Antibiotic Stewardship Against

Antimicrobial Resistance: Are we

Winning or Losing?

Chris Lee
Malaysia
 Antibiotic Stewardship
in the Era of
Antimicrobial Resistance

Dr Christopher KC Lee
Infectious Diseases Unit
Sungai Buloh Hospital
Malaysia
 Presentation Outline

• Antibiotic Resistance: Impact to Global Health!

• Antibiotic Usage and Resistance
• Antibiotic Stewardship
• Appropriate Antibiotic Usage in the Era of
Resistance
 ESKAPE Pathogens Today
North America Europe
VRE (E. faecium) 66.1% VRE (E. faecium) 14.4%
MRSA 50.6% MRSA 24.8%
ESBL-K. pneumoniae 9.8% ESBL-K. pneumoniae 17.0%
A. baumannii (Carb-R) 22.1% A. baumannii (Carb-R) 25.1%
P. aeruginosa (Carb-R) 8.7% P. aeruginosa (Carb-R) 12.3%
Enterobacter spp. (CFT-R) 25.3% Enterobacter spp. (CFT-R) 40.3%

Increasing Gram –ve resistance

In Asia-Pacific
Latin America Asia Pacific
VRE (E. faecium) 38.8% VRE (E. faecium) 21.7%
MRSA 46.6%
ESBL-K. pneumoniae 36.1% MRSA 45.0%
A. baumannii (Carb-R) 57.5% ESBL-K. pneumoniae 22.8%
P. aeruginosa (Carb-R) 25.3% A. baumannii (Carb-R) 41.9%
Enterobacter spp. (CFT-R) 44.9% P. aeruginosa (Carb-R 15.7%
Enterobacter spp. (CFT-R) 44.3%
Carb-R = imipenem and/or meropenem resistant; CFT-R = ceftriaxone-resistant
www.testsurveillance.com (Last accessed October 13, 2011).
Antimicrobial resistance in Asia
Macrolide-resistant Streptococcus pneumoniae

High prevalence of macrolide resistance in Asian countries

Erythromycin resistance > 70% Erythromycin resistance 30-50%

Erythromycin resistance 50-70% Erythromycin resistance < 30%

Song JH, ANSORP. Antimicrob Agents Chemother. 2012;56:1418-1426; Reinert RR,et al. Antimicrob Agents Chemother. 2005;49:2903-2913.
Sahm DF, et al. Otolaryn Head Neck Surg. 2007;136:385-389;Jacobs MR, et al. Antimicrob Agents Chemother. 2010;54:27162-2719.
Harimaya A, et al. J Infect Chemother. 2007;13:219-223; Liebowitz LD, et al. J Clin Pathol. 2003;56:344-347.
 Macrolide resistance
Changing trend in Asia (1996-2009)
1996-1997
2000-2001
2008-2009 72.7%
2012-2013
% of erythromycin resistance*

53.1
46.1

*Based on the CLSI breakpoint for erythromycin : R, ≥ 1 mg/L

Song JH, ANSORP. Clin Infect Dis. 1999;28(6):1206-1211;

Song JH, ANSORP. Antimicrob Agents Chemother. 2004;48(6):2101-2107; 7
Kim SH, ANSORP. Antimicrob Agents Chemother. 2012;56(3):1418-1426.
 …And a New Menace
New Delhi metallo-β-lactamase 1 (NDM-1)

• Most blaNDM-1 positive

plasmids are readily
transferable
• Multi-resistant to
fluoroquinolones,
β-lactams, and
aminoglycosides
• Potential for worldwide
endemicity

Kumarasamy KK, et al. Lancet Infect Dis. 2010;10:597-602.

 The Impact of Antimicrobial Resistance

A 2008 study of resistance in one hospital:

 6.5% increased mortality

 6.4 to 12.7 extra days of hospitalization

 $18, 588 to $27,069 increase in hospital costs

per patient

RR Roberts, et al. 2009. Clin. Infect. Dis. 2009; 49:1175-84.

Does published scientific literature indicate an inferior outcome in
infections with drug resistant bacteria?
 Does published scientific literature indicate an excess cost
outcome in infections with drug resistant bacteria?

MSSA MRSA

Infect Control Hosp Epidemiol, 2009, 30(5):453-460. doi:10.1086/596731.

