European Antibiotic Awareness Day (EAAD): any

J Antimicrob Chemother doi:10.1093/jac/dky206

European Antibiotic Awareness Day (EAAD): any impact on antibiotic consumption and public awareness in Slovenia? Milan Cizman1, Tina Plankar Srovin1*, Bojana Beovic1, Mitja Vrdelja2, Tom Bajec3 and Rok Blagus4 1

University Medical Centre, Department of Infectious Diseases, Japljeva 2, 1000 Ljubljana, Slovenia; 2National Institute of Public Health, Trubarjeva 2, 1000 Ljubljana, Slovenia; 3Tom&Tim d.o.o, Smtrnikova 5, 1000 Ljubljana, Slovenia; 4Medical Faculty, Institute for Biostatistics and Medical Informatics, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia *Corresponding author. E-mail: [email protected]

Received 18 December 2017; returned 21 March 2018; revised 3 May 2018; accepted 6 May 2018 Objectives: To evaluate the impact of European Antibiotic Awareness Day (EAAD) on antibiotic consumption, improvements in general public awareness and antibiotic resistance in Slovenia. Methods: Outpatient data for the period from 2002 to 2016 and hospital antibiotic consumption data for 2004–16 were collected using the Anatomical Therapeutic Chemical (ATC) classification/DDDs. Outpatient antibiotic consumption data were expressed in DDDs/1000 inhabitants/day (DIDs), number of packages/1000 inhabitant-days and number of prescriptions/1000 inhabitants/year. Hospital consumption data were expressed in DIDs, number of DDDs/100 bed-days and number of DDDs/100 admissions. Segmented regression analysis of interrupted time series was used to estimate the effects of these interventions on antibiotic consumption. Results: During the 8 year period since establishing EAAD, a 9%–17% decrease in outpatient antibiotic consumption has been observed, depending on the measurement unit, which was a little more than in the 6 years prior to EAAD (7%–12%). The trend change in hospital consumption after EAAD was established remained small, with a highly non-significant P value. Eurobarometer data did not show an increase in knowledge on antibiotic use. Resistance of Streptococcus pneumoniae to penicillin and macrolides decreased during EAAD activities. Conclusions: EAAD activities were associated with a decreasing trend in community consumption. Owing to many other national activities on the prudent use of antimicrobials in outpatients and inpatients it is difficult to analyse the direct effect of EAAD.

Introduction The European Antibiotic Awareness Day (EAAD) was established in 2008 as a platform for providing support to national campaigns across Europe.1,2 The decision to establish EAAD followed successful national campaigns in Belgium and France.3,4 In Belgium, outpatient antibiotic use, expressed in number of reimbursed packages/1000 inhabitants/day, decreased by 36% between the winter seasons of 1997–98 and 2006–07.3 The decrease in consumption was not evident when expressed in DDDs/1000 inhabitants/day (DIDs). In France, the national campaign was associated with a 26.5% reduction in the mean number of winter antibiotic prescriptions over the 5 years from 2002 to 2007.4 The aim of EAAD was to raise awareness about the importance of prudent use of antibiotics among community and hospital prescribers and the general public.1 During the first 5 years of EAAD the number of participating countries steadily increased and each country carried out at least

one activity targeting the general public, primary care or hospital prescribers.2 Slovenia has participated in EAAD activities since 2008. Activities during 2008–12 were published previously.2 The aim of this study was to evaluate the impact of national activities on antibiotic consumption in the community and in hospitals, on improvements in general public awareness and on antibiotic resistance.

Methods Population and hospital data Slovenia is a small Central European country with 2064188 inhabitants according to the census of January 2016.5 Almost all inhabitants (.99%) have compulsory health insurance. A prescription is required for each antibiotic purchase and antibiotics may only be prescribed by physicians. Slovenia has 29 hospitals, comprising 2 university hospitals, 10 general hospitals and 17 specialized hospitals; 26 hospitals are public and 3 are private.

