer (and the preceding intraepithelial lesions)
There is an epidemiologic association between HPV-infection and anogenital tumors and condylomataaccuminata
High risk HPV-infection is a necessary but not sufficient condition to develop cervical cancer
HPV-infections are very common and largely acquired soon after the onset of sexual activity
Cumulative proportional contribution of 8 HPV-types to cervical cancer in Europe and N-America (Arbyn, 2007)
65,4%
71.5%
77.1%
81.2%
84.1%
85.6%
86.8%
87.8%
100.0% +12.2%
+1.0%
+1.2%
+1.5%
+2.9%
+4.1%
+5.6%
+6.1%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Other
HPV 52
HPV 35
HPV 56
HPV 45
HPV 31
HPV 33
HPV 18
HPV 16
The virus
The capside consists of two protein molecules
‘late proteins’: L1 en L2
The genome of the virus codes for ‘early proteins’: E1, E2, en E4 t.e.m. E7
Virus-like particles (VLP)
• Neutralising epitopes are located upon the L1 capsularprotein
• Neutralising epitopes are expressed throughyeastcells/insectcells, resulting in VLP’s efficientlyexpressing the neutralising epitopes
• VLP’s resemble the round virion capsules, without DNA
• VLP’s induce antibody production without replication →no risk of infection or cancer
The vaccines
GARDASIL® CERVARIX®
TYPE VACCINE VLP L1 protein VLP L1 protein
COMPOSITION
VECTOR FOR PRODUCTION
ADJUVANS
SCHEME
PRODUCER
HPV 6 20µgHPV 11 40µgHPV 16 40µgHPV 18 20µg
Yeast cells
Al hydroxyde sulfate
0-2-6 months
Sanofi Pasteur MSD
HPV 16 20µgHPV 18 20µg
Insect cells
ASO4
0-1-6 months
GlaxoSmithKline
Health CouncilRecommendation 2007 (update 2008)
Systematic cervical screening must be continued and coverage of target groups increased
Yearly general profylactic vaccination of one birth cohort of girls between 10 and 13 years of age
Single profylactic (catch-up)vaccination campaign of additional cohorts until the age of 15 years (included) should be considered
Vaccination can be offered by the threating physician to all virgin female adolescents and young adults (14-26 years of age)
On the discretion of the threating physician vaccination can be offered on indivual basis to non-virgin female adolescents and young adults (14-26 years of age)
Implementation in Flanders
Profylactic vaccination of girls of the first year of secondary education, since September 2010
Catch-up vaccination through partial reimbursement of three doses 12 to 15 years of age (since 1 May 2008), 12 to 18 years of age (since 1 December 2008)
Individual vaccination of women > 18 years of age
Implementation strategy in Flanders
Collaboration• School Health Services, GPs, pediatricians, gynaecologists• In accordance with the strategy for HBV vaccination of pre-
adolescents
Communication• Leaflets for boys and girls, disseminated through school
health services• Agency website with FAQ’s• Letters to vaccinators with up-to-date information
Registration in Vaccinnet
Vaccination coverage in Flanders
First estimation of coverage of opportunistic vaccination in 13-14 year old girls, one year after launch of Belgian Superior Health Council recommendations (May 2007)
Study of the vaccination coverage in Flanders 2008 (Hoppenbrouwers et al., 2009)
• Birth cohort of girls: 1994• Data collection in April-May 2008 (WHO-EPI method)• Estimated coverage (compared to HBV in cohort 1994) :
25.0% at least 1 dose (HBV1: 92.5%)18.7% at least 2 doses (HBV2: 91.0%)4.2% at least 3 doses (HBV3: 89.2%)
Vaccination coverage in Flanders
First estimation of coverage in a cohort of 12 years old girls targeted for free of charge prophylactic vaccination (schoolyears 2010-2011 and 2011-2012)
HPV vaccination in Flanders (2010-2012) (Top & Paeps, 2012)• Birth cohorts of girls: 1998 and 1999• Vaccinnet: 1 September 2010 - 31 August 2012• Estimated coverage for cohorts 1998 and 1999, respectively
86.1% and 87.8% at least 1 dose84.8% and 86.6% at least 2 doses79.8% and 81.6% at least 3 doses
