Pr Robert Cohen CHI Créteil France

Transcription

1 EFFECT OF VACCINATION ON ANTIMICROBIAL RESISTANCE : THE EXAMPLE OF THE IMPACT OF PCVS ON ANTIBIOTIC RESISTANCE Pr Robert Cohen CHI Créteil France 1

2 DISCLOSURES I have received during the las 3 years honorarium for symposium and board from Astra-Zenzca GSK Merck Pfizer Sanofi-Pasteur My institution has received research grants from Astra-Zenzca GSK Merck Pfizer Sanofi-Pasteur 2

3 There is a growing interest for the role of vaccines in confronting the problem of antimicrobial resistance (AMR) Vaccines can reduce the prevalence of AMR by reducing : colonization and IPD due to resistant strains need for antimicrobial use by the incidence of diseases the number of pathogens that may be responsible for some clinical syndromes, leading to decreasing the severity of the diseases decreasing the need of broad spectrum antibiotics These effects may be amplified by herd immunity Vaccination can reduce pressure for resistance even in pathogens not included in the vaccine and present in microbiota H. influenzae E. coli

4 SYNERGISTIC EFFECTS BETWEEN ANTIBIOTICS AND PCVS CARRIAGE AND PENICILLIN SUSCEPTIBILITY ACCORDING TO VACCINATION STATUS AND ANTIBIOTIC USE WITHIN THE LAST 3 MONTHS % Vaccinated - Antibiotics - N=782 PSP IC95% PIP IC95% PRP IC95% Non Carriers IC95% 33 [29%;36%] 27 [24%;30%] 10 [8%;12%] 30 [27%;33%] Vaccinated - Antibiotics + N= [18%;24%] 34 [30%;38%] 15 [13%; 18%] 30 [26%;33%] Vaccinated + Antibiotics - N= [27%;35%] 24 [20%;27%] 4 [3%;6%] 41 [37%;45%] Vaccinated + Antibiotics - N= [20%;27%] 23 [20%;27%] 8 [6%;11%] 45 [41%;50%]

5 OF PNEUMOCOCCAL RESISTANCE - In pneumococcal diseases - In pneumococcal carriage 5

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8 PATIENTS AND METHODS September 2001 May pediatricians took part in this study Children 6-24 m with AOM NP specimens were taken with cotton-tipped wire swabs placed in transport medium and sent within 48 hours to National Reference Center for Pneumococci (HEGP) Robert Debré Hospital Isolates identification Serotyping Antibiotic susceptibility performed using standard microbiological methods! 8

9 % 66 PENICILLIN RESISTANCE OF S. PNEUMONIAE ISOLATED FROM NP FLORA OF YOUNG CHILDREN WITH AOM S I R (n=471) 2 (n=393) 3 (n=390) 4 (n=371) 5 (n=466) 6 (n=390) 7 (n=352) 8 (n=382) 9 (n=378) 10 (n=369) 11 (n=363) 12 (n=343) 13 (n=324) 14 (354) Cohen R et al. Vaccine 2015 Study Years (Year 1: Oct 2001/June 2002, Year 14: Oct 2014/ March 2015) 9

10 PNEUMOCOCCAL RESISTANCE DOES NOT INVOLVE ALL PNEUMOCOCCAL SEROTYPES > 94 serotypes Among them 20 are +/-resistant to antibiotics Strong correlation between the duration of carriage and the risk of occurrence of resistance According notably to the properties of the capsule, some serotypes are more adapted to persist in the NP microbiota 10

11 PNEUMOCOCCAL RESISTANCE DOES NOT INVOLVE ALL PNEUMOCOCCAL SEROTYPES S. pneumoniae strains are buried in biofilms that make it easier for them to resist immune defenses and antibiotics the long duration of carriage explains that these strains are more frequently challenged by antibiotics have more opportunity to exchange DNA materials with other streptococci from NP microbiome frequently resistant to antibiotics 11

12 BEFORE PCVS IMPLEMENTATION The serotypes implicated in pneumococcal infections (IPD and mucosal) in high income countries in young children The serotypes more frequently carried (generally for long periods ) The serotypes frequently resistant were the same [6,9,14,19,23] > 70 % 12

13 THE MAIN DRIVER OF PCVS IMPLEMENTATION FOR ANTIBIOTIC RESISTANCE WAS THE DISEAPPARENCE OF VT 13

14 % of children 71.2% PCV7 implementation SP NP CARRIAGE AOM FEVER± OTALGIA, 9659 CHILDREN, 16 YEARS PCV13 implementation Trend test from year 1 to 9 Trend test from year 10 to % p=0.02 p=0.6 65% 17.2% p<0.001 p<0.001 p=0.6 p< % 1.9% Study Years (Year 1: Oct 2001/June 2002, Year 16: Oct 2016/ May 2017) Cohen R et al. Vaccine

