The lecture presented by Professor Susanna Esposito at AMR 2019 on influenza vaccination and abuse of available antimicrobials. To learn more, please visit www.waidid.org.

1. INFLUENZA VACCINATION AND
PREVENTION OF ANTIMICROBIAL
RESISTANCE
Susanna Esposito
Pediatric Section Department of Surgical and Biomedical
Sciences, Università degli Studi di Perugia, Perugia, Italy

2. Disclosures
Research Grants: Abbott, DMG, GSK, Janssen,
Sanofi-Pasteur, Vifor
Advisory Board Membership: GSK, Janssen, MSD,
Sanofi-Pasteur, Pfizer, Vifor

3. Agenda
 Antibiotic use & antimicrobial resistance
 Overall burden and impact of influenza, including
antibiotic use
 Recommendations on the use of influenza vaccines
 Influenza vaccination as possible effective measure to
control antimicrobial resistance

4. A very short life-span

5. Antimicrobial resistance (AMR)
directly related to the
antibiotic use

6. Antibiotic Consumption, Europe
OECD 2016

7. AMR, Europe
OECD 2016

8. ANTIMICROBIAL RESISTANCE AND
USE OF ANTIBIOTICS
a) ABUSE: prescriptions for diseases
not due to bacterial infection
b) MISUSE: use with inappropriate
dosage and duration of administration

9. Effect of antibiotic
prescribing in primary
care on antibiotic
resistance
(From Costelloe C et al. BMJ 2010)

11. Distribution of Respiratory Viruses during the Winter Season 2003–
2004
0
5
10
15
20
25
30
45 46 47 48 49 50 51 52 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Influenza RSV hMPV Coronaviruses Rhinovirus Adenovirus
Weeks2003 2004
N=2060 children aged under 15 years
Esposito S, et al. J Med Virol 2006;78:1609–15 and author’s own data.
Percentageofcases

12. Effect of Age on Healthcare Burden
<6 months 6–12 months 1–<3 years 3 –<5 years 5 –<15 years
Excesseventsper100children
Outpatient visits16
14
12
10
8
6
4
2
0
Courses of antibiotics
Excess treatment events in otherwise healthy children under 15 years of
age; data over 19 consecutive seasons (US)
Neuzil KM, et al. N Engl J Med 2000;342:225–31.
Age

13. Subjects(%)
0
5
10
15
20
25
30
35
40
45
Acute otitis
media
Pneumonia Sinusitis Antibiotics
<3 years 3–6 years 7–13 years
Complications of influenza in different age groups, prospective cohort study, Turku, Finland, 2000–2002
Children Under 3 Years of Age are Most Likely to Develop Acute
Otitis Media and Require Antibiotics
Heikkinen T, et al. J Infect Dis 2004;190:1369–73.

14. Mortalityrate
per1,000people
0
0.02
0.04
0.06
0.08
0.10
6–23
months
2–4
years
5–9
years
10–19
years
20–49
years
50–64
years
≥ 65
years
< 6
months
Age group
Age-associated rates of influenza-related deaths; data from British Columbia, Canada, 1998–2004 influenza seasons
Mortality Rates due to Influenza and Pneumonia
Sebastian R, et al. Vaccine 2008;26:1397–1403.
Provincial and national influenza surveillance reports from the British Columbia Centre for Disease Control, the Public Health
Agency of Canada’s FluWatch Program, and the Canada Communicable Disease Report (CCDR) were analysed from 1 Sep 1998
to 31 Aug 2004, to determine influenza-related deaths in British Columbia, Canada.

15. Season
2007/2008
Seasonal
A/H1N1
(n=126)
Season
2008/2009
Seasonal
A/H3N2
(n=486)
Season
2009/2010
Pandemic
A/H1N1
(n=389)
CLINICAL OUTCOME
Hospitalisation rate, n (%)
Duration of hospitalisation, mean days ± SD
Absence from school, mean days ± SD
4 (3.1)°*
5.1 ± 3.5°*
5.9 ± 4.7°*
79 (16.3)
7.5 ± 4.4*
7.5 ± 3.4*
51 (13.1)
9.1 ± 7.5
8.9 ± 5.3
DRUG USE, n (%)
Antibiotics
Antivirals
Antipyretics
Aerosol therapy
Steroids
99 (78.6)°
0 (0.0)*
100 (79.4)°*
30 (23.8)°*
6 (4.8)
466 (95.9)
0 (0.0)*
460 (94.6)
203 (41.8)
36 (7.4)
297 (76.3)°
16 (4.1)
383 (98.5)
157 (40.4)
23 (5.9)
°p<0.01 vs seasonal A/H3N2 influenza; *p<0.01 vs pandemic A/H1N1 influenza
Clinical Outcomes and Drug Use by Influenza A Subtypes
Esposito S, et al. J Infect 2011;63:300−7.