• 97% of doses registered by School Health Services• Slight underestimation of real coverage since not all GP’s
make use of Vaccinnet
HPV-vaccination programmes in other European countries with coverage data
17% (2009)PrivateNational healthLuxemburg
58% (2011)PHNational healthNetherlands
55% (2011)SHSNational healthSlovenia
63% (2011)SHSNational healthNorway
64% (2011)50% PH, 50% SHSNational healthSpain
65% (2011)PHNational healthItaly
84% (2011)PHNational healthPortugal
80% (2009)94% SHSNational healthUK
Countries Financing vaccine Delivery strategy Coverage (3 doses)
Flanders National health 90% SHS > 80% (2010-2012)
Denmark National health PH 79% (2011)
France 65% national health 95% private 24% (2008)
Germany National health 95% private 10% (2011)
Adapted from ECDC Guidance – Introduction of HPV vaccines in European countries – an update – September 2012
Key factors of success – The Netherlands
Gefenaite G et al. Waarom ging de eerste ronde HPV-vaccinatieprogramma mis? Infectieziekten Bulletin 2011,22(5)
Reasons for refusal mentioned by parents:Information of governement was to brief and subjectiveLack of confidence in reaction of governement in case of side effectsIgnorance about effectivity of vaccineConcern about side effectsIgnorance about HPV-infectionsConviction government is influenced by industryReligious constraints
Key factors of success
Tailored and timely information for girls/boys, their parents and vaccinators – about disease burden of HPV-infection– about the vaccination programme– about the safety and effectiveness of the vaccine
Implementation through public health and/or school health services, in close collaboration with other vaccinating professionals
Vaccinnet as a tool for ordering and registration of vaccines, also linking all vaccinators to the same vaccination programme
Key factors of success - Germany
18 Jänner 2008Expertise zeigt HPV-Impfung "mögliche" Ursache für Tod der Studentin
In 2007, two young women died - one in Germany, one in Austria - shortly after being vaccinated against HPV. Although no causal relationship between HPVvaccination and death was established in either case, reports of these two deaths in the popular press markedly lessened public confidence in the safety of the HPV vaccine. The vaccination rate among 12- and 13-year-old girls, at one time 40%, has dropped to about 10%.
New Screening Practices for HIV.
Katrien FransenARL-ITM / WHO CC
Diagnose en surveillance van infectieuze aandoeningen.WIV/ISP22/nov/2012
OUTLINE
• Current • New • Breach recommendations• Conclusions
Current HIV Screening Practices
• Peripheral laboratories. If reactive -> confirmed in one of the 7 ARLs
-> + notification under code to IPH
• Tests: serological HIV ab and/or ag-EIA (enzyme immunoassays)-CII (chemiluminescent immunoassays)-Simple / rapid (immunoassays or
agglutination assays)
Evolution of HIV Immunoassays since 1985
1st generation Sensitivity % Specificity %Purified HIV lysates 99 95-99
2nd generationRecombinant proteins and/or synthetic peptides 99.5 99
3rd generation or sandwich ELISAsLabelled antigen as conjugateDetect Ab >99.5 >99.5
4th generation or DUO assaysDetect Ag and Ab without differentiation >99.8 >99.8orDetect Ag and Ab with differentiation
Laboratory Markers in HIV Seroconversion
Unknown Status (literature)
• Many people are unaware of their HIV infection (asymptomatic) 15-50% ECDC- WVDBerghe (ITM): Venue based HIV prevalence study among MSM (flanders).14 %, fingerprick (DBS)
• Individuals that are aware engage less in risky behaviors related to sex and IDU.
- Risk of transmission 3.5 X higher
Unknown Status (literature)
• Many people are unaware of their HIV infection (asymptomatic) 15-50% ECDC- WVDBerghe (ITM): Venue based HIV prevalence study among MSM (flanders).14 %, fingerprick (DBS)
• Individuals that are aware engage less in risky behaviors related to sex and IDU.
