Compilation of media attention and medical literature on antimicrobial stewardship

1. Antimicrobial Stewardship
(PROA): Media and
Literature Update
José Ramón Paño
Servicio de Enfermedades Infecciosas
Hospital Clínico Universitario
4 de octubre de 2016

2. Method: surveillance
• Lancet ID
• CID
• JAC
• CMI
• OFID
• EIMC
• @PROA_HCUZ
• @PROA_HULP
• @ESGAP_ABS
• @joserrapa

3. Outline
• Antimicrobial stewardship in the political agenda
• New antimicrobials: how to promote its
development
• Overall assessment of the impact of AMS programs
• “Shorter is better” (Apropos of CAP)
• Reported b-lactam allergy: more room for
improvement than expected?
• AS from the Microbiology Lab

4. 1. ECDC Draft Technical Report: July 2016
2. Open to public consultation: (Sept, 5th)
3. Draft Guideline: (Oct, 21st)

5. See here

6. Proposal for EU draft guidelines:
technical report or wish list?

7. Proposal for EU draft guidelines:
technical report or wish list?
• Ensure timely access to clinical microbiology laboratory services.
For acute care hospitals, these services should be provided on a
24/7 basis for critical specimens [expert consensus]
• Salary support and dedicated time for antimicrobial
stewardship activities. Example: 0.5–1.5 full-time equivalents
(FTEs) per 250 acute care beds [15,16]. Example of indicator:
number of FTEs for antimicrobial stewardship activities.
3. Healthcare facilities (resources, systems
and processes for healthcare facilities)

10. Nosotros, Jefes de Estado y de Gobierno y representantes de los
Estados y Gobiernos, reunidos en la Sede de las Naciones Unidas en
Nueva York el 21 de septiembre de 2016 (…)
(…) Por consiguiente, nos comprometemos a trabajar en los planos
nacional, regional y mundial para: (…)
(…) b) Movilizar financiación suficiente, previsible y sostenida,
recursos humanos y financieros e inversiones por conducto de
canales nacionales, bilaterales y multilaterales para apoyar la
elaboración y ejecución de planes de acción nacionales, la
investigación y el desarrollo sobre antimicrobianos nuevos (…)

12. New antimicrobials: how to promote
its development
“The findings support a form of a de-linkage model
and a combination of push and pull incentive
mechanisms”
Clinical Infectious Diseases. 2016 Aug 30

13. New antimicrobials: how to promote
its development
Sales-revenue de-linkage model
Clinical Infectious Diseases. 2016 Aug 30
• De-linkage model: Companies not paid on sales
volumes, but by established revenues (flat rates)
• Companies strive for high sale volumes to improve their
ROI, which can increase overuse of antimicrobials and can
contribute to resistance emergence.
- Allow R&D investments for a successful product w/o requiring high
product sales and could be adapted to simultaneously address
conservation

14. New antimicrobials: how to promote
its development
Clinical Infectious Diseases. 2016 Aug 30
Push incentives subsidize the overall development cost
Pull incentives reward successful development,
providing guaranteed return on investment (ROI)
• Tax credits
• Direct funding of research
• Public–private partnerships
• milestone or prize payments
• patent buyouts
• advanced market commitments
• and value-based or high reimbursement
• regulatory incentives

15. Objective: To describe implementation of AS
activities in 47 Southafrican private hospitals
Setting:
• Private hospitals operated by NetCare (7/9 SA regions)
• 64 pharmacists (employees) y 4290 médicos (self-employees)
• 9424 beds (ICU: 1601)
• ID scareceness

16. Intervention (2009-2014):
- 3 phases: pre, implementation y post-implementation
Phase I Preimplementation: 16 months
- Result indicators:
- Process indicators
1. Omission of blood cultures before starting antimicrobials
2. > 7 days duration in the absence of indication (local guideline)
3. > 7 days duration in the absence of indication (local guideline)
4. Simultaneous use of ≥ 4 antimicrobials
5. Redundant coverage
- Approach: Quality improvement (IHI)
I.1. Define goals and indicators
1. Global antimicrobial consumption
2. Implementation
Brink A. Lancet Infect Dis. 2016;16(9):1017–25.