15 SEROTYPE 19F AOM FEVER± OTALGIA, 9659 CHILDREN, 16 YEARS % of children PCV7 implementation PCV13 implementation 0 1 (n= 663) 2 (n= 573) 3 (n=658) 4 (n=622) 5 (n=750) 6 (n= 645) 7 (n=530) 8 (n=599) 9 (n= 601) 10 (n=596) 11 (n=581) 12 (n=558) 13 (n=591) 14 (n=578) 15 (n=547) 16 (539) Study Years (Year 1: Oct 2001/June 2002, Year 16: Oct 2016/ May 2017) Cohen R et al. Vaccine

16 % of children PCV7 implementation SEROTYPE 19A AOM fever± otalgia, 9659 children, 16 years PCV13 implementation 16 ST19A Linéaire (ST19A) % Trend test from year 10 to 16 Trend test from year 1 to 9 n=41 p<0.001 p<0.001 n=17 n=16 n=11 N=3 n=7 0,6% 1 (n= 663) 2 (n= 573) 3 (n=658) 4 (n=622) 5 (n=750) 6 (n= 645) 7 (n=530) 8 (n=600) 9 (n= 601) 10 (n=598) 11 (n=582) 12 (n=591) 13 (n=578) 14 (n=582) 15 (n=547) 16 (539) Cohen R et al. Vaccine 2015 Study Years (Year 1: Oct 2001/June 2002, Year 16: Oct 2016/ May 2017) 16

17 SEROTYPE 3 AOM fever± otalgia, 9659 children, 16 years % of children PCV7 implementation PCV13 implementation 5 4,5 ST3 4 Linéaire (ST3) 3,5 3 2,5 2 1, % Trend test from year 1 to 9 p=0.3 Trend test from year 10 to 16 p= % 0, Cohen R et al. Vaccine 2015 Study Years (Year 1: Oct 2001/June 2002, Year 16: Oct 2016/ May 2017) 17

18 However, the situation is evolving, according to the emergence in NP flora of NVT Among them, the great majority were present in NP flora before PCVs implementation (at low level : previously minor clones) have long duration of carriage have become resistant to antibiotics but have low disease potential 18

19 Pneumococcal carriage Expansion of previously minor clones Study Years (Year 1: Oct 2001/June 2002, Year 15: Oct 2015/ May 2016) Cohen R et al. Vaccine

20 % of children PCV7 implementation Emerging serotypes: ST 15A, 15B/C AOM fever± otalgia, 9659 children, 16 years PCV13 implementation Study Years (Year 1: Oct 2001/June 2002, Year 16: Oct 2016/ May 2017) Cohen R et al. Vaccine

21 % of children PCV7 implementation Emerging serotypes: ST 11A, 23A AOM fever± otalgia, 9659 children, 16 years PCV13 implementation Study Years (Year 1: Oct 2001/June 2002, Year 16: Oct 2016/ May 2017) Cohen R et al. Vaccine

22 % of children PCV7 implementation Emerging serotypes: ST 35B, 35F, 23B, 21 AOM fever± otalgia, 9659 children, 16years PCV13 implementation Study Years (Year 1: Oct 2001/June 2002, Year 16: Oct 2016/ May 2017) Cohen R et al. Vaccine

23 DYNAMICS OF PENICILLIN NON-SUSCEPTIBLE STRAINS AMONG PNEUMOCOCCAL CARRIERS FOR EMERGING SEROTYPES 12 I+R S B 35B 35F A 15A 15B/C 23A Cohen R et al. Vaccine

24 PENICILLIN SUSCEPTIBILITY AOM FEVER± OTALGIA, 9659 CHILDREN, 16YEARS % of carriers % S I R , , Study Years (Year 1: Oct 2001/June 2002, Year 16: Oct 2016/ May 2017) Cohen R et al. Vaccine

25 DISTRIBUTION OF SEROTYPES (AOM FEVER ±OTALGIA) (% of carriers) Year 1 (n=471) 35C 37 19B 18B 18A 10B 9L 24A 45 18C 6A 9V 6B 35A 7A 14 28A 24B 23F 29 12F 19A 38 6C F 9N 16F F 33F 24F 19F 10A 23A 15A 35F 35B 21 23B 11A 15B/C Year 16 (n=349) Cohen R et al. Vaccine 2015 S I R 25

26 AOM FEVER± OTALGIA: CHARACTERISTICS OF PATIENTS 2001/2005 N= /2008 N= /2010 N= /2017 N=2837 P Age (months) Mean±SD 13.6±5 13.5±5 13.7±5 13.9± Median Day care attendance Home <0.001 Childminder Day care center Temp 38.5 C <0.01 Otalgia Cohen R et al. Vaccine