C The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. V

For permissions, please email: [email protected].

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Table 1. National EAAD activities in Slovenia 2006–16 Year National activities Publication of articles in medical journals Scientific/professional conferencea Medical letter to hospitals Press conference Distribution of brochures or other materials Public relation activitiesd Public relation activities provided by NIPH Other activities not related to EAADf

2008 !!

2009 !

2010 !

2011

2013

2014

2015

2016

!!

!

!

!

!

!

!

!

!

!

! !

! !

! ! !

! ! !

! ! !c

web site

!!! web site

!!! web site

!!! web site

!!! web site

!!

!!!g

!!!

!!!

!!!

! ! !b

! ! !

! ! !

! !

! mediae; web site !

! mediae; web site !

!!! web site

!!! mediae; web site !!

!!

2012

!

!, 1 article/activity; !!, 2 articles/activities; !!!, 3 or more articles/activities Supported by Ministry of Health. b 2000 posters. c 300 posters. d TV spots, radio interviews, articles in magazines and newspapers. e Media indicates a message to the media was generated. f Infectious diseases symposia, workshops, regional meetings. g Treatment guidelines for antimicrobial use in hospitals.9 a

National EAAD activities National EAAD activities are shown in Table 1. National activities aimed at rational prescribing of antibiotics before 2008 were published in 2015.6 From 2008, EAAD activities were undertaken in addition to those in previous years. For each year from 2008 to 2016, except in 2015, an article on prudent use of antibiotics was published in the official Journal of the Medical Chamber of Slovenia to highlight EAAD and increase awareness among primary care and hospital physicians. In 2008 an article devoted to EAAD was also published in the Slovenian Medical Journal.7 Since 2011, expert conferences for the medical directors of hospitals and large primary care institutions have been organized to increase their awareness of the leading factors and outcomes of antibiotic resistance. The National Institute of Public Health (NIPH) publishes ECDC campaign materials on their web site yearly. A number of different activities targeting the general public were also organized in the period 2008–16. Each year a medical letter prepared by a member of the Intersectoral Coordination Mechanism (ICM) was circulated to all hospitals to inform the hospital doctors on prudent use of antibiotics.

Non-EAAD-associated national activities Other activities, including restrictive, educational and regulatory/structural activities before and after 2008, were published in 2015.6,8 Since 1995 an annual symposium targeted at primary care and hospital care physicians has been organized by the Slovenian Society of Antimicrobial Chemotherapy with the goal of improving antimicrobial prescription. Similarly, annual courses for young physicians on prudent antibiotic use have been organized since 2010. Audits on 12 out of 29 hospitals have been conducted since 2013. Following an audit visit, hospital authorities receive recommendations for improving prudent use of antimicrobials from the Ministry of Health. In 2013, treatment guidelines for antimicrobial use in hospitals were published, with .3000 copies sold by the start of 2017, meaning that .70% of primary and hospital care physicians purchased the guidelines.9 In the period 2013–15, expert meetings devoted to primary

care physicians in four (out of nine) high-prescription regions were organized. See Table 1.

Community and hospital antibiotic consumption data Consumption of antibiotics in outpatient care has been monitored since 1976. Data on the number of packages, the cost of antibiotics, the age and gender of the patients, the identity numbers of the physicians and healthcare institutions prescribing antibiotics were collected. Data on the number of packages of antibiotics was provided by the NIPH of the Republic of Slovenia. Outpatient data for the period 2002–16 and antibiotic consumption data from all hospitals for 2004–16 were collected using the Anatomical Therapeutic Classification (ATC)/DDDs (WHO version 2015).10 Outpatient antibiotic consumption data were expressed in DIDs, number of packages/ 1000 inhabitant-days (PIDs) and number of prescriptions/1000 inhabitants/year (RxIDs). Total hospital consumption was expressed in number of DIDs, number of DDDs/100 bed-days and number of DDDs/100 admissions. Departmental consumption data from university and general hospitals have been collected since 2006. The consumption in five departments was expressed as the number of DDDs/100 bed-days and number of DDDs/100 admissions. Hospital consumption data were provided by hospital pharmacists using ward dispensing records as the source data. National and regional EAAD activities have taken place yearly and involved many stakeholders. We reviewed several special Eurobarometer reports on antimicrobial resistance commissioned by the European Commission to identify public knowledge about and attitudes to antibiotic use among the Slovenian general public.11–13