Correlation Between Consumption of Imipenem
and Resistance of P. aeruginosa

Lepper PM, et al. Antimicrob Agents Chemother. 2002;46:2920-2925.

Antimicrobial Stewardship

“…. the microbes are educated to resist penicillin

and a host of penicillin-fast organisms is bred
out… In such cases the thoughtless person playing
with penicillin is morally responsible for the death
of the man who finally succumbs to infection with
the penicillin-resistant organism. I hope this evil
can be averted.”

- Sir Alexander Fleming, June 1945

 “Stewardship”????

• the office, duties, and obligations of a

steward
• the conducting, supervising, or managing of
something; especially: the careful and
responsible management of something
entrusted to one's care <stewardship of our
natural resources>
 Therefore,
Antibiotic Stewardship is…..

An activity that includes appropriate

selection, dosing, route, and
duration of antimicrobial therapy.
 Goals of Antibiotic Stewardship

• Optimizing clinical outcomes while

minimizing unintended consequences of
antimicrobial uses.
 Toxicity

 Selection of Pathogenic organisms

 Emergence of Resistance

• 2° goal is the reduction of health care costs

without adversely impacting quality of care
 Antimicrobial stewardship
+
Infection control program

Can limit the emergence and

transmission of antimicrobial-
resistant bacteria
 Antibiotic Stewardship: Does it save $?
Setting Intervention Effect on antimicrobial-related costs

860-bed private teaching •Guideline development Outcome: US$3267 reduction in total

hospital* drug-related costs,
Hartford Hospital, •Review (automatic iv.-to-  costs related to adverse effects and
Hartford, CT, USA oral conversion) costs of hospital-stay savings per
patient eligible for conversion

70-bed veterans affairs •Education Outcome: US$68,931 (16%) reduction

teaching hospital** •Computer assistance in antimicrobial costs per year
Edward Hines Jr •Automatic stop order
Veterans Affairs
Hospital, IL, USA •Restriction requiring
approval

730-bed community •Restriction requiring Outcome: 20% relative reduction in

teaching hospital *** approval antimicrobial costs per month over 3
Pitt County Memorial years
Hospital, NC, USA •Review and feedback

* Am. J. Health-Syst. Pharm. 59(22), 2209-2215 (2002). ** Am. J. Health Syst. Pharm. 60(13), 1358-1362 (2003).
***J. Antimicrob. Chemother. 53(5), 853-859 (2004).
 Ab Stewardship: Does it improve resistance?
Setting Intervention Effect on rates of antimicrobial
resistance

725-bed teaching hospital •Restriction requiring Vancomycin resistance:

Hospital of University of approval •Enterococcus spp.: 70% increase/10
Pennsylvania, Philadelphia, US years

730-bed community teaching •Restriction requiring Pip/tazo, cefepime, cipro, gentamicin

hospital; approval and imipenem resistance:
E. coli: NS/3 years
Pitt County Memorial Hospital, •Review and feedback P. aeruginosa: NS/3 years
NC, USA
K. pneumoniae: NS/3 years

Oxacillin resistance:
S. aureus (ICU): 15.3% /3 years
S. aureus (non-ICU): 20.5% /3 years

80-bed rural teaching hospital; •Restriction requiring NS/7 years for all organisms and all
Kantonsspital Schaffhausen, approval antimicrobials reported
Switzerland •Education
•Guideline
development
•Review and feedback
 Economics
• Antibiotic stewardship program can be
financially self supporting
• Decrease in Antibiotic use (22-36%) with
annual savings of $200,000 to $900,000 per
annum seen in large academic institutions
• Thus, healthcare facilities should be
encouraged to implement antimicrobial
stewardship programs
 GUIDELINES FOR DEVELOPING AN
INSTITUTIONAL PROGRAM TO ENHANCE
ANTIMICROBIAL STEWARDSHIP
 Stewardship Team
• ID Physician.
• Clinical Pharmacist with infectious disease
training
• Clinical Microbiologist
• An information system specialist
• Infection control professional.
• Hospital epidemiologist (Optional)
Collaboration between the antimicrobial
stewardship team, the hospital infection
control, pharmacy and therapeutics
committees is essential
 Active Antimicrobial Stewardship
Strategies
1. Prospective audit with intervention and
feedback.
• A medium-sized community hospital resulted in
a 22% decrease in the use of parenteral broad-
spectrum antimicrobials.
• They also demonstrated a decrease in rates of
C. difficile infection & nosocomial infection
compared with the preintervention period.

