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Antibiotic stewardshipMeasuring and improving antibiotic use in hospitalsKallen, M.C.

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Citation for published version (APA):Kallen, M. C. (2019). Antibiotic stewardship: Measuring and improving antibiotic use in hospitals.

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Download date: 30 Oct 2020

1General introduction and

outline of the thesis

13

General introduction

1ANTIBIOTIC RESISTANCE

In 1928 the Scottish medical microbiologist and pharmacologist Alexander Fleming discovered the fi rst antibiotic, to be used in the treatment and prevention of bacterial infection. 1 The use of antibiotics resulted in improved patient outcomes, and enabled procedures like chemotherapy and organ transplantation. 2,3 At present, antibiotics are indispensable in health care systems. 4

The eff ectiveness and easy availability of antibiotics in the past decades has, however, led to extensive use, which has caused selection of resistant bacteria. 5,6 Antibiotic resis-tance is the ability of a bacteria to adapt to their environment in order to survive. 7 The resistance mechanism when exposed to an antibiotic depends on the type of bacterium and antibiotic. 8-10 Bacteria resistant to all currently available antibiotics are also referred to as “superbugs”.

Along with the global increase of antibiotic resistance, there is a steady decline in the discovery of new antibiotic classes. 3,11,12 The main reason for a decline in the discovery of new antibiotics is a lack of fi nancial support for antibiotic research, as other drugs are economically more attractive to develop. 3,13 The World Health Organisation (WHO) signaled that the emerging antibiotic resistance, along with a decline in the discovery of new antibiotics, causes a major health threat. If no actions are taken, infection will be the leading cause of death in the near future. 14

The total consumption of antibiotics is the main driving force for the emergence of resistance. Globally, 25% – 50% of hospitalized patients receive antibiotics. An estimate of 20% - 50% of these antibiotics are either unnecessary (e.g. overtreatment of viral infections) or inappropriate (i.e. not in line with current guidelines). 15-17 Thus, to help control antibiotic resistance, better use of currently available antibiotics is pivotal. 18

ANTIBIOTIC STEWARDSHIP PROGRAMS

Antibiotic stewardship has been introduced to promote appropriate use of antibiotics. 19 In the past decade, Antibiotic stewardship programs (ASP) have been established in hospitals worldwide. ASPs are coordinated interventions designed to monitor and improve appropriate antibiotic use and clinical outcome, while minimizing unintended consequences of antibiotic use, including the emergence of resistance. 20 Several guidelines for the development and implementation of stewardship programs have been developed. 15,21,22 These guidelines provide recommendations on three “building

Chapter 1

14

blocks” for successful stewardship. 23 The fi rst building block includes recommendations on appropriate structural or system preconditions for embarking on stewardship. These preconditions include for example the presence of a locally established multidisciplinary antibiotic stewardship team (“A-team”) and salary support for these team members pro-vided by the Hospital Board of Directors. The second building block (‘the what’) includes recommendations on appropriate use, which constitute the objectives of stewardship teams. Such objectives include for example guideline adherence and timely switching antibiotic therapy from intravenous (IV) to oral. 22,24 The third building block (‘the How’) includes recommendations to guide the A-teams’ choice of potential improvement strategies to ensure adherence to the appropriate use objectives. These improvement strategies include for example audit and feedback or education. (Figure 1)

ANTIBIOTIC STEWARDSHIP IN THE NETHERLANDS

Despite relatively low antibiotic use, the problem of rising antibiotic resistance is also present in the Netherlands, in particular among gram-negative bacteria. 25 Our recent studies have shown considerable room for improvement in the treatment of bacterial infections in hospitals, in particular for respiratory and urinary tract infections. 26-28

Figure 1. Three building blocks for a successful Antibiotic Stewardship Program

ASP

Improvement

Strategies

ASP objectives: appropriate

antibiotic use at the patiënt level

Structural or system prerequisits for an ASP

e.g. availability of a stewardship team, financial

support for the team, availability of a local antibiotic

formulary or antibiotic guidelines

Stewardship strategies• Audit and feedback• Education• Educational outreach, e.g.• Academic detailing • Post prescription review• Prospective monitoring and advice• Reminders • IT Introduction and development• New diagnostic tests• Pre or post-authorisation • Formulary restriction• Antibiotic order forms• Computerised alerts • Stop orders