Statistical methods Segmented regression analysis of interrupted time series was used to evaluate the effect of disseminating guidelines on antibiotic prescription.14

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Table 2. Consumption of antibiotics for systemic use (J01) in the community and in the hospitals in Slovenia for 2002, 2004, 2008 and 2016 Year 2002

2004

Table 3. Absolute change in yearly antibiotic consumption in ambulatory and hospital care before and after the first EAAD in November 2008 Measure

2008

2016

Community consumption DIDs PIDs RxIDs

16.40 2.51 660

16.76 2.50 667

15.19 2.22 588

13.87 1.84 494

Hospital consumption DIDs DDDs/100 bed-days DDDs/100 admissions number of beds number of admissions number of bed-days average length of stay (days)

NA NA NA 10147 332107 2674727 8.1

1.70 47.28 354.70 9584 349431 2621464 7.5

1.68 48.22 334.54 9586 372577 2584591 6.9

1.68 51.95 332.34 9266 382053 2443920 6.4

NA, not available. Two segments were defined: the pre-intervention period, lasting up to the end of 2008, and the post-intervention period. Least squares modelling was used to test for any significant change in level or trend in the time series after implementing the guidelines, with controls for any preintervention differences in level and trend. We tested for autocorrelation with the Durbin–Watson test. In case of a significant autocorrelation, robust standard errors and P values were computed by using the estimators proposed by Newey and West,15 using the non-parametric bandwidth selection procedure of Newey and West.16 The assumption of normally distributed residuals was verified with the Shapiro–Wilk test. The most parsimonious model was obtained by backward elimination using the Bayesian information criterion (BIC) as a criterion, including baseline trend in the model irrespective of BIC. A P value ,0.05 was considered statistically significant. The analysis was performed with R.17

Results Consumption of antibiotics for systemic use in the community (2002–16) and in hospital care (2004–16) is shown in Table 2. Consumption of antibiotics in the community had decreased by between 7.4% (DIDs) and 11.6% (PIDs), depending on measurement unit, in the 6 year period before EAAD was established. The number of RxIDs decreased by 11.0%. In the 8 year period from 2008 to 2016, consumption decreased by 9%–17% depending on the measurement unit. From 2002 to 2008 antibiotic consumption in ambulatory care decreased yearly by 0.276 DIDs (P " 0.008; Table 3). Consumption dropped by 0.686 DIDs immediately after the EAAD was established, but afterwards yearly consumption only decreased by 0.047 DIDs; there was thus a positive, but not statistically significant, change in trend after the intervention (0.229 DIDs, P " 0.072). For the period from 2004 to 2008, hospital consumption decreased by 1.2% when expressed in DIDs and 5.7% when expressed in DDDs/100 admissions, while consumption expressed in DDDs/100 bed-days increased by 1.9% (Table 2). In the period 2008–16, hospital consumption showed no change when expressed in DIDs, decreased by 0.66% when expressed in DDDs/ 100 admissions and increased by 7.7% when expressed in DDDs/

Coefficient

95% CI

P value

Ambulatory care DIDs trend before EAAD level change after EAAD trend change after EAAD trend before EAADa trend change after EAADa

#0.276 #0.686 0.229 #0.344 0.229

#0.465 to #0.086 #1.724 to 0.352 #0.016 to 0.474 #0.508 to #0.181 #0.024 to 0.482