16. 0
20
40
60
80
100
Clinical presentation in children with
influenza A and B infection is similar
Esposito S, et al. BMC Infect Dis 2011; 11: 271.
LRTI, lower respiratory tract infection.
Influenza A/H1N1 (n = 143)
Influenza A/H3N2 (n = 519)
Influenza B (n = 239)
Children with influenza A/H3N2
had an higher number of LRTI,
wheezing and pneumonia than
those with influenza A/H1N1 o B
(all p < 0.05)
Percentage

17. 20
56
9
56
1 3
94 92
80
44
91
44
99 97
6 8
0
10
20
30
40
50
60
70
80
90
100
%InfluenzaBstrainsbylineage
Influenza season and vaccine lineage
Influenza B Circulation by Lineages in the USA and
Europe between 2001 and 2011
USA
23
100
7
74
19
77
2
17
84
94
77
93
2.8
81
23
98
83
16
6
0
10
20
30
40
50
60
70
80
90
100
%InfluenzaBstrainsbylineage
Influenza season and vaccine lineage
Europe
Recommended-Lineage Influenza B Opposite-Lineage Influenza B
Data not
available
Ambrose CS, et al. Human Vaccin Immunother 2012;8:81−8.

18. Hospitalisation during Influenza Season according to Age and
Presence of Underlying Chronic Disease
YEARS AGE
HOSPIT./
100,000 HR
SUBJECTS
HOSPIT./
100,000 HEALTHY
SUBJECTS
1973 − 1993
0 − 11 mos
12 − 24 mos
3 – 4 yrs
5 – 14 yrs
1900
800
320
92
496 – 1038
186
86
41
1992 – 1997
0 − 23 mos
2 – 4 yrs
5 – 17 yrs
−
−
−
144 – 187
0 – 25
8 – 12
1968 − 1973
15 – 44 yrs
45 – 64 yrs
≥65 yrs
56 – 110
392 – 635
399 – 518
23 – 25
13 – 23
−
1969 – 1995 < 65 yrs
≥65 yrs
−
−
20 – 42 (*)
125 − 228 (*)
(*) without a separation between high-risk (HR) and healthy subjects.
Izurieta HS, et al. N Engl J Med 2000;342:232–9.

19. PATIENTS TRADITIONALLY CONSIDERED AT
HIGHER RISK FOR INFLUENZA COMPLICATIONS
• THOSE WHO HAVE CHRONIC PULMONARY (INCLUDING
ASTHMA), OR CARDIOVASCULAR, RENAL, HEPATIC,
HEMATOLOGICAL OR METABOLIC DISORDERS (INCLUDING
DIABETES MELLITUS)
• THOSE WHO ARE IMMUNOSUPPRESSED
• THOSE WHO HAVE ANY CONDITION THAT CAN COMPROMISE
RESPIRATORY FUNCTION OR THE HANDLING OF
RESPIRATORY SECRETIONS OR THAT CAN INCREASE THE
RISK FOR ASPIRATION
• THOSE WHO ARE RECEIVING LONG-TERM ASPIRIN THERAPY
WHO THEREFORE MIGHT BE AT RISK FOR EXPERIENCING
REYE SYNDROME AFTER INFLUENZA INFECTION

21. INFLUENZA VACCINATION RATES IN ADOLESCENTS
WITH HIGH-RISK CONDITIONS (USA)
(From Nakamura MM and Lee GM, Pediatrics 2008)

22. VACCINATED HIGH-RISK CHILDREN
(No.=72)
Why is your child vaccinated against
influenza?
ANSWER FREQUENCY
Pediatrician’s
recommendation
63 (87.5%)
Protection of parents 6 (8.3%)
Protection of an elderly
family members
2 (2.8%)
Previous serious
influenza-like illness
1 (1.4%)
Esposito S et al., Vaccine 2006