Stewardship objectives

• Guideline adherence• Timely IV-to oral switch• Streamlining or de-escalation• Discontinuation of AB therapy• Dose optimization (TDM)• Appropriate use of surgical prophylaxis• Correct use of diagnostics (e.g. performance ofblood and site cultures)• Appropriate use of restricted AB• Bedside consultation

15

General introduction

1In their 2012 vision document, drafted at the request of Dutch Health Care Inspector-ate (IGZ), the Dutch Working Party on Antibiotic Policy (SWAB) has stressed the need to establish ASPs in every Dutch hospital. 25 Improving appropriate antibiotic use is the cornerstone of this plan, and an important role has been assigned to local A-teams, responsible for the implementation of local ASPs. 29 These teams are recommended to consist of at least one clinical microbiologist, one hospital pharmacist and one infectious diseases (ID) specialist. 30,31 Financial support for these stewardship teams is required and a standard has been set on 1.25 – 3.18 FTE per year depending on hospital size, assuming that three stewardship objectives are monitored. 32

To date, stewardship activity varies substantially between hospitals. In the Netherlands, trends in the consumption of antibiotic agents and antibiotic resistance patterns are an-nually reported in a publication called NethMap. The Dutch Working Party on Antibiotic Policy (SWAB) is developing a third registry that will report on the quality of hospital antibiotic use and the progress of ASPs in the Netherlands. Data on the quality of anti-biotic use and the level of ASP activity will ultimately be related to the national data on antibiotic consumption and resistance.

MEASURING THE APPROPRIATENESS OF ANTIBIOTIC USE

Essential in every ASP is the availability of data that allow the local stewardship teams to gain insight into current quality of antibiotic use and the aspects that are most in need of improvement in their hospital. Many studies have shown that the volume and appropriateness of antibiotic use in hospitals vary between hospitals and wards. 17,26,33,34 Not every hospital and not every ward needs the same level of improvement, therefore an institutional stewardship program should be tailored for that particular hospital and for each ward, depending on its particular pattern of pathogens and the appropriate-ness of use of (particular classes of ) antibiotics.

Various methods can be used to systematically evaluate the quality of antibiotic use in hospitals, the most important being point-prevalence studies (PPS) on the appropriate-ness of antibiotic use in individual patients and the continuous or regular monitoring of quantitative antibiotic use at an institutional level. 28,35,36

A PPS is a cross-sectional measurement of the quality of antibiotic use within the hospital at one time point. An acknowledged method is to perform a point prevalence survey (PPS) using quality indicators (QIs). 28 Quality indicators (QIs) are measurable ele-ments of practice performance for which there is evidence or consensus that they can

Chapter 1

16

be used to assess the quality of antibiotic care provided. 37 A QI consist of a numerator and a denominator and the QI score is the quotient of the numerator and denominator. (Table 1) A well-known classifi cation to categorize QIs is: structure, process and outcome indicators. 38 Structure QIs measure the organisational factors that defi ne the health system under which care is provided (e.g. availability of staff or diagnostic tools). Process QIs measure the actual delivery and receipt of care at the patient level. Outcome QIs measure the eff ects or consequences of antibiotic care on the health status of patients and population (e.g. morbidity, complications of health status or patient satisfaction). 39

In the past years many QIs for appropriate antibiotic use have been developed in order to give insight in the quality of antibiotic treatment. It is unclear which QIs for appropri-ate antibiotic use in hospitalized adult patients are currently available and how they have been developed. Such information is important in order to support healthcare professionals to select QIs that are considered reliable in their healthcare setting.

A second acknowledged method to perform a PPS is using a non-validated, simpler set of indicators developed by the European Center for Disease Control and Prevention (ECDC). 36 These indicators include for example the type of antibiotic prescribed, route of administration, prescription indication (prophylaxis or therapy) and type of infection.

