Public policy to reduce antibiotic resistance Prof. Niels Frimodt-Moller

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Public Policy to Reduce Antibiotic Resistance Niels Frimodt-Moller, Professor, MD DMSc Head,

Copenhagen, Denmark 1 Factors of importance for low antibiotic use: main points covered Examples of

antibiotic consumption and how to maintain a low use Importance of diagnostic microbiology also at

1 Public Policy to Reduce Antibiotic Resistance Niels Frimodt-Moller, Professor, MD DMSc Head, Antibiotic Research National Center for Antimicrobials and Infection Control Statens Serum Institut Copenhagen, Denmark 1 Factors of importance for low antibiotic use: main points covered Examples of correlation between antibiotic resistance and antibiotic consumption Factors of importance for antibiotic consumption and how to maintain a low use Importance of diagnostic microbiology also at GP level Based on the Danish experience 2 Proportion of MRSA isolates in participating countries in 27 EARSS 3 1

million DDD 4 3 2 1 Primary Hospitals Health Care Source: Danish Medicines Agency, 2

2 Source: ECDC 4 Consumption of systemic antibacterials (ATC group J1), Denmark, 1999 Primary Health Care 23.6 million DDD DDD / 1, person-days Hospitals 2. million DDD Primary Hospitals Health Care Source: Danish Medicines Agency, 2 Proportion of carbapenems resistant P. auruginosa isolates in participating countries in 27 EARSS 6 2

3 Proportion of fluoroquinolone resistant E. coli isolates in participating countries in 27 EARSS 7 Change in fluoroquinolone use in various European countries Country 8 Fluoroquinolones and E. coli: Correlation between increasing resistance and increasing use DDD/1, occu upied bed-days DANMAP a) Use of fluoroquinolones (J1MA) Fluoroquinolones resistance among E. coli % resistan nt isolates Figure 4. Trends in the use of fluoroquinolones (J1MA) and occurrence of fluoroquinolone resistance among E. coli from blood infections a) Estimated number of occupied bed-days 9 3

against outpatient sales of beta-lactam antibiotics in 11 European countries; antimicrobial resistance data are from 1998 to 1999 and antibiotic sales data are from 1997; DDD = defined daily dose 1

4 Relation between antibiotic use and resistance for Pneumococci in EU-countries (Bronzwear et al., Emerg Infect Dis 22, 8) ln (R R/(1-R)) DDD beta-lactam antibiotics/1 The logodds of resistance to penicillin among invasive isolates of Streptoccus pneumoniae (PNSP; ln(r/[1-r])) is regressed against outpatient sales of beta-lactam antibiotics in 11 European countries; antimicrobial resistance data are from 1998 to 1999 and antibiotic sales data are from 1997; DDD = defined daily dose 1 Azithromycin: Selection of resistant S. pneumoniae during treatment for trachoma % Before RD 2-3 week 2 months 6 months RD, single dose azithromycin % carriage % resist. Leach et al., CID 1997; 24: er 1, inh. No. invasive ERSP p Invasive erythromycin-resistant Streptococcus pneumoniae (ERSP) and consumption of macrolides (J1MA) in Danish counties, ,2 1,8,6,4,2 R 2 =.41 P<.1 1 1, 2 2, 3 3, Consumption of macrolides (J1MA, DDD per 1, inh.-days) Multiple linear regression model for prediction of no. invasive ERSP per 1, inhabitants Antimicrobial consumption Standardized regression coefficient Erythromycin <.1 Azithromycin <.1 R 2 =.76, all variables Ln transformed Source: Nielsen HUK, et al., 41st ICAAC, Chicago (IL), 16-19/12/21, #1867 t P 12 4

5 Correlation between consumption and resistance: azithromycin and pneumococci criptions per inhabitants Pres 1, /96 96/97 97/98 98/99 99/ MRSP among in nvasive S. pneumonia ae (%) Azithromycin Roxithromycin Clarithromycin Erythromycin MRSP 13 xime use bed-days) Cefurox (DDD per 1. Cefuroxime and ciprofloxacin use and resistance against these in E. coli, in hospitals, Blood R E. coli, (%) (cipro) use bed-days) Fluorokinolon (DDD per Urine R E. coli, %) 4 3 Cefuroximeblood Ciprofloxacinurine (% 2 1 Cefuroxime use Fluoroquinolone (cipro) use Cefuroxime resistance Ciprofloxacin resistance Reference: DANRES and Danish Medicines Agency for DANMAP, Correlation between antibiotics and resistance: selection Mutation or horizontal R-transfer Antibiotic Modified from F. Baquero 1

