This document discusses the problem of increasing antimicrobial resistance and outlines strategies for antimicrobial stewardship programs. It recognizes antimicrobial resistance as a serious global problem that requires immediate action. Antimicrobial stewardship is defined as optimizing antibiotic use through selecting appropriate treatment duration, dose, and spectrum of coverage. The document recommends establishing multidisciplinary stewardship teams and implementing interventions like guidelines, audit and feedback, and streamlining of therapy to improve antibiotic use and slow the development of resistance. Physicians are identified as key players that can help address the problem through their antibiotic prescribing practices.

1. Let’s Shore Up Our Defenses
Presented by:
Carmenchu Echiverri Villavicencio, MD, DPCP, DPSMID
Slides by
Marion Priscilla A. Kwek, MD, FPCP, DPSMID
July 4, 2015

2. Outline
• Introduction
– History of Antibiotics
– Magnitude of the Problem
• Antimicrobial Stewardship
– Definition & Rationale
– Interpretation of Antibiogram Data
– Developing Institutional Program
– Stewardship for the primary care physician

3. Objectives
• Recognize the problem of antimicrobial
resistance
• Understand the benefits of an antimicrobial
stewardship program
• Apply antimicrobial stewardship in clinical
practice

6. - Alexander Fleming upon accepting the
1945 Nobel Prize in Medicine

8. The Bad News
• Increasing resistance to available antimicrobials
• Stagnant antibiotic development
– Investment lacking
– Slow to recognize the need and inherent delays in
finding and developing new antimicrobials
• The increasing importance of antimicrobials in
modern medical practice
– Increasing use of antimicrobials for those patients on
immunosuppressants and managed in critical care

9. Antibiotic Resistance
• A worldwide problem
• Can cross international boundaries and spread
with ease
• Pose a catastrophic threat to people in every
country in the world
• At least 2M people acquire serious infections
with bacteria resistant to one or more of the
antibiotics designed to treat those infections
Antibiotic Resistance Threats in the United States, 2013. Centers for Disease Control and Prevention

10. Antibiotic Resistance
• At least 23,000 people die each year as a direct
result of these antibiotic-resistant infections
• Many more die from other conditions that were
complicated by an antibiotic resistant infection
• Infections add considerable and avoidable costs
• Require prolonged and/or costlier treatments,
extend hospital stays, necessitate additional
doctor visits and healthcare use, and result in
greater disability and death
Antibiotic Resistance Threats in the United States, 2013. Centers for Disease Control and Prevention

11. Antibiotic Resistance
The use of antibiotics is
the single most
important factor leading
to antibiotic resistance
around the world
Antibiotic Resistance Threats in the United States, 2013. Centers for Disease Control and Prevention

12. http://lumibyte.eu/microbiology-news/antimicrobial-resistance-timeline/
http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf

13. Pucci & Bush Clin Micro Rev 2013;26:792–821

14. What is “Collateral Damage”?
• Refer to ecological adverse effects of antibiotic
therapy; namely,
– Selection of drug-resistant organisms and
– Unwanted development of colonization or
infection with multidrug resistant organisms (eg,
Clostridium difficile Infection)
• Two antibiotic classes commonly linked to
collateral damage:
– Cephalosporins & Fluoroquinolones
Paterson DL. Clin Infect Dis. 2004;38(suppl 4):S341-S345.

15. Difficult to Treat Organisms
• MRSA
• Antibiotic-resistant
GNBs
• MDR-TB
• C. difficile

16. Staphylococcus aureus
• MRSA rate 53% (n=
2,317)
• Possible emergence of
resistance against
vancomycin with 2013
reported rates at 1%
(n=1,176).
• No reported VRSA in
2012
2013 Antimicrobial Resistance Surveillance Program Summary Report, RITM

17. 2013 Antimicrobial Resistance Surveillance Program Summary Report, RITM

18. Escherichia coli
• ESBL-suspects at 22%
• Resistance rate:
– AMP 82% (n=4,333)
– SAM 32% (n=4,056)
– CXM 29% (n= 2,210)
– CRO 31% (n= 4,364)
– SXT 66% (n= 3,893)
– AK 4% (n= 4,478)
– CIP 43% (n= 4,332)
2013 Antimicrobial Resistance Surveillance Program Summary Report, RITM

19. 2013 Antimicrobial Resistance Surveillance Program Summary Report, RITM

20. 2013 Antimicrobial Resistance Surveillance Program Summary Report, RITM

21. Cost of Drug Resistance
Staphylococcus aureus Drugs (PO) Cost per
antibiotic day
Methichillin-Susceptible Cloxacillin Php 118
Cefalexin Php 94
Co-Amoxiclav Php 135
CA-Methicillin-Resistant Clindamycin Php 299
HA-Methicillin-Resistant Linezolid Php 6,900
Vancomycin
Intermediate
Vancomycin Resistant