Measuring quantitative antibiotic use is a third method to measure antibiotic use. Several units of measurement are available to standardize total antibiotic use. 40 Recom-mended metrics are Defi ned Daily Dose (DDD) and Days of Therapy (DOT). 41-44 DDD is defi ned by the World Health Organisation (WHO) as the assumed average maintenance dose per day for a drug used for its main indication in adults. 45,46 One DOT represents the administration of a single agent on a given day regardless of the number of doses administered or dosage strength. 41 Using DDDs and DOT allows hospitals to compare their antibiotic use with that of other similar hospitals, recognizing the challenges of inter-hospital comparisons and the potential need for “risk adjustment.” 41,42

Table 1. Example of a quality indicator

Numerator Number of patients suspected of a complicated urinary tract infection requiring antibiotic therapy in whom urine cultures were performed before start of antibiotic therapy

56

Denominator Total number of patients suspected of a complicated urinary tract infection requiring antibiotic therapy

100

QI score 56%

17

General introduction

1These three methods, however, have never been compared and the (cost) eff ectiveness of measuring and feeding back performance data on the quality of antibiotic use is unknown. 47

IMPROVING THE QUALITY OF ANTIBIOTIC USE

In their Cochrane review on antibiotic prescribing practices for hospital inpatients, Davey and colleagues estimated the eff ectiveness of improvement strategies on reducing the incidence of antibiotic-resistant pathogens and their impact on clinical outcome. 16 The selected studies had a high degree of clinical heterogeneity and eff ect sizes, varying between no eff ect and an improvement of about 40%. The studies also diff ered regard-ing outcome parameter (including both overall use of antibiotics and appropriate use), setting, what information was provided and how it was provided. So, to date, the com-parative eff ectiveness of the various improvement strategies is unknown.

More importantly, the most optimal improvement strategy can vary substantially between diff erent hospitals and wards, since performance might be hindered by a variety of barriers, and barriers in one setting may not be present in another. 48 A barrier is a factor that might hinder (the improvement of ) clinical performance. Improvement strategies should primarily be guided by the local barriers for clinical practice. Flottorp et al. developed an improvement tool that includes a checklist with possible barriers for clinical practice. 49 This tool aims to guide in the systematic development of both tailored improvement strategies, based on local barriers, and a structured action plan, providing clear focus to improve the quality of daily care (Figure 2).

OUTLINE OF THE THESIS

This thesis contributes to answering the question: how to measure, feedback and im-prove the appropriateness of inhospital antibiotic use. In addition, it describes the (cost) eff ectiveness of antibiotic stewardship interventions in hospitals.

To date, stewardship activity varies substantially between hospitals. It remains unclear which structural prerequisites are implemented in hospitals, which stewardship objec-tives on appropriate antibiotic use are pursued and which strategies are used to improve adherence to these objectives. In Chapter 2, we systematically developed a survey to evaluate local stewardship prerequisites, objectives and improvement strategies. Fur-thermore, we evaluated the current state of antibiotic stewardship in 80 Dutch hospitals.

Chapter 1

18

This survey will ultimately be incorporated in the Dutch national registry and reported in NethMap. Subsequently, in Chapter 3 we evaluated antibiotic stewardship programs in acute care hospitals in four European countries. In cooperation with ESGAP (ESCMID Study Group for Antimicrobial stewardshiP) the stewardship survey was sent to all Dutch (n=80) and Slovenian (n=29), and to 215 French (25%, random stratifi ed sampling) and 61 Italian (6%, convenience sampling) acute care hospitals, for a European-wide assess-ment.

A requirement for an eff ective stewardship program is the ability to measure the ap-propriateness of antibiotic use in individual patients. In the past years many QIs for appropriate antibiotic use have been developed in order to give insight in the quality of antibiotic treatment. In Chapter 4 we performed a systematic review to assess the currently available QIs for appropriate antibiotic use in hospitalized adult patients. Moreover, we assessed the development methodology and validation procedures of these QIs, in order to support healthcare professionals to select QIs that are considered reliable in their healthcare setting.

One of the cornerstones of ASPs is monitoring quantitative antibiotic use. However, the best approach to retrieve reliable quantitative data for stewardship purposes is not yet clear. Frequently used metrics are defi ned daily dose (DDD) and Days of Therapy (DOT). In Chapter 5 we compared both metrics when used for benchmarking antibiotic use on a specialty level. In addition, we provided recommendations on how to reliably measure quantitative antibiotic use in order to support an ASP.