Reasons for development of resistance: Selection 16 Factors of importance for low antibiotic use Monitoring of antibiotic National monitoring via pharmacies: Danish Medicines Agency Local monitoring:

6 Reasons for development of resistance: Selection 16 Factors of importance for low antibiotic use Monitoring of antibiotic National monitoring via pharmacies: Danish Medicines Agency Local monitoring: county pharmacist communicates with GP s about their own antibiotic use as compared to GP s in that region (e.g. Ordiprax system) Reimbursement of antibiotics Centrally regulated pharmacies Rostering of General Practitioners 17 Factors of importance for low antibiotic use (2) Antibiotics must only be prescribed by a medical doctor Import of medicine incl. antibiotics over the internet should not be allowed Advertising for prescription antibiotics in TV, newspapers or public magazines not allowed 18 6

Factors of importance for low antibiotic use (3) Reimbursement of cost restricted to certain antibiotics has been used as a strong weapon in Denmark 19 Differential public reimbursement of

PHENOXYMETHYLPENICILLIN J1CF1 J1CF J1CR2 J1EA1 J1EB2 J1FA1 J1FA6 J1FA9 J1FA1 J1XC1 J1XE1 DICLOXACILLIN FLUCLOXACILLIN AMOXICILLIN and ENZYM-INHIBITOR TRIMETHOPRIM SULFAMETHIZOLE ERYTHROMYCIN

7 Factors of importance for low antibiotic use (3) Reimbursement of cost restricted to certain antibiotics has been used as a strong weapon in Denmark 19 Differential public reimbursement of antimicrobials in the Danish primary healthcare sector J1CA1 AMPICILLIN J1CA2 PIVAMPICILLIN J1CA4 AMOXICILLIN J1CA8 PIVMECILLINAM J1CA11 MECILLINAM J1CE1 BENZYLPENICILLIN J1CE2 PHENOXYMETHYLPENICILLIN J1CF1 J1CF J1CR2 J1EA1 J1EB2 J1FA1 J1FA6 J1FA9 J1FA1 J1XC1 J1XE1 DICLOXACILLIN FLUCLOXACILLIN AMOXICILLIN and ENZYM-INHIBITOR TRIMETHOPRIM SULFAMETHIZOLE ERYTHROMYCIN ROXITHROMYCIN CLARITHROMYCIN AZITHROMYCIN FUSIDIN NITROFURANTOIN J1A J1D J1DH J1FF1 J1G J1MA J1XD1 J1XX8 Tetracyklines Cefalosporines Carbapenems Clindamycin Aminoglycosides Fluoroquinolones Metronidazol Linezolid % % 2 Monthly tetracycline prescription rate, Denmark, 1/ /1999 No. prescr. per 1, inh. 4 Change in reimbursement: from to % Months Source: Danish Medicines Agency,

) Monthly tetracycline prescription rate and tetracycline- resistant Escherichia coli hospital isolates, Copenhagen and

Isolates (%, -month moving average) 2 1 Tetracycline Use (# prescriptions per 1, inhabitants) Months Source: Danish Medicines

Westh, Hvidovre Hospital, 2 22 DANMAP 23; Statens Serum Institut Nalidixin-resistant Escherichia coli from urine and

coli fro (%, -mth average 8 6 4 2,2,2,1,1, use day, e) Fluoroquinolone (DDD/1. inh.

8 ) Monthly tetracycline prescription rate and tetracycline- resistant Escherichia coli hospital isolates, Copenhagen and Frederiksberg Municipalities, 1/ / Change in reimbursement: from to % Tetracycline-R Escherichia coli Hosp. Isolates (%, -month moving average) 2 1 Tetracycline Use (# prescriptions per 1, inhabitants) Months Source: Danish Medicines Agency, and H. Westh, Hvidovre Hospital, 2 22 DANMAP 23; Statens Serum Institut Nalidixin-resistant Escherichia coli from urine and fluoroquinolone consumption, North Jutland County, 1/1996-6/24 Change in reimbursement: from to % om UTI Nalidixin-R E. coli fro (%, -mth average ,2,2,1,1, use day, e) Fluoroquinolone (DDD/1. inh.-d 3-mths average DANMAP DANMAP 23; Statens Serum Institut Ciprofloxacin use in general practice - correlation between price and consumption Ciprofloxacin co (defined daily dos inhabitants per da moving ave nsumption se per 1, ay, -month erage) Average price of one dose of ciproflox e defined daily xacin (DKK) Danish Medicines Agency,

Unfortunately the prize seems to determine the policy and the resistance level!

average) Average price of one defined daily dose of cip rofloxacin (DKK) Figure 4.