- Risk of transmission 3.5 X higher
• Why ?- Personal perception of not being at risk of HIV- Fear of a possible positive result- Belonging to marginalised, stigmatised groups in society;
HIV Testing a Matter of Time
• Early diagnosis is essential: timely referral of patients for treatment and care
• Early treatment reduces morbidity and mortality• People diagnoses early may be less likely to
transmit the virus• Early diagnosis remains a critical public health
priority.
What is New?
• At the level of sampling, type of specimen- Finger prick (DBS), OF, self sampling…
• At the level of tests- POC tests, Simple Rapid tests (VCT)
• Combined - OF tests combined with SR and/or ELISA
Simple/Rapid Tests
Principles• Agglutination assays
• Immunofiltration assays (flow through)
• Immunochromatographic assays (lateral flow through)
• Dipsticks
SRTests (new?)
More than 100 different assays (WHO procurement list).serum, plasma, whole blood.
www.who.int/diagnostics_laboratory/en
Two 4th generation tests with WHO label:- SD BiolineTM HIV Ag/Ab Combo test (Standard diagnostics) - DetermineTM HIV-1/2 Combo (Alere)
Only one 4th generation tests CE label:- DetermineTM HIV-1/2 Combo (Alere)
SRTests with CE Label
Test kit name Supplier
Determine™ HIV-1/2 Alere
LaboQuick Anti HIV1/2 Test kit LaboQuick Turkey
Genie ™ Fast HIV1/2 Bio-Rad Laboratories
VIKIA HIV1/2 rapid test Bio Mérieux
ImmunoComb™ Alere/Orgenics, Ltd
INSTI™ HIV Antibody Biolytical Laboratories
Uni-Gold™ HIV Trinity Biotech
…
…
Determine ™ HIV-1/2 Ag/Ab Combo Rapid Test Kit Alere
Helpcenter ITM: Determine Ab/Ag
Year Test (n) HIV + (n) HIV + (%)
2006 203 4 2,00%
2007 493 0 0,00%
2008 792 10 1,30%
2009 1160 15 1,30%
2010 1278 11 0,90%
2011 1384 16 1,20%
totaal 4989 56 1,10%
CE Label Criteria: HIV Screening AssaysELISA Panel Criteria
Sensitivity (Ab) 400 HIV1 (40 nB),100 HIV2
100%
20 commercial panels, 10 extra panels
State of the art
Analytical senstivity no
Specificity 5000 blood donations200 hospitilized p,100 poss cross react
≥ 99.5%≥ 99 %
Simple / rapid
Sensitivity (Ab) id 100%
Analytical sensitivity no
Specificity 1000 blood donations,200 clinic specimens,200 pregn women,100 poten interfering
≥ 99 %
CE Label Criteria: HIV Screening Assays
Ag Panel Criteria
Sensitivity 50 HIV-1,50 SN (HIV-1, HIV-2),20 seroconversion panels
Correct identification
State of the art
Analytical sensitivity
International Standard < 50 pg/ml
Specificity 200 blood donations,200 clinical samples,50 pos interfering
≥ 99,5%
Analytical sensitivity of Ag detecting testsTest Analytical sensitivity (pg p24 ag/ml)
Vidas HIV DUO Ultra 11,5
Vidas HIV Duo Quick 13
Genscreen HIV Ag/Ab Ultra 13
Architect HIV1/2 Combo 18
Modular HIV Combi, Elecsys 126,5
AxSYM HIV1/2 Combo 21
Cobas Core HIV Combi 29
Murex HIV Combo 29
Genscreen Ag/Ab Plus 140
Vironostika HIV Uniform II Ag/Ab 150
Enzygnost HIV integral 160
Coulter HIV P24 15,7
Innotest HIV Ag mAb 9,3
HIV P24 Core 14,2
Additional Requirements for Ab/Ag
• Claims for single p24 detection
-> CE label for 4th generation tests is not sufficient-> WHO label id
Extra evaluations are needed !OrMore stringent acceptance criteria for 4th
generation tests
New: Oral Fluid Tests (no Ag)
- SRT (CE, FDA): OraQuick Advance Rapid HIV-1/2Cons: expensive (40$-60$), 3rd generation, variable in quality ? (NY), IQC and EQC ?
- Conventional ELISA using OF
18
Study ITM: Using Conventional HIV tests for HIV diagnosis on OF Specimens.