In Chapter 6 we performed a cluster-randomized multicenter trial (“the IMPACT study”) in which we assessed the diff erence in eff ect on length of hospital stay (LOS) and days of antibiotic therapy (DOT) between three recommended methods to measure and feedback information on hospital antibiotic use, when used as the fi rst step of a stew-ardship intervention. Twenty-one Dutch hospitals participated in the study, including three university hospitals, sixteen teaching hospitals, and two non-teaching hospitals. (Figure 2) We divided each hospital into two clusters: surgical wards (i.e. surgery, urol-ogy and orthopaedics) and non-surgical wards (i.e. internal medicine, gastroenterology and pulmonology). Both clusters were randomly allocated to one of three methods (i.e.

Figure 2. Improvement tool for clinical practice, Flottorp et al.

Identify and prioritize

improvement foci

Identify and assess local

barriers

Prioritizelocal barriers

Develop an improvement

strategy

Set an action plan

19

General introduction

1quantitative antibiotic use, a PPS with validated QIs, and a PPS with non-validated QIs), stratifi ed by hospital (i.e. in each hospital, each method was allocated to no more than one cluster). First, hospital stewardship teams performed measure-ments for each cluster and received a feedback report for both clusters in their hospital. Second, stewardship teams were trained in applying an implementation tool that supported a structured approach to stewardship, i.e. the systematical de-velopment and performance of setting-specifi c stewardship improvement strategies based on the feedback reports. Third, stewardship teams performed the local improvement strategies.

Impact of the stewardship interventions was assessed and specifi ed per method using length of hospital stay (LOS) as primary outcome measure. Main secondary outcome measures were total and restricted antibiotic use (DOT). Data on outcomes were col-lected for 100 patients per cluster before (February-May 2015) and for 100 patients per cluster after the intervention period (February-May 2017). A total of 8,440 patients receiving antibiotic treatment were included. We performed ‘intention-to-treat’ (ITT) analyses according to randomization of the methods, and ‘as-treated’ (AT) analyses according to the feedback methods that were actually used to develop improvement strategies, using mixed linear models.

As economic evaluations are important to effi ciently select stewardship interventions for daily practice, in Chapter 7 a cost-benefi t analysis was performed alongside the clustered-randomized trial. We reported the costs associated with the study interven-tion, specifi ed for each of the three recommended methods to measure and feedback information on hospital antibiotic use, in relation to economic benefi ts of the interven-tion, in terms of reductions in LOS and DOT.

Extensive antibiotic use makes the ICU an important focus for antibiotic stewardship programs. In 1996, the National Intensive Care Evaluation (NICE) foundation was es-tablished, facilitating a registry which enables participating intensive care units to give insight in and improve the quality of care they off er, by providing feedback and bench-marking on patient outcomes and health care processes. In Chapter 8 we developed a set of actionable QIs and an implementation toolbox for appropriate antibiotic use in the treatment of adult patients at an ICU. The QIs and toolbox will be incorporated in an

Figure 3. Participating hospitals IMPACT study

Chapter 1

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online quality dashboard as part of the NICE registry. In Chapter 9 we tested the compli-ance with these QIs, and with a set of QIs for selective digestive tract decontamination (SDD), in the ICU of one general teaching hospital in the Netherlands.

Chapter 10 includes the general discussion, in which we summarize and discuss the main results of this thesis, followed by a fi nal conclusion and implications for further research.

21

General introduction

1REFERENCES

1. Tan SY, Tatsumura Y. Alexander Fleming (1881-1955): Discoverer of penicillin. Singapore Med J. 2015;56:366-7.

2. Bud R. Antibiotics: the epitome of a wonder drug. Bmj. 2007;334 Suppl 1:s6. 3. Hughes JM. Preserving the lifesaving power of antimicrobial agents. Jama. 2011;305:1027-8. 4. Heddini AN, R. The path of least resistance. Public service review: European science & technology

2014, issue 9. http://www.reactgroup.org/uploads/publications/react-publications/the-path-of-least-resistance.pdf.

5. Goossens H, Ferech M, Vander Stichele R, Elseviers M. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet. 2005;365:579-87.