0.008 0.174 0.064 0.001 0.072

Hospital care DIDsb trend before EAAD level change after EAAD trend change after EAAD trend before EAADa

#0.005 0.023 #0.006 #0.007

#0.043 to 0.033 #0.111 to 0.156 #0.049 to 0.037 #0.026 to 0.012

0.775 0.712 0.765 0.455

Hospital care DDDs/100 bed-daysb trend before EAAD 0.324 level change after EAAD 1.28 trend change after EAAD #0.308 trend before EAADa 0.241

0.074 to 0.574 #3.256 to 5.816 #1.396 to 0.780 #0.031 to 0.513

0.017 0.539 0.538 0.077

Hospital care DDDs/100 admissionsb trend before EAAD #4.97 level change after EAAD 11.799 trend change after EAAD 1.41 trend before EAADa #2.65

#5.299 to #4.640 #45.54 to 69.14 #15.16 to 17.98 #6.216 to 0.915

,0.001

0.653 0.852 0.13

a b

Most parsimonious model. Correction for autocorrelation was needed in the statistical analysis.

100 bed-days. The trend change, when expressed in DDDs/100 bed-days or DDDs/100 admissions, was statistically significant before the EAAD; after EAAD the trend change was small and the P value was non-significant (Table 3). The mean length of stay decreased in the two periods by 8.1% and 7.3%, respectively. Consumption, expressed in DDDs/100 bed-days, increased for all the departments analysed; consumption expressed in DDDs/100 admissions increased in all departments apart from internal medical and paediatric departments. In internal medical and paediatric departments the average consumption decreased by 1.4% and 4.5%, respectively, without any focused activities.

Antimicrobial resistance The prevalence of Streptococcus pneumoniae with reduced susceptibility to penicillin was 19%, 15% and 7% in 2002, 2008 and 2016, respectively, and to macrolides 10%, 15% and 14%, respectively. In the same years, consumption of penicillins was 9.54, 9.48 and 9.29 DIDs, respectively, while that of macrolides decreased from 2.81 to 2.24 and 1.38 DIDs. Public knowledge and attitudes to antibiotic use among the Slovenian general public between 2009 and 2016 are shown in Table 4. Table 4 shows that a smaller percentage of patients were treated with antibiotics during the previous 12 months in 2016 than in 2009 and 2013, but public knowledge of antibiotic use and awareness about not taking antibiotics unnecessarily was lower. 3 of 6

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Table 4. Knowledge regarding antibiotic use among the Slovenian general public11–13 Year Measure

2009

2013

2016

Antibiotic therapy during the previous 12 months Knowledge of antibiotics Does unnecessary use of antibiotics make them ineffective? Taking information on board

27%

28%

25%

33% 94%

29% 95%

26% 91%

50%

37%

44%

Discussion To our knowledge, this is the first study to analyse the impact of national EAAD activities on antibiotic consumption and resistance in the community, consumption in hospitals and public awareness of prudent use of antibiotics for systemic use. In the 8 year period after establishing EAAD a 9%–17% decrease in outpatient antibiotic consumption was recorded, which was slightly higher than in the 6 years prior to EAAD (7%–12%). Time series analysis showed that antibiotic consumption was decreasing significantly before the first EAAD and, although yearly consumption was still decreasing after 2008, the trend was smaller than before the first EAAD (Table 3). The described EAAD activities are not the only initiatives in the field of rational prescribing of antimicrobials and should be recognized in addition to other activities that were introduced before the first EAAD. Comparing outpatient consumption in European Union/European Economic Area (EU/EEA) countries between 2016 and 2008 showed a mean increase in antibiotic consumption of 4.3% (from 21.0 to 21.9 DIDs). Seventeen out of 25 countries decreased their consumption, but it appears that the average increase was larger than the decrease.18,19 In Slovenia, national activities regarding EAAD were similar to those in many EU/EEA countries.2 We found other activities not related to EAAD, such as restrictive interventions in outpatients and regional meetings in high-prescribing regions, to be effective.20 Regional meetings in high-prescribing areas did show a small [on average 5.7% (0.3–12.0%)] decrease in antibiotic consumption 2 or 3 years after the meeting. In Sweden, decreases in antibiotic consumption have occurred after county meetings in smaller groups.21 Data for Belgium and France, two countries with successful preEAAD campaigns, showed an increase in ambulatory antibiotic consumption in France of 8.2% (28.0 versus 30.3 DIDs) and a decrease in Belgium of 0.7% (27.7 versus 27.5 DIDs).18,19 The decrease in hospital consumption in our country was statistically significant before the EAAD; after the first EAAD in 2008 the trend decrease, as expressed in DDDs/100 admissions, was small and the P value was close to 1. The consumption of antibiotics expressed in DDDs/100 bed-days has steadily increased, which can be explained by reduced length of stay. In contrast, the consumption expressed in DDDs/100 admissions showed a small trend of reduced antibiotic consumption, which is probably a consequence of more rational prescribing of antibiotics. Mean hospital consumption of antibiotics for systemic use in 15 EU/EEA countries has shown a decrease of 1.9% (from 2.1 to 2.06 DIDs). Trends in