17. Brink A. Lancet Infect Dis. 2016;16(9):1017–25.
Fase I Preimplementation (16m)
I.2. AS model design
• Non-restrictive (preserving prescribers’ autonomy) -> audit &
feedback: detection-review-feedback1-registry-feedback2
• Backbone = PharmD -> Voluntary involvement (no monetary
involvement)…but dedicated time
I.3. “Champions” (PharmD) recruitment
I.4. Assessment of baseline situation (survey)
• Set-up of an AS multidisciplinary committee
• Implementation (speed) adapted to institution circumstances

18. Brink A. Lancet Infect Dis. 2016;16(9):1017–25.
Fase II Implementation
(24 m)
Fase III PostImplementation
(20m)
• Fase II: 31 learning cycles
• Fase III: AS as “standard of care” (22 cycles)

19. Results (i): Antibiotic consumption
Brink A. Lancet Infect Dis. 2016;16(9):1017–25.

20. Brink A. Lancet Infect Dis. 2016;16(9):1017–25.
Results (i): Antibiotic consumption

21. Results (iii): Process indicators
Brink A. Lancet Infect Dis. 2016;16(9):1017–25.

22. Results (iv): process indicators
Interventions: 7934 (6.8%)
Period: 24m (730 d)
Hospitals: 47
Interventions hospital/day*: 7934/34310 = 0.21*
Pacients receiving antibiotics: 116.662

23. Conclusions
• Non-restrictive AS approach based on prescribers’
involvement with PharmD as program leader ->
significant impact in antimicrobial consumption (SA)
• How much of the results are due to audit & feed-back?
(reduced number of time-consuming interventions)
• Patient outcomes? Antimicrobial resistance?
Brink A. Lancet Infect Dis. 2016;16(9):1017–25.

25. • Población: Adultos ingresados con NAC* en 4
hospitales vascos
*NAC: nuevo infiltrado + 1 síntoma (fiebre / tos / disnea / dolor torácico)
• Período: Enero 2012 a agosto 2013

26. Uranga A. JAMA Intern Med. 2016 Jul 25.
Criterios de exclusión
• Inmunosupresión
• Riesgo de patógenos resistentes
Trasplante de órgano sólido
Prednisona > 10mg/día x 30 días u otros inmunosupresores
Esplenectomía
Neutropenia
Institucionalización
Ingreso en los últimos 15 días
Uso de antibióticos sistémicos en los últimos 30 días
• Existencia de criterios de duración prolongada
Infección por P. aeruginosa o S. aureus
Complicaciones locales o a distancia

27. Uranga A. JAMA Intern Med. 2016 Jul 25.
Diseño
• Screening: Días 0-5: comprobar criterios inc/excl
• Aleatorización: día 5
- Máxima Tª 48h: 37.8ºC
- ≤ 1 criterios de estabilidad clínica
TAS < 90mmHg
FC > 100/min,
FR > 24 /min
SatO2 < 90%, o PaO2 <60 mm Hg (aire ambiental)
- Intervención: suspensión AB* el día 5
- Control : duración AB* según criterio clínico
*AB : antibiótico elegido por el médico responsable

28. Uranga A. JAMA Intern Med. 2016 Jul 25.
Variables resultado
A) Variables principales:
• Buena evolución clínica (d10 y d30): Resolución o mejoría
de los síntomas de neumonía sin reintroducir antibiótico
• Síntomas NAC (d10 y d30): Cuestionario validado
B) Variables secundarias:
• Duración de tratamiento antibiótico (días): desde la primera
dosis hasta el día 30
• Tiempo hasta mejoría/vuelta a rutina/resolución Rx
• Mortalidad (30 d)
• Recurrencia NAC