Estimated number of occupied bed-days 2 Cost after reimbursement and consumption of tetracyclines and fluoroquinolones in

in 6 4 2 [ ] [ ], 1 1, Average cost of 1 DDD of oral tetracycline after reimbursement (PPP US$, 1998) oroquinolones e ATC J1MA

, Lancet 21; 37: 181-3, and EudraMat, April 1998 4 3 2 1 [ ] [ ] 2 4 6 Average cost of 1 DDD of oral fluoroquinolone after

9 Unfortunately the prize seems to determine the policy and the resistance level! occupied bed-days DDD/1, o DANMAP a) Use of fluoroquinolones (J1MA) Fluoroquinolones resistance among E. coli esistant isolates % re Ciprofloxacin consu mption (defined daily dose per 1, in habitants per day, -month mov ving average) Average price of one defined daily dose of cip rofloxacin (DKK) Figure 4. Trends in the use of fluoroquinolones (J1MA) and occurrence of fluoroquinolone resistance among E. coli from blood infections a) Estimated number of occupied bed-days 2 Cost after reimbursement and consumption of tetracyclines and fluoroquinolones in primary health care, EU member states, 1997 tetracyclines se ATC J1A nh-days, 1997) Consumption of for systemic us (DDD per 1, in [ ] [ ], 1 1, Average cost of 1 DDD of oral tetracycline after reimbursement (PPP US$, 1998) oroquinolones e ATC J1MA nh-days, 1997) Consumption of flu for systemic use (DDD per 1, in Sources: Cars O, et al., Lancet 21; 37: 181-3, and EudraMat, April [ ] [ ] Average cost of 1 DDD of oral fluoroquinolone after reimbursement (PPP US$, 1998) 26 Factors of importance for low antibiotic use (4) Role of pharmacies Over the counter (OTC) sale of antibiotics; Antibiotics are prescription only in all EU countries but the rule is not enforced in all countries Disregard of the regulation is probably a consequence of competition; the more pharmacies the less the income and the higher the OTC sale 27 9

10 I Overall consumption of systemic antibacterials (ATC J1) in primary health care and consumption of medicines without prescription, EU, f medicines scription ed, 1996) Consumption of without pres (% interviewe tibacterials ATC J1 days, 1997) 4 3 R 2 =.37 P= Consumption of medicines without prescription (% int., 1996) Sources: Monnet DL; Eurobarometer 44.3, European Commission; Cars O, et al., Lancet 21; 37: E FIN A UK S DK IRL Consumption of ant for systemic use (DDD per 1, inh-d Consumption of medicines without prescription, no. inhabitants per pharmacy, and annual revenues from sales of pharmaceuticals per pharmacy, EU, Consumption of medicines without prescription (% pop., 1996) No. inhabitants per public pharmacy (1997) from sales s per public PP US$, 1997) Annual revenues of pharmaceuticals pharmacy (Million PP,,4,3 R 2 =.9 P=.1 Sources: Frimodt-Moller N, Monnet DL; Eurobarometer 44.3, European Commission in Key Data on Health 2, Eurostat; and GIRP and IMS Health,2, No. inhabitants per public pharmacy (1997) 29 Factors of importance for low antibiotic use () Rostering of patients, i.e. patients are allocated to one general practitioner (GP), must use this GP at any time and can only shift GP during a narrow time-window once a year Without rostering, patients can choose any GP in the region, even from visit to visit 3 1

Overall consumption of systemic antibacterials (ATC J1) in primary health care, fee-for-service and rostering of patients by GPs, EU, 1997 ibacterials ATC J1 nh-days) Consumption of ant for systemic