the consumption of antibiotics for systemic use in the hospital sector varied from one country to another and average annual changes were commonly non-significant.18,19 The impact of EAAD on antibiotic resistance is difficult to evaluate. Without reductions in antibiotic consumption and no improvement in infection prevention, we cannot expect a decrease in antibiotic resistance. In Slovenia, we observe lower resistance of invasive strains of S. pneumoniae to penicillin and macrolides.22,23 Lower resistance of S. pneumoniae to penicillin can be explained by decreased use of total antibiotics and penicillins.24,25 The substantial (38.4%) decrease in macrolide use was not associated with a significant decrease in resistance of S. pneumoniae, which indicates a complex relationship between the use of antibiotics and resistance.26 Owing to the decreased use of all classes of macrolides we are looking for the clonality of S. pneumoniae.25,26 To decrease outpatient antibiotic consumption, additional interventions focusing on the most common prescribers and most common infectious diseases should be introduced. In Slovenia, general physicians, specialists in family medicine, paediatricians and physicians without specialization are responsible for prescribing 80% of antibiotics, with upper respiratory tract infections (URTIs) and acute bronchitis being the most common reasons for antibiotic prescription.27 In 2017, we produced four leaflets for URTIs, covering otitis media, acute sinusitis, throat infections and acute bronchitis, which were distributed to all primary care physicians by the Health Insurance Institute in the late autumn. Pilot workshops in smaller groups with primary care physicians are being planned as part of a national strategy. A decrease in hospital consumption is more difficult to achieve due to the greater number of physicians, larger number of different specialists and a broader spectrum of infectious diseases.28,29 Totally guided antibiotic prescribing by infectious diseases specialists and face-to-face communication has proved to be an effective and safe method, but it is costly and labour intensive.30–32 More staff are urgently needed to cost-effectively conduct antibiotic stewardship programmes in hospitals. A minimum of two full-time equivalents (FTEs) of 0.5 personnel/250 beds (infectious diseases physician, pharmacist, IT specialist) is recommended by the German Society for Infectious Diseases.33 In Slovenia’s largest university hospital, one FTE is employed for 2400 beds; in the remaining hospitals the function is covered by infectious diseases specialist consultants. Computer support to control adherence to guidelines, de-escalation and appropriate antimicrobial prescriptions is needed. An alternative method could be offering incentives to general practitioners and hospitals to reduce antibiotic prescribing.34 The special Eurobarometer report on antimicrobial resistance helps to identify improvements in public knowledge and attitudes to antibiotic use. Data from several Eurobarometer reports did not indicate increased knowledge on antibiotic use among the Slovenian general public despite many yearly national activities.11–13 The general public should be aware that antibiotics fight bacteria, not viruses. They should be informed not to request antibiotics for illnesses that show no benefit from antibiotic treatment. Patients should follow directions for proper use of antibiotics, including completing the full course of the drug, not skipping any doses, not saving antibiotics, not taking antibiotics prescribed for someone else and talking with a healthcare professional, especially in case of uncertainty.35

