Sesión de Revisión Bibliográfica con recopilación de artículos recientes sobre PROA (antimicrobial stewardship)

1. Antimicrobial Stewardship
(PROA)
Journal Watch
(Nov´14-Feb´15)
José Ramón Paño
Unidad de Enfermedades Infecciosas y Microbiología Clínica
Hospital Universitario La Paz (Madrid)
February 11th,2015

2. Methods
Surveillance (RSS feeds)
• CID, JID, JAC, AAC, The Lancet Infectious Diseases,
JAMA, NEJM
• Twitter
Period: Nov 2014-Feb 2015
Selection
• I have followed my own criteria 
• Of initially selected articles, some will be
commented
All references are linked to PubMed

3. Outline
• Determinants of antimicrobial use
• Monitoring/quality of antimicrobial use
• Interventions to improve antimicrobial use
• Thinking out of the box (antimicrobial
stewardship)

4. Determinants of antimicrobial use

5. Linder JA. JAMA Intern Med. 2014 Dec;174(12):2029–31.
• Decision fatigue: erosion of self-control after making
repeated decisions
Easy choice
(frequently inappropriate)
Judges: Prolonged sessions  % Parole
Doctors &: At the end of the day ABX in URI?

6. Linder JA. JAMA Intern Med. 2014 Dec;174(12):2029–31.
Setting
• 23 primary care practices (USA) -204 physicians-
• Acute respiratory infections (ARI) in adults (18-64)
• May 2011-September 2012
Methods
• Billing and electronic health records were merged
• ARI were classified diagnoses as “antibiotics sometimes
indicated” or “antibiotics never indicated”
• ARI visits by which occurred during two 4-hour sessions—8
AM to noon and 1 PM to 5 PM
• Using logistic regression, the probability of antibiotic prescribing
as a function of session hour, N of visits per session, calendar
month of visit, patient- level confounders was estimated

7. Linder JA. JAMA Intern Med. 2014 Dec;174(12):2029–31.
• Otitis
• Pneumonia
• Strep
Pahryngitis
• URI
• Influenza
• Non-Strep
Pharyingitis
21 867 ARI visits

8. Linder JA. JAMA Intern Med. 2014 Dec;174(12):2029–31.
Remedies for decision fatigue might
include time-dependent decision
support, modified schedules, shorter
sessions, mandatory breaks, or snacks
Any hospital-based antibiotic prescribing-related
decision fatigue circumstance?

9. Monitoring/Quality of
antimicrobial use

10. Objectives:
• The frequency with which patients were started on empirical ABX
• characteristics of the empirical regimen
• clinical characteristics of patients at the time of starting
antimicrobials
• patterns of changes to empirical therapy at different timepoints
• and modifiable factors associated w/ changes to the empirical
regimen (day 5)
To assess:

11. Methods
• Multicenter chart-review 2009-10 by ID physicians: 6 centers/4 days for
each center/50 records/center-day (randomly selected)
• Only adult patients in non-psychiatric wards were included
• Variables: demographics, outpatient antimicrobial use and
allergies, and the name, indication, start and stop dates, and
documentation source, with a standardised electronic form.
• When documentation was conflicting, reviewers were asked to make a clinical
judgment based on all the information available in the record
• Microbiology and radiology studies were deemed relevant to this analysis if
they were collected on or before the day antibiotic therapy was started
• Review of therapy adjustments: The analysis was focused on
patterns and factors associated with the decision to modify
antimicrobial therapy in the first 5 days of treatment (Kollef
criteria) Braykov NP. Lancet Infect Dis. 2014 Dec;14(12):1220–7.

12. Results
• 6812 patients were admitted to hospital on the four review dates, of
whom 4119 (60%) had an active antimicrobial order (46.6-78.8)
Braykov NP. Lancet Infect Dis. 2014 Dec;14(12):1220–7.
• 67% pacientes sin fiebre
• 33% sin fiebre ni leucocitosis
• Cultures obtained before ABX in 59%
(58% of which were negative)
• If cultures obtained after ABX onset:
71% were negative)
• Most frequently prescribed antibiotic:
quinolones (18%)
• Pip/Tazo and or Vancomycin (22%)

13. Results
• Factors associated with de-escalation
Braykov NP. Lancet Infect Dis. 2014 Dec;14(12):1220–7.

14. Interventions to improve
antimicrobial use

15. • Multifaceted, continuous educational approach to
disseminate an up-to-date internal guideline adapted
from published guidelines for management of intra-
abdominal infections (IAI)
• Surgical unit at a tertiary care teaching hospital in
Hamilton, Ontario, Canada
Popovski Z, et al. J Antimicrob Chemother. 2014.