11 Overall consumption of systemic antibacterials (ATC J1) in primary health care, fee-for-service and rostering of patients by GPs, EU, 1997 ibacterials ATC J1 nh-days) Consumption of ant for systemic use A (DDD per 1, in NS ntibacterials e ATC J1 inh-days) Consumption of an for systemic use (DDD per 1, P <.1 Sources: Monnet DL; Cars O, et al., Lancet 21; 37: 181-3, and Highlights on Health, WHO/EURO 31 Factors of importance for low antibiotic use: Antibiotic treatment guidelines Classification of all medical specialties registered in Denmark National guidelines made by specialists appointed for a period of years Published by the Danish Medical Association in collaboration with the association of pharmaceutical companies Executive committee of renowned professors and medical doctors who guarantee professional integrity Delivered free of charge to all Danish MDs and also accessible on-line 32 Institute for Rational Pharmacotherapy (IRF) IRF is a part of the Danish Medicines Agency Publishes so called National Recommandation Lists for all groups of diseases incl. infectious diseases The Recommendation List for antimicrobial treatment is in full agreement with the National Antibiotic Guideline in as well as the Danish issue of Happy Audit guideline That means that in Denmark we now have only one national guideline for antimicrobial treatment of infectious diseases in primary health care But: medical doctors can prescribe the antibiotics they want! 33 11

Factors of importance for low antibiotic use (6) Monitoring of antimicrobial use On a

Institut and the Danish Medicines Agency in 28 launched the Barometer of Antimicrobials The

month The total consumption as well as each class of antibiotics expressed by DDD/1, inh.

asp 3 DANMAP Danish Integrated Antimicrobial Monitoring and Research Programme Collaborative

12 Factors of importance for low antibiotic use (6) Monitoring of antimicrobial use On a national scale For each GP individually 34 National antibiotic barometer Statens Serum Institut and the Danish Medicines Agency in 28 launched the Barometer of Antimicrobials The barometer shows the development of antibiotic consumption in primary health care month by month The total consumption as well as each class of antibiotics expressed by DDD/1, inh./day is shown 3 DANMAP Danish Integrated Antimicrobial Monitoring and Research Programme Collaborative project: Danish Veterinary Institut Danish Food & Veterinary Adm. Danish Medicines Agency Statens Serum Institut Since 1996 Yearly report since

J1CE Beta-lactamase sensitive penicillins J1F Macrolides, lincosamides and streptogramins

J1D Cephalosporins and related substances J1CA Penicillins with extended spectrum J1AA

of penicillins, incl. beta-lactamase inhib.

of antibacterials in the primary health care sector, Denmark 37 Resistance (%) to

from humans, Denmark 38 Ordiprax on-line database allowing Danish GPs to compare their

total use of antibiotics (DDD/1 patients per practice) from 2-8; black line shows the

$all other general practitioners in that county in different fractiles (min to max) DDD/1$

13 J1CE Beta-lactamase sensitive penicillins J1F Macrolides, lincosamides and streptogramins J1CF Beta-lactamase resistant penicillins J1XE Nitrofuran derivatives J1XX Methenamine J1D Cephalosporins and related substances J1CA Penicillins with extended spectrum J1AA Tetracyclines J1E Sulfonamides and trimethoprim J1MA Fluoroquinolones J1CR Comb. of penicillins, incl. beta-lactamase inhib. J1G&X Aminogyclosides and other antibacterials Distribution of the total number of DDDs of antibacterials in the primary health care sector, Denmark 37 Resistance (%) to penicillin and macrolides in Streptococcus pneumoniae blood and spinal fluid isolates from humans, Denmark 38 Ordiprax on-line database allowing Danish GPs to compare their own prescription of antibiotics with colleagues in the same region The figure shows the total use of antibiotics (DDD/1 patients per practice) from 2-8; black line shows the antibiotic use for a single practice, the colour shades represent the antibiotic use of all other general practitioners in that county in different fractiles (min to max) DDD/1 Patients for each general practitioner Fractiles (of antibiotic use, DDD/patients), general practitioners in the county Quarter Danish Medicines Agency 39 13

14 Factors of importance for low antibiotic use: microbiology services Well developed clinical microbiology (CM) laboratories in all counties, i.e. short distance from patient/gp to lab Clinical microbiology as a medical specialty ie i.e. the Clinical Microbiologist corresponds with physicians at same level, i.e. his/her views are respected among all clinicians Rapid microbiology at bedside level; many general practitioners can perform diagnostic microbiology, e.g. group A strep antigen test and urine microscopy or urine culture 4 Factors of importance for low antibiotic use: Can GPs help to minimize the selection of antibiotic resistance? Through good clinical microbiology More diagnostics, especially point-of-care-tests used on the correct indications 41 Acute tonsillitis Choice of antibiotic compared to use of Strep-A antigen test % of cases Strep-A not used Strep-A positive Strep-A negative No antibiotic V-penicillin Broadspectrum Macrolides Other antibiotics Source: B. Gahrn-Hansen, Personal communication 42 14

