Trial lecture for the PhD dissertationSeptember 25th, 2014

Jon Birger HaugUniversity of Oslo

Lett omarbeidet for nettundervisning NFIM, 18.12.2014

Effects of interventions on

antibiotic use in hospitals

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Antibiotic stewardship

Intervention studies – design and methods

The effects of interventions: current knowledge

Are intervention effects sustainable?

Factors modifying the effects of interventions

Novel concepts in interventions

A global view

Conclusion

Disposition of the lecture

Scope of the lecture

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• Only interventions in acute care hospitals are discussed. To be excluded are:

Rehabilitation centres Long term care facilities

• Outcome effect ("antibiotic use") may also include: Microbial outcomes / antibiotic resistance incidence Degree of adherence, e.g. to antibiotic guidelines Patient outcomes, and the effects on costs

Scope of the lecture

• The effect of vaccinations to reduce antibiotic use is less relevant in a hospital setting and will not be discussed

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"Stewardship ….. an ethic that embodies the responsible planning and management of resources"

Antibiotic Stewardship

IDSA & SHEA Recommendations, 2007

Dellit et al, CID 2007;445

Core interventions • Prospective audit with intervention and feedback• Formulary restriction and preauthorization

Supplementary activities / interventions

• Education• Guidelines and clinical pathways• Antimicrobial cycling• Antibiotic order forms• Combination therapy

• Streamlining of therapy• Dose optimization• Parenteral to oral

conversion

Antibiotic Stewardship program (ASP): interventions

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Essential ASP elements (not to be confused with intervention measures)

• An established antibiotic stewardship team, optimally including specialist(s) of infectious diseases, microbiology, and clinical pharmacy

• Timely and relevant service from the microbiology laboratory and the hospital pharmacy

• Computer-based technology (health-care information databases and surveillance systems)

• Regular reporting of the hospital's antibiotic use

• Regular reporting of antibiotic resistance patterns

• Reporting of "alert microorganisms" (multi-drug resistant)7

Local pre-intervention requirements

• Ensure the support from hospital administrators

• Secure the approval from key members of the medical staff

• Coordinate activities with infection control personnel

• Coordinate also with other hospital units for patient safety

To organize for optimal interventions….

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Identify local areas of major deficits

Prioritize targets

The Pareto Principle, or "Law of the Vital Few"

80 % of outcomes results from only 20% of the potential causes

• Identification of these causes is important!

• Identification may be achieved by discussions, patient chart reviews, and surveillance reports

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• Multicentre intervention studies are needed to support an optimal applicability of results

• More studies should incorporate end-points related to patient survival and cost/benefits of interventions

• Interventions should be planned Unplanned interventions (e.g, acute responses to an outbreak) may be seriously biased because of "regression to the mean" – which denotes the tendency for extreme conditions to return to the normal

Intervention studies: design and methods

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• Less used in interventions studies of antibiotic use

• RCTs are resource demanding (manpower, money)

• Randomization is often difficult, and subject to biases (especially one-centre studies)

• " Cluster randomization" is the preferred method: - hospitals are randomized, not wards within one hospital - possible to control for the "contamination" bias

Randomized controlled trials (RCTs)

• The concept is well-known and the "gold standard" in research

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Example: study of antibiotic treatment duration with a simple RCT design

• Clearly defined clinical condition: → «Pulmonary infiltrates in the ICU»

• Highly relevant for the appropriate use of antibiotics: → «Is a shorter antibiotic treatment course sufficient?»

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Inclusion based on a pretreatment clinical score (0 – 10)

Compare short-course of antibiotics with standard treatment duration

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Interrupted time-series analysis (ITS)

• Step 1: construct a time series of rates for your particular improvement focus (antibiotic use)

• Step 2: test statistically for a change in the outcome rates in the time periods before and after the implementation

The analyses should involve several data points before and after intervention (ideally, 24 monthly rates)

An ITS is particularly useful when a randomized trial is not feasible or unethical

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ITS: design and interpretation

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Example: ITS analysis with antibiotic use outcome

Intervention

• New policy for the appropriate use of "Alert Antibiotics"

• Concurrent, patient-specific feedback by clinical pharmacist

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Ansari et al, JAC 200317

Other analytic methods used in intervention studies

Controlled clinical trialsStudy of one or more intervention groups

compared to one or more control groups (without randomization)

Controlled before / after studies (CBAs)Prospective evaluation of outcomes in one population, before and after intervention(s)

Observational studies are usually not included in reviews of intervention effects!