16. • IAI are very common and are associated with high rates of
morbidity and mortality
Popovski Z, et al. J Antimicrob Chemother. 2014.
Why intrabdominal (IAI) infections?
• IAI often need treatment with broad-spectrum antimicrobials
• Guidelines highlight the importance of risk stratification
and local susceptibility patterns to guide empirical
treatment
• The availability of clinical practice guidelines does not
necessarily change practice

17. A) Local consensus process to develop a guideline
Intervention
• Multidisciplinary team: ID, Micro, epidemiologists, surgeons
• items: empiric ABX, duration, iv to po switch
• Risk stratification:
Non-complicated communitiy acquired: ceftriaxone + metronidazole
Complicated* communitiy acquired: Piperacillin/Tazobactam
HA-IAI: Piperacillin/Tazobactam
* Previous ABS, comorbidity, APACHE >15
B-lactam allergic: ciprofloxacin + metronidazole
Popovski Z, et al. J Antimicrob Chemother. 2014.

18. A) Local consensus process to develop a guideline
Intervention(ii)
• Endorsed by hospital and programme leadership
B) Guideline implementation
• Multimodal educational and collaborative approach (Dec´10-Mar´11)
1) educational tools: handouts, posters and pocket cards
2) providing educational sessions/meetings
• ID, surgery, pharmacists, nurses
• Rotating residents at the surgery ward (beginning)
Popovski Z, et al. J Antimicrob Chemother. 2014.

19. Baseline
(preintervention)
Design. Patients
• “Pre-Post intervention quasi-experimental design”*
April ´10 Nov ´10 Jan ´11 Dec ´11
*Interrupted time series?
Postintervention
Patients were included if hospitalized in the surgical ward and:
• IAI (appendicitis, cholangitis, cholecystitis, diverticulitis,
peritonitis, intra-abdominal abscess or perforation)
• or if receiving pre-emptive antibiotics for intra-abdominal
trauma
Popovski Z, et al. J Antimicrob Chemother. 2014.

20. Baseline
(preintervention)
Analysis. Variables
• “Pre-Post intervention quasi-experimental design”*
April ´10 Nov ´10 Jan ´11 Dec ´11
*Interrupted time series?
Postintervention
Outcome variables
1. % patients with ceftriaxone/% patients with
fluoroquinolones
Primary
2. DOT¥/1000 patient-days∞
¥Days of therapy
∞ All patients in the study ward
Secondary
1. Duration of therapy
2. Clinical outcomes:
mortality/readmission
Popovski Z, et al. J Antimicrob Chemother. 2014.

21. Results
Baseline: 512 antimicrobial regimens (152 unique patients)
Intervention: 484 regimens (145 unique patients)
Popovski Z, et al. J Antimicrob Chemother. 2014.

22. Results
In DOT/1000 PD, there was a decrease in:
• Ciprofloxacin: from 221 to 74 (OR 0.3, 95% CI 0.2–0.3;
P,0.001)
• Piperacillin/tazobactam: from 116 to 67 (OR 0.6, 95% CI 0.5–
0.7; p 0.001)
• Cefazolin: from 49 to 38 (OR 0.8, 95% CI 0.6–1.0).
• Metronidazole: from 266 to 207; OR 0.7, 95% CI 0.6–0.8;
p<0.001)
• The rate of ceftriaxone use increased from 6 to 92 (OR 17,
95% CI 10–25;
Popovski Z, et al. J Antimicrob Chemother. 2014.