29. Resultados

30. Resultados
Características basales de grupos de intervención y control:
equilibradas
AB: 80% quinolona

31. Resultados
Variable Control Intervención p
Buena evolución clínica (ITT) d10
d30
48.6%
88.6%
56.3%
91.9%
0.18
0.33
Buena evolución clínica (PP) d10
d30
50.4%
92.7%
59.7%
94.4%
0.12
0.54
Síntomas CAP (ITT) d10
d30
24.7
18.6
27.2
17.9
0.10
0.69
Síntomas CAP (PP) d10
d30
24.6
18.1
26.3
17.6
0.16
0.81
Tiempo con antibiótico
mediana (p25-p75)
10
(10-11)
5
(5-6.5)
< 0.001
Pacientes tratados 5 d 4 (2.9%) 101 (70.1%) <0.001
Tiempo hasta mejoría clínica 12 (8-18) 12 (7-15) 0.41
Recurrencia (día 30) 6 (4.4%) 4(2.8%) 0.53
Reingreso (día 30) 9 (6.6%) 2 (1.4%) 0.02

32. Resultados

33. Conclusiones/discusión
“Our study indicates that the IDSA/ATS recommendations for
shorter duration of antibiotic treatment based on clinical stability
criteria can be safely implemented in hospitalized patients with
CAP, leading to a significant reduction in treatment
duration.”
Fortalezas:
• Estudio pragmático (vida real) con buen diseño y variables
relevantes
Limitaciones:
• Extrapolación a determinadas poblaciones
1. b-lactámicos
2. Fine V
3. Atención a criterios de exclusión

34. • Reported allergy to b-lactam antibiotics is common and often
leads to unnecessary avoidance in patients who could tolerate
b-lactam therapy.
• Majority of reported prior reactions are misclassified as allergies
• Moreover, many individuals with true prior immunoglobulin (Ig)
E–mediated reactions have loss of hypersensitivity over time
• Hypothesis: receipt of alternative therapy when a b-lactam agent
is the preferred therapy leads to worse clinical outcomes
MacFadden DR. Clinical Infectious Diseases. 2016 Ahead of print

35. “Trainee-led* prospective cohort study to determine
the burden and clinical impact of reported beta-
lactam allergy on patients seen by an infectious
diseases consultation service at 3 academic hospitals”
MacFadden DR. Clinical Infectious Diseases. 2016 Ahead of print
*Infectious diseases residents developed and initiated the study as the initial phase of a
division-wide, trainee-led quality improvement initiative
Methods (ii)
Study population: All inpatients seen in consultation
by ID service (Apr 2014-Jan 2015) on days that the ID residents were
present** for the review of cases.
**both weekdays and weekends. Routinely absent for 1 half-day per week of scheduled
teaching), without other systematically excluded days.

36. MacFadden DR. Clinical Infectious Diseases. 2016 Ahead of print
Methods (ii)
Prospective assessment of b-lactam allergy:
• During consultation review rounds
• Characterization of previous allergic reaction in:
- High risk: IgE-mediated (urticaria, bronchospasm, angioedema, or anaphylaxis),
Stevens Johnson syndrome [SJS], toxic epidermal necrolysis [TEN], and DRESS
- Low risk: rash, serum sickness, others
Preferred and chosen antibiotic therapies
• Determined by the consultant ID service based on the initial
patient presentation and assessment
Review of patient outcomes
• After the initial assessment, using comprehensive EMR
• Quality control: 7 covariates; random 10% pts; k:0.94 + 2 ID doc

37. Results
Reported b-lactam allergy
95 (19%)
Rececived b-lactam
47 (65%)
Didn’t receive b-lactam
25 (35%)
History of severe reaction
48%
Patients included
507
b-lactam preferred agent
72 (76%)
History of severe reaction
15%
P = 0.004

38. MacFadden DR. Clinical Infectious Diseases. 2016 Ahead of print
Results (ii)
Characteristic
No
reported
allergy
Reported
allergy but b-
lactam non
preferred
Reported allergy and b-
lactam preferred
Received
preferred AB
Did not
receive
preferred AB
N (507) 412 23 45 27
Inmunocompromised 72 5 9 3
Reported allergy description
IgE mediated 7 7 11
Other severe 0 0 1
Rash 9 15 9
Unknown 7 25 4