6. Tacconelli E. Antimicrobial use: risk driver of multidrug resistant microorganisms in healthcare settings. Curr Opin Infect Dis. 2009;22:352-8.

7. Laxminarayan R, Duse A, Wattal C, et al. Antibiotic resistance-the need for global solutions. Lancet Infect Dis. 2013;13:1057-98.

8. Alanis AJ. Resistance to antibiotics: are we in the post-antibiotic era? Arch Med Res. 2005;36:697-705.

9. Munita JM, Bayer AS, Arias CA. Evolving resistance among Gram-positive pathogens. Clin Infect Dis. 2015;61 Suppl 2:S48-57.

10. Holmes AH, Moore LS, Sundsfj ord A, et al. Understanding the mechanisms and drivers of antimi-crobial resistance. Lancet. 2016;387:176-87.

11. European Centre for Disease Prevention and Control. Last-line antibiotics are failing. http://ecdc.europa.eu/en/press/news/_layouts/forms/News_DispForm.aspx?ID=1510&List=8db7286c-fe2d-476c-9133-18ff 4cb1b568.

12. Arias CA, Murray BE. A new antibiotic and the evolution of resistance. N Engl J Med. 2015;372:1168-70.

13. Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JE, Jr. Trends in antimicrobial drug develop-ment: implications for the future. Clin Infect Dis. 2004;38:1279-86.

14. World Health Organization. Report 2012: The envolving threat of antimicrobial resistance - Op-tions for action. World Health Organization 2012Available from: URL: https://whqlibdoc.who.int/publicatiions/2012/9789241503181_eng.pdf.

15. Dellit TH, Owens RC, McGowan JE, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:159-77.

16. Davey P, Brown E, Charani E, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2013:Cd003543.

17. Hulscher ME, Grol RP, van der Meer JW. Antibiotic prescribing in hospitals: a social and behav-ioural scientifi c approach. Lancet Infect Dis. 2010;10:167-75.

18. WHO. Antimicrobial resistance: global report on surveillance 2014. [http://www.who.int/drugresis-tance/documents/surveillancereport/en/].

19. Dyar OJ, Huttner B, Schouten J, Pulcini C, Esgap. What is antimicrobial stewardship? Clin Microbiol Infect. 2017;23:793-8.

20. MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev. 2005;18:638-56.

Chapter 1

22

21. Pollack LA, van Santen KL, Weiner LM, et al. Antibiotic Stewardship Programs in U.S. Acute Care Hospitals: Findings From the 2014 National Healthcare Safety Network Annual Hospital Survey. Clin Infect Dis. 2016;63:443-9.

22. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an Antibiotic Stewardship Program: Guide-lines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62:e51-77.

23. Hulscher M, Prins JM. Antibiotic stewardship: does it work in hospital practice? A review of the evidence base. Clin Microbiol Infect. 2017;23:799-805.

24. Schuts EC, Hulscher ME, Mouton JW, et al. Current evidence on hospital antimicrobial steward-ship objectives: a systematic review and meta-analysis. Lancet Infect Dis. 2016;16:847-56.

25. SWAB. NethMap 2013. Consumption of antimicrobial agents and antimicrobial resistance among medically important bacteria in the Netherlands. https://www.swab.nl/swab/cms3.nsf/uploads/5FD2BE2700E8B433C1257A680028D9F0/$FILE/visiedoc%20SWAB%20vs%2021%20junifi nal.pdf.

26. Schouten JA, Hulscher ME, Wollersheim H, et al. Quality of antibiotic use for lower respiratory tract infections at hospitals: (how) can we measure it? Clin Infect Dis. 2005;41:450-60.

27. Hermanides HS, Hulscher ME, Schouten JA, Prins JM, Geerlings SE. Development of quality indica-tors for the antibiotic treatment of complicated urinary tract infections: a fi rst step to measure and improve care. Clin Infect Dis. 2008;46:703-11.

28. van den Bosch CM, Geerlings SE, Natsch S, Prins JM, Hulscher MEJL. Quality indicators to measure appropriate antibiotic use in hospitalized adults. Clin Infect Dis. 2015;60:281-91.