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The confounding factors in development of antibiotic resistance were not evaluated, which is a limitation of the study. Non-EAADassociated national activities could be a confounder in the present study as well. We have shown that EAAD activities were associated with decreased consumption of antibiotics in community care and with a small decrease in consumption in hospital care expressed in DDDs/100 admissions. The decrease in hospital consumption in our country was statistically significant before the EAAD due to many interventions, including structural, restrictive and educational interventions.8 During EAAD activities, resistance of S. pneumoniae to penicillin and macrolides decreased. To improve antibiotic awareness in prescribers and the general public, repeated and targeted national activities should be intensified and new interventions should be introduced.

Acknowledgements Part of the manuscript was presented at the Twenty-eighth European Congress of Clinical Microbiology and Infectious Diseases, Madrid, Spain, 2018 (E0019). We would like to thank all hospital pharmacists for provid ing hospital consumption data and Tamir Azaz, TA TOCKA, Tamir Samuel Azaz s.p. for English language editing.

Funding This study was carried out as part of our routine work. English language editing was funded from WHO support for World Antibiotic Awareness Week (small grant support - PO 201862684).

8 Cizman M, Bajec T, Sibanc B et al. Hospital antibiotic management in Slovenia—results of the ABS maturity survey of the ABS International group. Wien Klin Wochenschr 2008; 120: 316–20.  zman M, Beovic B. How to Prescribe Antimicrobials in Hospitals. Ljubljana, 9 Ci Slovenia: Slovenian Society of Chemotherapy, 2013 (in Slovene). 10 WHO Collaborating Centre for Drug Statistics Methodology. ATC Index with DDDs 2015. Oslo, Norway: Norwegian Institute of Public Health, 2015. 11 TNS Opinion & Social 2010. Special Eurobarometer 338—Antimicrobial Resistance. http://data.europa.eu/euodp/en/data/dataset/S802_72_5_EBS338. 12 TNS Opinion & Social 2013. Special Eurobarometer 407—Antimicrobial Resistance. https://data.europa.eu/euodp/data/dataset/S1101_79_4_407. 13 TNS Opinion & Social 2016. Special Eurobarometer 445—Antimicrobial Resistance. https://ec.europa.eu/health/amr/sites/amr/files/eb445_amr_gen eralreport_en.pdf. 14 Wagner AK, Soumerai SB, Zhang F et al. Segmented regression analysis of interrupted time series studies in medication use research. J Clin Pharm Ther 2002; 27: 299–309. 15 Newey WK, West KD. A simple, positive semi-definite, heteroskedasticity and autocorrelation consistent covariance matrix. Econometrica 1987; 55: 703–8. 16 Newey WK, West KD. Automatic lag selection in covariance matrix estimation. Rev Econ Stud 1994; 61: 631–53. 17 R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing, 2017. https://www.Rproject.org/. 18 ECDC. Surveillance of Antimicrobial Consumption in Europe 2012. Stockholm, Sweden: ECDC, 2014.

Transparency declarations

19 ECDC. Summary of the Latest Data on Antibiotic Consumption in the European Union. ESAC-Net Surveillance Data. Stockholm, Sweden: ECDC, 2017.  zman M, Plankar Srovin T, Blagus R et al. The long-term effects of re20 Ci strictive interventions on consumption and costs of antibiotics. J Glob Antimicrob Resist 2015; 3: 31–5.

M. C. and T. B. are Slovenian participants in ESAC-Net. All other authors: none to declare.

21 Molstad S, Cars O, Struwe J. Strama - a Swedish working model for containment of antibiotic resistance. Euro Surveill 2008; 13: pii"19041.

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