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The effects of interventions:current knowledge

• A majority of studies have methodological flaws!

• Effect evaluation is often made difficult by considerable heterogeneity of studies

• Low external validity (applicability) of results from carefully monitored studies (e.g. RCTs) is a general aspect to be considered in "real life" situations…

General remarks on current scientific evidence

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Cochrane Collaboration (Davey et al)

"Interventions to improve antibiotic prescribing practices for hospital inpatients"

Selected for review were:1. Randomized clinical trials 2. Interrupted time series studies3. Controlled clinical trials4. Controlled before-and after studies

Issue published 2005: studies from 1980 up to November 2003

Issue publisher 2013: studies from 1980 up to December 2006

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Cochrane 2013: Studies overview

Type of studies:

• 89 studies, 95 interventions reported

• 56 studies (63%) used interrupted time-series analysis • 25 studies (28%) were randomized

controlled trials, of which 5 were cluster RCTs

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Main comparisons Effect size difference at 1 month post-intervention

Quality of evidence

Appropriate prescribing of antibiotics (40 ITS studies) 32% (95% CI 2–61%) Low

Microbial outcomes (14 ITS studies) 53% (95% CI 31–75%) Low

Patient outcomes (11 cRCT, RCT and CCT studies )

Mortality risk 0.92% (N.S.)Diff. length of stay (N.S.)Frequent readmissions

ModerateVery lowVery low

Patient outcomes (improve prescribing for pneumonia – 3 CBA, 1 RCT)

Mortality risk 0.89% (CI 0.82 - 0.97) Low

Summary of the main findings

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Persuasive interventions: use of e.g. education, feedback and reminders to change prescribers behaviour

Restrictive interventions: restriction of the freedom of prescribers to select some antibiotics

A majority of the 89 Cochrane studies were "multi-

faceted" – that is, more than one type intervention

was used, often with a mix of persuasive and

restrictive components.

Main categories of interventions

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Persuasive intervention that are effective

Type of intervention Methods used

Educational material, guidelines

- Teach or otherwise disseminate knowledge of best practices - Implement updated guidelines

Educational outreach("Academic detailing")

"Interactive education" by an expert, orone-to-one discussion with the prescriber

Audit with feedback Prospective audit with feedback to prescribing physician in case of inappropriate use

Reminders Manual or electronic advice at point-of-care; e.g. to check indication, microbiology results, parenteral to oral switch

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Restrictive interventions that are effective

Type of intervention Methods used

Expert approvalPrescribing of certain antibiotic agents needs to be approved by an infectious disease specialist

Compulsory order forms

When prescribing an antibiotic agent, a form has to be filled out stating e.g. the indication for use

Removal of drug choice Certain antimicrobials are removed from the hospital's formulary

Review prescriptions and make change

Prescriptions are reviewed by an expert and inappropriate use is corrected without further discussions

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Structural interventions that are effective

Type of intervention Methods used

Rapid microbiology reporting

- Reduced time to pathogen detection (whole genome sequencing)- Faster susceptibility results by dectecting resistance markers in microorganisms - MRSA, VRE and ESBL screening tests

New inflammatory marker – Procalcitonin

- Decision aid to discontinue antibiotic in sepsis, respiratory tract infections (No substitute for clinical judgement) (Not a test for primary diagnosis)

Use of computerized desicion support systems

"Antibiotic stop orders" Context-sensitive guideline advice

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• Persuasive interventions: Average median effect across all study types: 3.5% – 42.5%

• Restrictive interventions: Average median effect across all study types: 34.7% – 40.5%

Effect sizes of intervention categories

• Importantly, restrictive interventions work faster than persuasive interventions and should be used when the need is urgent

• This difference between restrictive and persuasive interventions diminishes over time ( ≥ 6 months)

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Newer intervention studies, "post-Cochrane" (2007 – 2014)

1. exp Anti-Bacterial Agents/ - 5385612. exp Antibiotic Prophylaxis/ - 89653. 1 or 2 5430224. hospital.mp. or exp Hospitals/ - 9710845. 3 and 4 - 297156. antibiotic us*.mp. 71217. stewardship*.mp. - 19038. antibiotic stewardship*.mp. – 4069. antimicrobial stewardship*.mp. - 63110. behavioral change.mp. - 217011. behavioral interventi*.mp - 433712. exp Guideline Adherence/ - 2144913. Intervention studies.mp. or Intervention Studies/ 1301714. 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 - 4902815. 5 and 14 - 214616. limit 14 to (English language and humans and yr="2007 -Current") - 1059

1059 studies evaluated on the basis of title and abstracts:

92 studies described interventions for appropriate antibiotic use in hospitals

Medline search, Sept. 15th 2014

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Are intervention effects sustainable?