22. Drivers of Emergence
• Natural Selection Driven By:
– Antimicrobial use in humans
– Antimicrobials in food production
• Spread of Resistant Organisms
– Population density
– Importation
– Affected by infection control and
community hygiene practice
• Concern is not just spread of
organisms but of transposable
genetic elements conferring
resistance

23. Global Antibiotic Consumption by
Class 2000-2010
www.thelancet/infection Vol 14 August 2014

24. Global Antibiotic Consumption by
Class 2000-2010
• Consumption of antibiotics increased by 36%
Brazil, Russia, India, China, and South Africa
accounted for 76% of this increase
• There was increased consumption of
carbapenems (45%) and polymixins (13%),
two “last-resort” classes of antibiotic drugs.
Van Boeckel et al Global antibiotic consumption 2000 to 2010: an analysis of national
pharmaceutical sales data Lancet Infect Dis 2014; 14: 742–50

25. Nicolau ,DP

27. Perspective of Pharmaceuticals
• All pharmaceutical companies are under pressure by
shareholders to maximize returns and sustain strong
growth rates
– Chronic care medications > acute care medications
– Innovation > Me-too’s
– Specialized disease products > primary care products
• Pressures to maximize profitability do not necessarily
align with appropriate use, promotion, or consumption
of antibiotics
• Recognition of antibiotics as a finite strategic resource
is rarely compatible with corporate commercial
aspirations
Alasdair MacGowan, University of Bristol

29. Approach to Reducing Antimicrobial
Resistance
• Infection Prevention and Control
• Improve diagnostics (i.e. respiratory
infections)
– Minimize unnecessary antimicrobial use
– Targeted (narrow spectrum) therapy
• Continued discovery of new antimicrobials
• Reduce resistance reservoirs (i.e.
animal/environmental use)
• Antimicrobial stewardship programs
Fishman N. Am J Med 2006; 119 (Suppl 1): S53-S61
Dellit TH et al. Clin Infect Dis. 2007;44(2):159-77.

30. WHAT IS ANTIMICROBIAL
STEWARDSHIP?

32. Antimicrobial Stewardship
• After confirming that the patient has an
indication for antimicrobial therapy,
antimicrobial stewardship is the:
Drug
Time
Dose
Duration
Route
Dryden M et al. J Antimicrob Chemother 2011; 66(11): 2441-3
http://www.idsociety.org/stewardship_policy/

33. Why the Need for Antimicrobial
Stewardship?
• Up to 50% of antimicrobial use in hospitals is
inappropriate
• 77% (51/66) studies of interventions to
improve antimicrobial use in hospitals had
beneficial results
Davey P. et al. Cochrane Database of Syst Rev 2005.

34. Understanding Your Local Antibiogram
Most Common Isolates Per Specimen
(eg. Urine)
Total Isolates (262) Percent
Escherichia coli 111 42%
Klebsiella pneumoniae 34 13%
Enterococcus faecalis 26 10%

35. Understanding Your Local Antibiogram
% Susceptibility of E. coli
Ampicillin 32.2
Amoxicillin Clavulanate 73.9
Piperacillin/Tazobactam 100.0
Cefuroxime 78.5
Ceftriaxone 91.5
Ceftazidime 90.6
Cefepime 93.4
Ertapenem 99.4
Imipenem 100.0
Meropenem 100.0
Levofloxacin 71.4
Amikacin 100.0
Cotrimoxazole 47.0

36. INAPPROPRIATE ANTIBIOTIC USE

37. Treating Viral Infections with
Antibiotics
• Most common cause of
acute upper respiratory
tract infections is viral
• Giving quinolones in
viral gastroenteritis

38. Treating Colonizers
• Isolates from respiratory specimens in
patients who are clinically well or
asymptomatic
• Asymptomatic Bacteriuria

39. • Pyuria accompanying asymptomatic
bacteriuria is not an indication for
antimicrobial treatment (A-II).
• Treatment for AB for:
– Pregnant (A-I)
– TURP (A-I) or urologic procedures with anticipated
bleeding (A-III)

40. Surgical Prophylaxis
• Prolonged duration of Prophylaxis
• Timing
• Giving of prophylactic antibiotic even when
not indicated

41. • Single dose or continuation for < 24h
• Dose within 1 hr from cutting time (2h for FQ and
VA)
• Clean head and neck surgery eg. thyroidectomy

42. Antimicrobial Stewardship
• Coordinated interventions to monitor and
direct antimicrobial use at a health care
institution
• Provides a standard evidence-based approach
to judicious antimicrobial use
http://www.idsociety.org/stewardship_policy/