27 ATB 3 MONTHS BEFORE AOM FEVER± OTALGIA, 9659 CHILDREN, 16 YEARS PCV7 implementation PCV13 implementation ,6 51, ,3 42,8 38,5 45,3 45,3 43,6 43,2 38,1 43,5 42,4 37,8 42, Trend test p=< Cohen R et al. Vaccine

28 TIME SERIE ANALYSIS : PNEUMOCOCCAL RESISTANCE TRENDS Cohen R et al. Unpublished data 28

29 TIME SERIE ANALYSIS : EMERGING SEROTYPES: RESISTANCE TRENDS Cohen R et al. Unpublished data 29

30 AMONG THE EMERGING SEROTYPES 3 DIFFERENT PROFILS 30

31 1) HIGHLY RESISTANT, SLIGHTLY CHANGE AFTER PCVS: 35B AND 15A Cohen R et al. Unpublished data No significant change after the PCVs 31

32 2) LOW LEVEL OF RESISTANCE, SLIGHTLY CHANGE AFTER PCVS 21, 23A AND 35F Cohen R et al. Unpublished data No significant change after the PCVs 32

33 3) EVOLUTION OF THE RESISTANCE AFTER PCVS 11A AND 23B Cohen R et al. Unpublished data 33

34 Predominant non-pcv13 serotypes overall were: 22F, 12F, 33F, 24F, 38 15C, 15B, 23B, 10A Rank order varied by region 34

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36 DISEASE POTENTIAL 36

37 DISEASE POTENTIAL I. Yildirim et al. / Vaccine 35 (2017)

38 IMPACT OF PCVS ON ANTIBIOTIC PRESCRIPTIONS Dagan : -17% (CI% = 13-21%) Day care center, efficacy PCV7 Pediatr Infect Dis J 2001;20:951 Fireman : - 6% (CI95%= 4-7%) General population, efficacy PCV7 Pediatr Infect Dis J 2003;22:10 Palmu : - 7% (CI95% = 1-13) General population, efficacy PCV10 Lancet Infect Dis 2014;14:205 Palmu : - 17% (CI95% = 17-18) General population, effectiveness PCV10 Pediatr Infect Dis J

39 Overall antibiotic prescribing decreased 18% (risk ratio (RR) 0.82, 95% confidence interval (95% CI) 0.72 to 0.94) among children and adolescents, remained unchanged for adults increased 30% (1.30, 1.14 to 1.49) among older adults

40 TRENDS IN ANTIBIOTIC PRESCRIPTIONS ADULTS OVERALL CHILDREN IMS COURTESY PIERRE CHAHWAKILIAN

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43 TRENDS OF PEDIATRIC VISITS FOR AOM (IMS DATA) PCV 7 AOM 30 months 7 years AOM <30 months PCV Courtesy of Pierre Chahwakilian 43

44 ANTIBIOTIC PARADIGM CHANGES ARE NEEDED Reduction of the the risk of severe disease in front of some clinical syndromes have to redefine : Diagnosis methods The role and the type of antibiotics Clinical syndromes AOM Pneumonia Fever without source 44

45 Trend of pneumonia (2009/2015) % N=2032 N=738 N=172 N=66 PCV13 Influenza (winter 2014/2015) PrePCV13 Transition Post PCV13(1) Post PCV13(2) Post PCV13(3) CAP -26% [24;28] Hospitamized -31% [28;35] Pleural effusion -52%[45;60] P-CAP 86% [76;94]

46 % N=165 N=310 N=520 N=440 PCV13 N=144 N=275 N=471 N=344 N=163 N=293 N=489 N=150 N=394 N=245 N=159 N=441 N=255 N=188 N=549 N=324 N=548 N=313 N=154 Level CRP<20 of CRP mg/l CRP<40 CRP<100 CRP H1N1 influenza (winter 2009/2010) N=261 N=223 N=217 N=216 Influenza (winter 2014/2015) N=243 PrePCV13 Transition Post PCV13(1) Post PCV13(2) Post PCV13(3) Post PCV13(4) Post PCV13(5) 2009/ / / / / / /

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48 OTHER EXISTING VACCINES WITH POTENTIAL EFFECT TO REDUCE ANTIBIOTIC USE AND ANTIBIOTIC RESISTANCE B A C T E R I A L Diphteria Pertussis Hib Meningococal V I R A L Influenza Measle Varicella

49 IN CONCLUSION Implementation of PCVs in vaccination programs has reduced pneumococcal antibiotic resistance particularly in countries where the level of resistance was high The decreases of resistance were mainly due to the disappearance of VT pneumococci The reduction of antibiotic prescriptions secondary to the pneumococcal diseases decrease play certainly also a role Finally, an indirect effect due to the dramatic decrease of the risk of severe diseases was not sufficiently taking into account 49