Sadly --- NO!29

A classical intervention, using updated antibiotic

guideline dissemination and "academic detailing" in

two paediatric wards of a St. Petersburg hospital.

For example….

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Significant reduction in total antibiotic use in the intervention ward, but not in the control ward

In the follow-up period, both wards had the same level of use, similar to the baseline condition

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Factors that modify the effects of interventions

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Barriers to intervention effects

• Lack of infectious diseases personnel

• Lack of financial resources

• Inadequate health-information systems

• Resistance from hospital administrators• Opposition from prescribing physicians• Physicians' lack of knowledge; cultural

factors; "irrational behaviour” 33

Beneficial to the effect of interventions

• Local strategies tailored to the needs!• Avoid the "ceiling effect": to intervene on

already optimal areas

• National initiatives An "Antimicrobial self-assessment toolkit" for

acute hospitals (UK – 2009) A national consensus statements on quality

indicators for antimicrobial prescribing (Germany – 2014)

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• 99 indicators were suggested in a questionnaire to professionals for detailed ratings (1-9) of relevance and practicability - 67 were approved

• "Efforts to collect data" and "Implementation barriers" were often given suboptimal scores

• In a consensus workshop, 21 structure and 21 process of care indicators were finally selected

How to proceed?

• The 42 quality indicators will be piloted and undergo feasibility studies in German hospitals

• The indicators would appear to prove valid in similar health-care settings, e.g. in Scandinavia

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Novel concepts in interventions

Innovative approaches are increasingly being sought to enhance the effect and sustainability of stewardship efforts

Rapidly improving old, as well as new "tools"• Electronic health records with antimicrobial

stewardship modules & integrated clinical decision support

• Web- or smartphone "app"-based prescriber aids

• Social marketing & behaviour science theories37

Computer-based decision support and health records

Already described in the "Annals of Internal Medicine" in 1996:

Computer-based antibiotic stewardship aids: • Have large potentials to facilitate, improve and prolong the

effect of intervention activities

• Unintentional effects must be considered, especially when applying restrictive prescribing measures

• Observed increase in number of studies after 2006

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Example:Electronic support system with a sustained intervention effect

28 antibiotics were restricted (given temporal computer-based approval) but for a duration that varied, based on the indication for use and the prescribed antibiotic

Pilot Permanent39

• To date, no study has described the effect of singular behavioural change interventions on antibiotic use in hospitals

• Enhancement potential:

Recognize "key drivers" for prescribing behaviour and identify incentives to alter behaviour

Target intervention according to physicians "behaviour profiles"

• A potential is recognized for behaviour sciences to enhance antibiotic stewardship measures

Behaviour sciences

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A global view• Antibiotic resistance is a world-wide problem, low-income

countries need international support (WHO)• Large populations and deficient hospital structures calls for

alternative antibiotic stewardship measures

Important to consider: Treatment options in low-income countries are more often limited by the unavailability of antibiotics than by antibiotic-resistant pathogens….

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Intelligent use of smartphones and computer technology may be one approach …

… being widely used by even by poor patients

- and also their doctors

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Some national sale trends for carbapenem antibiotics *S

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* "Antibiotic resistance—the need for global solutions" - The Lancet (2013) 43

Conclusions

• For optimal effects of interventions, an Antibiotic Stewardship Program is essential and should be tailored to your hospital's need

• An array of interventions have proven effective without compromising patient safety, in the size of 30% for antibiotic use and 50% for microbial outcomes

• Up until 2006, intervention studies have had low quality; RCTs are often biased and ITS analysis is the preferred method

• A generally low sustainability of intervention effects is problematic

• To find intervention strategies which will work in low-income countries is a global challenge

• Computer support and behaviour change strategies are promising novel approaches to enhance the effects of interventions

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