M &M: 302 HIV pos and HIV neg, OF (Oracol) versus serum
3 EIA: Vironostika HIV Ag/Ab, Enzygnost Anti HIV ½ Plus and Genscreen HIV
Samples tested at three different timepoints between 1-7 daysInfluence of drinking water just before sampling
Results: - protocol was optimized and new cut off calculation was established for each of the tests. Genscreen no change.
Other tests double sample volume
7days,Lowest misclassification rate
Sensitivity % (CI 95%) Specificity % (CI 95%)
Vironostika 97.8 (92.3 – 99.4) 100 (98.2 – 100)
Enzygnost 97.8 (92.3 – 99.4) 99.5 (97.3 – 99.9)
Genscreen 100 (95.9 – 100) 97.6 (94.5 – 99.0)
Proposed HIV Testing Algorithm using Oral Fluid Specimen
Ongoing Studies using OF at ITM
• SIALON II: European HIV/STI prevalence study (Brussels) in Gay venues (MSM)-OF + EIA (Genscreen HIV-1/2 v2 and Vironostika HIV Uni- form II Ag/Ab)-Serum (HIV incidence, Syphilis, Heb B, Heb C)
• TOL 2: Improving HIV diagnosis by using oral fluid tests in outreach settings. Swab 2 Know.-high risk population in Antwerp (MSM, SAM)
-OF self sampling, send to ARL Antwerp-webbased communication of the result and counseling
New: Home Testing, Self Testing, Self sampling.
Home testing
Pro Autonomy, less risks if status is known…Cons Expensive, no proved, consistant quality, obscure companies,
no CE label, ethical issues, link with care (for counseling and treatment)?
Self sampling
Pro Link with care, conventional tests, cheep, consistant quality,..
Cons Ethical issues…
22
Test, link and treat : the reality.The spectrum of engagement in HIV care in the United States spanning from HIV acquisition to full engagement in care, receipt of antiretroviral
therapy, and achievement of complete viral suppression. We estimate that only 19% of HIV-infected individuals in the United States have
an undetectable HIVload.
Gardner et al. CID 2011
Recommendations of BREACH
• Belgian HIV prevention summit Sept 28-29• Breack out session B on HIV testing strategies
Recommendation 1
1)Develop national Belgian guidelines for testing based especially on HIV indicator conditions and implement them in health care settings (GP and specialists)Set up of a sub working group to assess cost-
effectiveness for all testing procedures (standard and rapid tests) in Belgium.
Recommendation 2
2) About the type of HIV test-Fourth generation standard screening test must be mandatory for all laboratories in Belgium (80%).-Different ways/methods/type of tests should be explored for different target groups.
Recommendation 3
3) About the use of rapid tests
•3rd and 4th generation rapid tests are currently used in VCT screening centers and outreach programs•Rapid test has to be confirmed on blood•More 4th generation rapid tests with CE label are needed
•There is a need for regulatory rules, policy framework, specific legislation+ implementation of quality assurance guidelines to enable the use of rapid tests in Belgium•In a high risk population: the use of rapid test must be well prepared
(made by medical staff or not?, pre/post test counselling, confidentiality, location…)If rapid test are used outside VCT centers, need to implement/improve a link to care for reactive rapid tests Reimbursement to be discussed
Incentives for GPs are needed
• OF tests (only antibodies)-One is CE labeled and FDA aproved:
Oraquick Advance rapid HIV test-Can be recommended in some case (home testing) but they are expensive and need more evaluations about consistant quality (false negative)
Recommendation 4
4) About education on HIV testing/prevention-Training of the GPs (pre-counselling, confidentiality, post-test counselling, partner notification…-Training of the specialists-Training of the patients (treatment often perceived as an ‘enemy’ longer life expectancy, better quality of life,…-Breaking down the taboo about HIV (discrimination, reduce the fears about HIV tests,..) and the treatment
Last but not least.
• Need to develop tools for risk assesment and for self risk assesment (web). Ugent. Prof Dirk Avonts.
Conclusions
In order toGet more people tested, aware of their status and treated•Improve current screening practices (at all levels)•Study all aspects of new screening technologies, maintain link with care ->Get the prevalence down (1000 new infections/y)