23. Popovski Z, et al. J Antimicrob Chemother. 2014.
Results

24. • However, there is often a reluctance to de-escalate these
broad-spectrum antimicrobials once they have been initiated
Lew KY. J Antimicrob Chemother. 2014 Dec 3.
• Carbapenems are appropriate empirical therapy in patients
with moderate to severe infections and risk factors for
infection with MDR Gram-negative organisms
• These concerns may be legitimate given the paucity of data in
settings where Gram-negative resist- ance is endemic

25. Lew KY. J Antimicrob Chemother. 2014 Dec 3.
• 1500-bed Taiwanese academic hospital (ASP est. in 2009)
Setting
• ESBL producers: 29% E. coli; 40% K. pneumoniae of all isolates
cultured in the microbiology lab
• The ASP team comprises 4 ID physicians on rotation (making up
0.5 full-time equivalents daily) and 3 ASP pharmacists.
• Cases are reviewed every working weekday (8am to 5pm)
from the day of carbapenem initiation.
a) Days 1 & 2 by the ward pharmacists for appropriate indications and
dosage (institutional guidelines)
b) From day 3: Ward pharmacists and ASP team for a de-escalation
opportunity based on clearly defined criteria

26. Lew KY. J Antimicrob Chemother. 2014 Dec 3.
Setting (ii)
Day ≥3
Institution-approved guideline
Switch to other
antimicrobials as per
empirical therapy
institutional guidelines

27. Lew KY. J Antimicrob Chemother. 2014 Dec 3.
• Feedback are made to the primary care team where
appropriate.
Setting (iii)
• All recommendations are communicated to the primary care
team through documentation in the patient’s chart and
frequently include telephone or in-person discussions.
• Cases where the primary care team does not accept the
ward pharmacist’s recommendations or the case is
complicated are referred to the ASP team

28. Lew KY. J Antimicrob Chemother. 2014 Dec 3.
• All patients receiving meropenem or imipenem from
September 2011 to December 2012, for whom a
recommendation for de-escalation was made
Patients
• Patients who received ≥1 course of were only included
once
• Ertapenem was excluded as it is a narrower spectrum
carbapenem recommended for the de-escalation from
imipenem or meropenem

29. Primary outcome
Outcomes. Definitions
Proportion of patients who achieved clinical success
Clinical success: When all of the following criteria were met at 7 days after the ASP
recommendation for de-escalation:
(i) the patient was alive
(ii) there were no positive microbiological results
(iii) the patient did not require a readministration of carbapenem or the addition of
other antimicrobials
(iv) the patient still met the criteria for de-escalation
Secondary outcomes
• Duration of carbapenem use
• Duration of antimicrobial therapy
• Length of hospitalization,
• Survival at hospital discharge
• 30 day mortality from the start of treatment with the carbapenem
• Readmission to hospital due to infection within 30 days.
• Adverse effects
Outcomes were compared between those
patients in whom de-escalation
recommendations were followed and
those in whom not

30. Results: flowchart
Imipenem/meropenem
courses reviewed
(2433)
De-escalation
recommendations
(428; 17.6%)
Randomized to study (300)
De-escalation accomplished
(304; 68%)
De-escalation ignored
(96; 32%)
% to improve?
Conservative approach?
NNR (number needed
to review)!!!
Any thoughts?
Why? Convenience?
Time-frame?

31. Results (ii)
• No differences in patients´demographics, comorbidity, severity of
illness and type of antimicrobial therapy (empiric vs targeted)

32. Results (iii)

33. Results (iv): Outcomes
Primary outcome Proportion of patients who achieved clinical success
Secondary outcomes
De-escalated Non de-escalated
183/204 (89.7%) 85/96 (88.5%)
De-escalated Non de-escalated
Duration of carbapenem use 6 (4–8) 8 (7 – 11); IC95 (-3 to -2)
Duration of antimicrobial therapy 9 (7–14) 9 (7–14)
Length of hospitalization 18 (9–35) 20 (9-40)
Survival at hospital discharge 173 (84.8) 79 (82.3)
30-day mortality 25 (12.3) 14 (14.6)
30-day readmission 15 (7.4) 8 (8.3)
Adverse effects 11/204 (5.4%) 12/96* (12.5%) ; p=0.037
*diarrea