Acute tonsillitis 12 1 Lithuania 96.8 8 6 4 2 79.3 No strep-a 2.7 3.2 Strep-A positive 36.4 Strep-A negative 63.

antibiotic prescribing if appropriate By educating the patients 44 Factors of importance for low antibiotic use (8) Registration of antibiotic use Participation in national and international audits

15 Acute tonsillitis 12 1 Lithuania No strep-a Strep-A positive 36.4 Strep-A negative AB No AB Source: 43 Factors of importance for low antibiotic use (7) GPs must pursue a rational antibiotic policy Stick to guidelines for treatment as well as non-treatment Make use of delayed antibiotic prescribing if appropriate By educating the patients 44 Factors of importance for low antibiotic use (8) Registration of antibiotic use Participation in national and international audits like Creating official on-line tools like the Danish Ordi-prax, that allow GPs to benchmark their prescriptions with colleagues DDD/1 Patients for each general practitioner The figure shows the antibiotic use in general practice (DDD/patients in that practice) in a Danish county during a year; the black line represents one practice and the various colours the different fractiles of use in all other practices in that county Danish Medicines Agency Quarter Fractiles (of antibiotic use, DDD/patients), general practitioners in the county 4 1

16 Are some antibiotics better (~causing less resistance) than others? Bad: Tetracyclines Cefalosporines Fluoroquinolones Amox/clavul. Makrolides Carbapenems Good (better): Mecillinam Fosfomycin Nitrofurantoin Piperacillin/ Tazobactam 46 Factors of importance for low antibiotic use (9) Patient knowledge How to acquire antibiotics How to use antibiotics Press Educate the public including the politicians about antibiotic resistance and correlation with antibiotic use 47 Attitudes, beliefs and knowledge concerning antibiotic use and self-medication: a comparative European study Grigoryan L, et al., Pharmacoepid Drug Safety 27; 16: Key points Large differences in the above parameters in 11 European countries The levels of misconceptions contributing to inappropriate use were the highest in Southern and Eastern countries Awareness about resistance was the lowest in countries reporting high prevalence of antibiotic resistance 48 16

Prevalence of possession of leftovers (%) in respondents who obtained antibiotics by filling a new prescription or being given antibiotic by a medical professional (N= 3649).

17 81.% 84.1% 9.% 67.% 48.9%.% 1.8% 1.% 13.% 24.1% 27.3% 3.2% Netherlands USA Philippines South (N=378) (N=444) (N=29) Africa (N=338) Japan (N=266) Turkey (N=326) Russia (N=28) Italy (N=418) Mexico (N=348) Brazil (N=333) Fig. 1. Prevalence of possession of leftovers (%) in respondents who obtained antibiotics by filling a new prescription or being given antibiotic by a medical professional (N= 3649). Grey bars, pack countries (countries where antibiotics are dispensed in fixed packs rather than exact numbers of doses); white bars, non-pack countries P. Kardas et al., International Journal of Antimicrobial Agents 3 (27) 3 36 China (N=39) Total (N=3649) 49 Conclusion A national strategy for rational antibiotic use based on up-dated guidelines is mandatory Over-the-counter sale of antibiotics must be stopped Reduction of public re-imbursement of costs can to some degree regulate the use Monitoring antimicrobial use both nationally and individually on a monthly basis is a useful tool Interventions to control the emergence and spread of multi-resistant bacteria must be established Increased use of valid point-of-care tests should be advocated Audit programmes for general practitioners Education of the public about indication for antibiotic use, risk of self-medication, relation between antibiotic use and resistance Thank you for your attention! 1 17

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Initiatives taken to reduce antimicrobial resistance in DK and in the EU in the health care sector

Initiatives taken to reduce antimicrobial resistance in DK and in the EU in the health care sector Niels Frimodt-Møller Professor, MD DMSc Dept. of Clinical Microbiology Hvidovre Hospital, Copenhagen,