Carling P et al. Favorable impact of a multidisciplinary antibiotic management program

conducted during 7 years. Infect Control Hosp Epidemiol 2003; 24:699–706.
2. Formulary restriction & preauthorization
requirements for specific agents
 Most hospitals have a pharmacy and
therapeutics committee or an equivalent group
 They evaluate drugs for inclusion on the hospital
formulary on the basis of
therapeutic efficacy
toxicity
cost
 They also limit redundant new agents with no
significant additional benefit.
Rahal et al Clinical Infect Dis 2002 Feb 15;34(4):499-503.
Nosocomial antibiotic resistance in multiple gram-negative species:
experience at one hospital with squeezing the resistance balloon at
multiple sites.

• In response to an increasing incidence of

cephalosporin-resistant Klebsiella, a preapproval
policy was implemented for cephalosporins.
• This resulted in an 80% reduction in hospital-
wide cephalosporin use and a subsequent 44%
reduction in the incidence of ceftazidime-resistant
Klebsiella throughout the medical center.

However, imipenem use increased 141%, accompanied by a

69% increase in the incidence of imipenem resistant P.
aeruginosa
“Squeezing the balloon” effect
 Supplemental Antimicrobial
Stewardship Strategies
• Education
• Guidelines and clinical pathways
• Antimicrobial cycling
• Antimicrobial order forms
• Combination therapy
• Streamlining or de-escalation of therapy
• Dose optimization
• Conversion from parenteral to oral therapy
 Antimicrobial cycling and
scheduled antimicrobial switch
“Antimicrobial cycling”
refers to
the removal and substitution of a specific
antimicrobial or antimicrobial class to prevent or
reverse the development of antimicrobial resistance
within an institution or specific unit.
• Substituting one antimicrobial for another may
 transiently decrease selection pressure
 reduce resistance
• But, reintroduction of the original antimicrobial is
again, however, known to develop resistance
• There are insufficient data to recommend the
routine use over a prolonged period of time
 Antimicrobial order forms

• The use of automatic stop orders and the

requirement of physician justification for
continuation
• Decrease antimicrobial consumption in
longitudinal studies
Use of peri-operative prophylactic order forms with
automatic discontinuation at 2 days resulted in a decrease
in the mean duration of antimicrobial prophylaxis
(from 4.9 to 2.4 days)
 Streamlining or
De-Escalation of Therapy
 On the basis of culture and sensitivity
reports we can more effectively target the
causative pathogens, by elimination of
redundant combination therapy
 Resulting in decreased antibiotic exposure
and substantial cost savings
Review by pharmacist & an ID physician of 625 patients
receiving combination antimicrobial therapy led to
streamlining recommendations in 54% of antimicrobial
courses over 7 months, resulting in a projected annual
savings of $107,637.
37
 The Therapy Conundrum

Avoid emergence
of multidrug-resistant
micro-organisms Immediate treatment
of patients with
serious sepsis

Objective 1
Objective 2
 Mortality associated with initial inadequate
therapy in patients with serious infections
Initial adequate therapy
Rello et al
Infection-related mortality Initial inadequate therapy

Kollef et al
Crude mortality
Ibrahim et al
Infection-related mortality

Luna et al
Crude mortality

0 20 40 60 80 100
Mortality (%)
Rello et al. Am J Respir Crit Care Med 1997;156:196–200.
Kollef et al. Chest 1998;113:412–420. Ibrahim et al. Chest 2000;118:146–155; Luna et al. Chest 1997;111:676–685
 Mortality risk with increasing delay in initiation of
effective antimicrobial therapy
Odds ratio of death (95% CI)

100

10

Time (hours)
Kumar, et al. Crit Care Med 2006;34:1589–1596
“The development of new antibiotics
without having mechanisms to
ensure their appropriate use is
much like supplying your alcoholic
patients with a finer brandy.“

Dennis Maki 1998

University of Wisconsin School of

Medicine and Public Health
(SMPH) infectious disease
researcher, physician and
professor