39. Results (iii)
Characteristic
No
reported
allergy
Reported
allergy but b-
lactam non
preferred
Reported allergy and b-
lactam preferred
Received
preferred AB
Did not
receive
preferred AB
Antibiotic administered
Penicillin 45 0 7 0
Ceph 124 0 22 1
BL/BLI 101 0 8 1
Carbapenem 34 1 10 3
FQ 22 5 0 8
Clindamycin 1 1 0 5
Glycopeptide 50 12 0 5
Aminoglycoside 3 1 0 1
Other 32 3 0 1

40. Results (iii)
Characteristic
No
reported
allergy
Reported
allergy but b-
lactam non
preferred
Reported allergy and b-
lactam preferred
Received
preferred AB
Did not
receive
preferred AB
Site of infection
Bacteremia (primary) 59 4 14 4
Skin and soft tissue 54 3 7 5
Bone/Joint 53 5 5 2
Gastrointestinal 60 5 5 4
Genitourinary 52 2 5 5
Pulmonary 56 2 8 4

41. Results (iv)
Characteristic
No
reported
allergy
Reported allergy
but b-lactam
non preferred
Reported allergy and b-lactam
preferred
Received
preferred AB
Did not
receive
preferred AB
Primary outcome: Readmission + C. difficile + drug reaction + Acute kidney injury
67(16%) 5(22%) 11(21%) 10(40%)*
Secundary outcome
Readmission 24 (6%) 1(4%) 2 (4%) 6(24%)*
CDI 18 (4%) 1 (4%) 0 0
Drug reaction 2 (0.5%) 0 4 (9%)* 2 (8%)+
AKI 29 (7%) 3 (14%) 5 (11%) 4 (16%)
Mortality 55 (13%) 1 (4%) 10 (21%) 2 (8%)
Multivariate analysis
Primary outcome 3.18 (1.28–7.89)
Patient outcomes: univariate analysis
*p< 0.05

42. Conclusions
• “Reported b-lactam allergy was common and led to
a significant proportion of patients receiving
alternative antimicrobial therapy.”
• “Avoidance of preferred b-lactam therapy was
associated with increased adverse outcomes (mainly
readmission and adverse reactions that required
discontinuation of therapy).”
• The risk of antibiotic-related reactions that required
discontinuation of therapy was higher among
patients carrying a label of allergy, regardless of
whether or not they received beta-lactam

43. Conclusions (ii)
• There is a significant need to develop formal models
of care within infectious diseases practices in order to
objectively assess reported b-lactam allergies and
optimize b-lactam use among patients without IgE-
mediated allergy or other serious reactions.
• There is need to introduce self-audit skills and
practice improvement and resource stewardship
at the trainee level.

44. Limitations
• Selection bias (referral)
- Frequency of ABX allergy
- Complexity of patients (maximum benefit
of optimized therapy)
• Questions
- No aztreonam prescribed? How was it
considered (preferred/non-preferred?

45. Dietz J. Am J Infect Control. 2016
• “62% of the patients had urine culture completed without
specific symptoms of urinary tract infection”
• Starting in April 2006, the facility automatically started sending
urinalyses with + nitrite or leukocyturia (≥8 WBC) for culture.
• Laboratory policy was changed in September 2014 to remove
the reflex urine cultures and instead require providers to o
• The patient’s urine sample is held in the laboratory for 3 days to
allow for urine culture to be added. A message was also added to
the laboratory results for all urinalysis and urine cultures

46. Langford BJ. J Clin Microbiol. 2016 Aug 24;54(9):2343–7
Antimicrobial Stewardship in the Microbiology Lab: Impact of
Selective Susceptibility Reporting on Ciprofloxacin Utilization and
Gram-Negative Susceptibility in a Hospital Setting
• A selective reporting policy was implemented which
involved the suppression of ciprofloxacin susceptibility
to Enterobacteriaceae when there was lack of resistance
to the antibiotics on the Gram-negative panel
• 400-bed community teaching hospital in Toronto, Canada
• On-site microbiology laboratory, with staff available
during daytime and evening hours
• Problems with C. diff and FQ-resistant P. aeruginosa