34. Conclusions
• De-escalation of carbapenem is feasible, even in the
absence of microbiological data
• An institutional de-escalation guideline could be of help
• A back-end approach with a high burden of prescriptions
might not be an efficient approach (low-sensitive
screening)
• A Front-end approach* (education/protocols/prescribing
assistance) are likely to be complementary tools
*Involving the clinician

35. Gerber JS. JAMA. 2014 Dec 17;312(23):2569–70

36. • A score to evaluate ASP was developed
• The score comprised 2 main categories:
1. Structures: Staff/Automated surveillance software
2. Strategies: preauthorization/audit & feedback,
education, guidelines, iv to po programmes, de-
escalation of therapy, antimicrobial order forms
• Multiple regression analysis to correlate score with targeted
AB use

37. Pakyz AL. J Antimicrob Chemother. 2015

39. Pubmed

40. Pubmed

41. Thinking out of the box

42. Meeker D. JAMA Intern Med. 2014 Mar 1;174(3):425–31.

44. Front-end Approaches to Antimicrobial Stewardship
Hamilton KW. Clinical Infectious Diseases. 2015
• Guidelines have focused on the creation of top-down or
centralized processes (preauthorisation/antimicrobial restriction
or postprescription audit and feedback)…BUT
1. Most hospitals have challenges in implementing centralized ASPs: lack of
dedicated personnel/financial resources
2. This approach may fail to affect the many episodes of antimicrobial use
not subject to scrutiny by the stewardship team
3. Feedback occurs subsequent to the prescribing process with an inherent
lag between antimicrobial exposure and the provision of feedback
• Frontline providers* have opportunities to enhance AS
* multidisciplinary healthcare providers (eg, nurses, pharmacists, and physicians) that
assume direct responsibility for the daily care of pa- tients or patient care unit

45. Front-end Approaches to Antimicrobial Stewardship
Hamilton KW. Clinical Infectious Diseases. 2015
How to get the principles of antimicrobial prescribing
incorporated into daily prescribing practice?
…shifting AS from the primary responsibility of centralized ASPs to
a more universal practice among primary healthcare teams/units.

46. Front-end Approaches to Antimicrobial Stewardship
Hamilton KW. Clinical Infectious Diseases. 2015
1. Paperforms (policy) + Implementation strategy
…and present their pilot experience with an antimicrobial
flowsheet
Authors review several original papers on the topic
Thakkar J. J Antimicrob Chemother 2011; 66:1916–20
2. Check-list (policy) + Implementation strategy
Fleet E. J Antimicrob Chemother 2014; 69:2265–73
3. Electronic Medical Records (#EMR)

47. Front-end Approaches to Antimicrobial Stewardship
Hamilton KW. Clinical Infectious Diseases. 2015

48. Front-end Approaches to Antimicrobial Stewardship
Hamilton KW. Clinical Infectious Diseases. 2015

49. Front-end Approaches to Antimicrobial Stewardship
Wenzler E. Clinical Infectious Diseases. 2015
• Point-of-prescription interventions with frontline healthcare
providers have the potential to expand existing ASPs and
provide alternative approaches to performing stewardship at
institutions without ASPs
• If we are to rely on prescribers a 2-tiered approach may need to
be considered:
1. To create a robust antimicrobial stewardship effort that involves a multifaceted
approach built around core strategies that do not rely solely on physician practices
• Knowledge and perceptions of prescribers about infections,
antimicrobial prescribing and resistance are far from optimal

50. Front-end Approaches to Antimicrobial Stewardship
Wenzler E. Clinical Infectious Diseases. 2015
• If we are to rely on prescribers a 2-tiered approach may need to
be considered:
1. To create a robust antimicrobial stewardship effort: multifaceted approach
built around core strategies that do not rely solely on physician practices
• Point-of-prescribing intervention could supplement an existing ASP or be a
strategy for performing stewardship in hospitals without an ASP
2. To develop a program to allow antimicrobials to be prescribed only by
those physicians who are certified within an institution and have
demonstrated the necessary education and competency to truly understand
the risks and complexities associated with antibiotic use
• Analogous to those proposed by the Institute for Healthcare Improvement, The
American Society of Clinical Oncology, and the American Society of Health-
System Pharmacists to ensure the safe and effective prescribing of
chemotherapeutic agents