23. Impact on the Community of Childhood Influenza Vaccination in
Japan and the USA
Optional
60
50
40
30
20
10
0
14
12
10
8
6
4
2
0
70
Excessdeathsduetopneumoniaand
influenza(per100,000population)
Most schoolchildren
Vaccination programme
Excessdeathsfromallcauses
(per100,000population)
Japan, pneumonia and influenzaJapan, all causes
USA, pneumonia and influenzaUSA, all causes
Vaccination of school children against influenza, Japan, 5-year moving average
excess mortality due to influenza and pneumonia, all age groups
Reichert TA, et al. N Engl J Med 2001;344:889–96.

24. Influenza vaccination recommendations
WHO/Europe
Recommend that member states vaccinate all individuals ≥6 months1
EU
Member states currently recommend paediatric vaccination;2,3,4
recommendations vary by country:
• 6 months to <18 years of age: Austria, Estonia and Slovakia
• 6–35 months: Finland
• 6–24 months: Slovenia, Latvia
• 24 months-10 yrs: UK
USA, Canada and PAHO countries
• US: All individuals ≥6 months of age5
• Canada: Children 6–24 months of age, and encourages all individuals ≥6
months of age to be vaccinated6
• Currently, 27 PAHO countries and territories recommend paediatric seasonal
influenza vaccination7*

25. Age group and costs (€)
Without
vaccination
With
vaccination
Total
savings
6 months to <3 years (N=140 000)
Medical costs 3 473 091 694 521 2 778 571
Vaccination program costs 0 1 057 916 -1 057 916
Health care costs 3 473 091 1 752 437 1 720 654
Travel costs 247 972 889 016 -641 043
Total direct costs 3 721 064 2 641 453 1 079 611
Productivity costs 3 355 692 1 631 008 1 724 684
Societal costs 7 076 756 4 272 461 2 804 295
Assumed vaccine efficacy 60%.
Vaccination of young children is cost-saving, investing €1 million
will save an estimated €2.8 million in societal costs
Influenza vaccination in young children is
cost effective
Salo et al. Vaccine 2006
The Finnish experience (assumed vaccine efficacy 60%)

27. The GISA call to action for the appropriate use
of antimicrobials and the control of
antimicrobial resistance in Italy.
•
Prevention, primary & secondary
1. Vaccines
2. Antibiotic prophylaxis in surgery & in the patient at risk
Control of the spread of infections & AMR
3. Infection Control
Prevention of AMR in animals & foods
4. Control of antibiotic use in animals & foods (One Health)
5-10 Appropriate use of antibiotics in humans (ASP)
•
Menichetti F et al. Int J Antimicrob Agents. 2018 Aug;52(2):127-134

29. Messieurs,
c'est les
microbes qui
auront le
dernier mot.
Louis Pasteur
1822-1895

30. MICROBIOTA and EPIGENETIC
PROGRAMMING
Heredity deals
the cards;
environment
plays them

31. The microbiome,
and its rapid
modulation by
factors such as
vaccines may impact
multiple aspects of
personalized
medicine.
Taking it Personally: Personalized Utilization
of the Human Microbiome in Health and Disease
Cell Host & Microbe 19, 2016

32. Pediatr Allergy Immunol. 2016 Feb;27(1):22-7.

33. Resting memory B cell gene expression signature rather than
frequency defines responders
Functional response in terms of gene expression in T
follicular Helper cells characterizes HIV Responders
De Armas L et al ; J Immunol. 2017 Mar 1;198(5):1995-2005.
Novel genetic biomarkers can predict responsonsiveness
to vaccination in immunocompromised children
Cotugno N et al. under review

34. Take home messages
• Abuse and misuse of available antimicrobials have increased AMR,
with relevant adverse health and economic impacts
• AMR is a relevant clinical problem that should be fought with all
potentially effective measures
• Influenza vaccine is a possible effective measure to control AMR
through a significant reduction in antibiotic consumption
• The evidence that AMR can be combatted with influenza vaccines can
promote greater use of these preventive measures

35. I AM VACCINATED. WHAT ABOUT
YOU?