43. Antimicrobial Stewardship: Goals
• Optimal clinical outcomes
• Minimize toxicity and ADRs
• Limit selection for antimicrobial resistant
strains
• Reduce costs of health care
http://www.idsociety.org/stewardship_policy/

44. Stewardship: Recommendations
• Multidisciplinary team
– IDS physician
– PharmD
– Clinical Microbiologist
– IT
– Infection Control Practitioner
– Hospital Epidemiologist
• Compensated
http://www.idsociety.org/stewardship_policy/

45. Stewardship: Recommendations
• Collaboration b/w the ff:
– Stewardship team
– Infection control
– Pharmacy/Therapeutics Committee
• Administrative/Leadership support
http://www.idsociety.org/stewardship_policy/

46. Examples of ASP
Strategies/Interventions
• Education
• Formulary
• Formulary restriction and preauthorization
• Selective reporting
• Prospective audit with intervention and feedback
• Guidelines and clinical pathways
• Antimicrobial order forms
• Streamlining and de-escalation of therapy
• Dose optimization (optimize PK/PD)
• Parenteral to oral conversion
http://www.idsociety.org/stewardship_policy/

47. Education
• Essential
• Alone, insufficient (II-B)
• No sustained impact
• Education + Intervention (xA-III)
http://www.idsociety.org/stewardship_policy/

48. Formulary (A-II)
• Therapeutics Committee
• Evaluating therapeutic efficacy, toxicity and
cost
• Limit redundant new agents
http://www.idsociety.org/stewardship_policy/

49. Formulary Restrictions (A-II) and Pre-
authorization (B-II)
• Restriction of Antibiotics
• ID approval
• ID consult
http://www.idsociety.org/stewardship_policy/

50. Selective Reporting A-III
• Clinical Microbiology
• Limiting Antibiotic Susceptibility Reports in
Cultures
• Example:
– Urine E. coli isolate susceptible to ampicillin, and
all tested antibiotics
– Official culture report: E. coli susceptible to
ampicillin, cefuroxime
http://www.idsociety.org/stewardship_policy/

51. Prospective Audit with Intervention
and Feedback (A-I)
• Very effective
• Resource intensive
http://www.idsociety.org/stewardship_policy/

52. Guidelines and Clinical Pathways
• National Guidelines
• Local Guidelines
• Very Effective

53. Antimicrobial Order Forms (B-II)
• Automatic stop orders
• Clear communication of renewal requirements

54. Streamlining and de-escalation of
therapy (A-II)
• Early de-escalation once with available
microbiologic data
• For Severe Infections
– Empiric Broad Spectrum Treatment
– Re-evaluate after 3 days and streamline
• De-escalation:
– 1 agent: change to narrow spectrum
– 2 agents: change to 1 agent
– Discontinue antibiotics if no evidence of infection

55. Exceptions to general approach
• Do not discontinue antibiotics in a patient
who is decompensating
• Patients may be ill and require therapy,
notwithstanding negative culture results
1. Weber DJ. Int J Infect Dis. 2006;10(suppl 2):S17-S24. 2. Höffken G, Niederman MS. Chest. 2002;122:2183-2196.
3. American
Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA). Am J Respir Crit Care Med. 2005;171:388-
416. 4. Singh
N et al. Am J Respir Crit Care Med. 2000;162:505-511.

56. Dose Optimization (A-II)
• Optimize PK/PD
– Septic patients: Increased Vd
• T/MIC for β-lactams
• AUC/MIC and Cmax/MIC for FQ and
aminoglycosides

61. Parenteral to oral conversion (A-III)
• High bioavailability antibiotics
– Fluoroquinolones
– TMP/SMX
– Metronidazole
– Clindamycin
– Linezolid
– Minocycline
– Fluconazole
– Voriconazole
– Chloramphenicol

62. Stewardship: Recommendations
• Health care information technology
• Surveillance
http://www.idsociety.org/stewardship_policy/

63. Antibiotics in Development
• As of December 2014, an estimated 37 new
antibiotics 1 that have the potential to treat
serious bacterial infections are in clinical
development for the U.S. market.
• Success rate for drug development is low; at
best, only 1 in 5 candidates that enter human
testing will be approved for patients.
http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-development

65. Learning Points
• Antimicrobial resistance is a global concern
and needs immediate action
• Antimicrobial stewardship is one way of
combating antimicrobial resistance
• Physicians are key players in promoting or
curbing antimicrobial resistance

66. Learning Points
• Treatment of infections should be based on
most likely organism following local resistance
patterns
• New antibiotics are in the pipeline but
preserving available antibiotics is still vital