29. NethMap 2017. Consumption of antimicrobial agents and antimicrobial resistance among medically important bacteria in the Netherlands: http://www.rivm.nl/bibliotheek/rap-porten/2017-0056.pdf.

30. Dyar OJ, Tebano G, Pulcini C, Esgap. Managing responsible antimicrobial use: perspectives across the healthcare system. Clin Microbiol Infect. 2017;23:441-7.

31. Schouten JA, Hulscher ME, Natsch S, Grol RP, van der Meer JW. Antibiotic control measures in Dutch secondary care hospitals. Neth J Med. 2005;63:24-30.

32. Dutch Working Party on Antibiotic Policy. Practice guide Antimicrobial Stewardship in the Nether-lands. http://www.ateams.nl/documenten.

33. Spoorenberg V, Geerlings SE, Geskus RB, et al. Appropriate antibiotic use for patients with compli-cated urinary tract infections in 38 dutch hospital departments: a retrospective study of variation and determinants. BMC Infect Dis. 2015;15:505.

34. van den Bosch CM, Hulscher ME, Natsch S, et al. Applicability of generic quality indicators for ap-propriate antibiotic use in daily hospital practice: a cross-sectional point-prevalence multicenter study. Clin Microbiol Infect. 2016;22:888.e1-.e9.

35. Kallen MCN, S. Opmeer, B.C. Hulscher, M.E.J.L. Prins, J.M. Van Der Linden, P. How to measure quantitative antibiotic use in order to support antimicrobial stewardship in acute care hospitals (abstract). fi le:///H:/Downloads/P0133_abstract%20(1).pdf. 2018.

36. Control. ECfDPa. Point prevalence survey of healthcare-associated infections and antimicrobial use in European acute care hospitals - protocol version 4.3. Stockholm: ECDC.; 2012. Available at: http://www.ecdc.europa.eu/en/publications/Publications/0512-TED-PPS-HAI-antimicrobial-use-protocol.pdf.

37. Campbell SM, Braspenning J, Hutchinson A, et al. Research methods used in developing and applying quality indicators in primary care. Bmj. 2003;326:816-9.

38. Donabedian A. The quality of care. How can it be assessed? Jama. 1988;260:1743-8. 39. Campbell SM, Roland MO, Buetow SA. Defi ning quality of care. Soc Sci Med. 2000;51:1611-25.

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General introduction

1 40. Stanic Benic M, Milanic R, Monnier AA, et al. Metrics for quantifying antibiotic use in the hospital

setting: results from a systematic review and international multidisciplinary consensus proce-dure. J Antimicrob Chemother. 2018;73:vi50-vi8.

41. Polk RE, Fox C, Mahoney A, Letcavage J, MacDougall C. Measurement of adult antibacterial drug use in 130 US hospitals: comparison of defi ned daily dose and days of therapy. Clin Infect Dis. 2007;44:664-70.

42. Kuster SP, Ruef C, Ledergerber B, et al. Quantitative antibiotic use in hospitals: comparison of measurements, literature review, and recommendations for a standard of reporting. Infection. 2008;36:549-59.

43. de With K, Bestehorn H, Steib-Bauert M, Kern WV. Comparison of defi ned versus recom-mended versus prescribed daily doses for measuring hospital antibiotic consumption. Infection. 2009;37:349-52.

44. de With K, Maier L, Steib-Bauert M, Kern P, Kern WV. Trends in antibiotic use at a university hos-pital: defi ned or prescribed daily doses? Patient days or admissions as denominator? Infection. 2006;34:91-4.

45. WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classifi cation and DDD assignment 2013. Oslo, 2012.

46. Natsch S, Hekster YA, de Jong R, et al. Application of the ATC/DDD methodology to monitor antibiotic drug use. Eur J Clin Microbiol Infect Dis. 1998;17:20-4.

47. Davey P, Marwick CA, Scott CL, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2017;2:CD003543.

48. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. Jama. 1999;282:1458-65.

49. Flottorp SA, Oxman AD, Krause J, et al. A checklist for identifying determinants of practice: a systematic review and synthesis of frameworks and taxonomies of factors that prevent or enable improvements in healthcare professional practice. Implement Sci. 2013;8:35.