Patrick R. Murray, PhD, F(AAM), F(IDSA)
VP, WW Scientific Affairs
Becton Dickinson Life Sciences
Antimicrobial Resistance:
The Global Response
1
Antimicrobial Resistance
is a Global Problem
Global Prevalence of ESBL CTX-M Strains Doi et al, J Travel Med, 2017
Carbapenem Resistance in Enterobacteriaceae Friedman et al, Infect Control Hosp Epidemiol 2017
Colistin Resistance Sun et al, Trends Microbiol, 2018
Evolution of Antibiotic Resistance
in Gram-Positive Bacteria
Bacteria have shown a remarkable ability to develop
resistance to new antibiotics:
• 1950s – Penicillin was used to treat S. aureus infections;
resistance developed due to penicillinase
• 1970s – Penicillinase-resistant penicillins introduced (e.g.,
methicillin, oxacillin); MRSA strains developed
• 1980s – Vancomycin used to treat MRSA; vancomycin resistance
developed in Enterococcus
• 2000s – Linezolid used to treat MRSA and Enterococcus;
linezolid resistance developed
Evolution of Antibiotic Resistance
in Gram-Negative Bacteria
• 1970s – Ampicillin and 1st generation cephalosporins used to
treat E. coli and Klebsiella; resistance due to TEM and SHV beta-
lactamases
• 1980s and 1990s – 2nd and 3rd generation cephalosporins used
to treat Enterobacteriaceae; resistance to all penicillins and
cephalosporins developed due to extended spectrum beta-
lactamases (ESBLs)
• 1990s and 2000s – ESBL strains treated with carbapenems;
resistance to all beta-lactams developed due to carbapenemases
• Today – Colistin used to treat antibiotic resistant
Enterobacteriaceae, Pseudomonas, and Acinetobacter; colistin
resistance developed
Global Infections with Drug-Resistant Microbes 2017 Organization for Economic Co-operation and Development (OECD) Report
8
Antibiotic Usage by European Country European Centre for Disease Prevention and OECD Health Statistics
9
The 193 countries of the United Nations agreed a landmark
declaration to rid the world of drug-resistant infections or
"superbugs“ BBC News September 21, 2016
Global Pledge to Stamp Out
Drug-resistant Infections
Rio Olympics Pollution
A Global Problem Requiring a Global Solution
10
WHO Global Action Plan on Antimicrobial
Resistance (AMR) – One Health Plan
• Education – educate the medical community and public about
antimicrobial resistance
• Surveillance – monitor AMR globally, regionally, locally
• Infection prevention – prevent transmission from environment,
animals, and patients (asymptomatic and symptomatic)
• Infection control and antibiotic stewardship – optimized use of
antibiotics in human and animal health
• Diagnostics and therapeutics – Increase investments in new
medicines, diagnostics, vaccines, and other interventions; transition
from empiric treatment to directed treatment through the use of
diagnostics
Antibiotic Resistance - Surveillance
Antibiotic Resistance - Surveillance
• Global surveillance programs
– WHO Collaborating Centre for Surveillance of Antimicrobial Resistance
(WHONET)
– UN Interagency Coordination Group on Antimicrobial Resistance (IACG)
– European Antimicrobial Resistance Surveillance Network (EARS-Net)
– EUCAST reports
– Large research collaboratives
• GLASS – Global Antimicrobial Resistance Surveillance System
• AWARE – Assessing Worldwide Antimicrobial Resistance and Evaluation
Antibiotic Resistance - Surveillance
• Global surveillance programs
– WHO Collaborating Centre for Surveillance of Antimicrobial Resistance
(WHONET)
– UN Interagency Coordination Group on Antimicrobial Resistance (IACG)
– European Antimicrobial Resistance Surveillance Network (EARS-Net)
– EUCAST reports
– Large research collaboratives
• GLASS – Global Antimicrobial Resistance Surveillance System
• AWARE – Assessing Worldwide Antimicrobial Resistance and Evaluation
• Regional surveillance programs
– Country-wide programs
Antibiotic Resistance - Surveillance
• Global surveillance programs
– WHO Collaborating Centre for Surveillance of Antimicrobial Resistance
(WHONET)
– UN Interagency Coordination Group on Antimicrobial Resistance (IACG)
– European Antimicrobial Resistance Surveillance Network (EARS-Net)
– EUCAST reports
– Large research collaboratives
• GLASS – Global Antimicrobial Resistance Surveillance System
• AWARE – Assessing Worldwide Antimicrobial Resistance and Evaluation
• Regional surveillance programs
– Country-wide programs
• Local surveillance programs
– Hospital antibiograms
– Published community records
Education and Surveillance
• In the last 2 years, I have worked on AMR programs in
countries in Asia including China, Western and Eastern
Europe, the Middle East, and North and South America; all
have initiated educational programs and country-wide
surveillance programs.
• Many of the surveillance programs are not comprehensive
and are not integrated with specific antibiotic stewardship
programs.
• In general, the programs do not have well-defined, realistic
goals for impacting the development and spread of resistant
bacteria and fungi.
• Targeted goals and metrics to assess progress are needed for
all AMR programs.
Infection Prevention and Control
Infection Prevention and Control
• Goal: Reduce the risk of transmission of pathogens from
both recognized and unrecognized sources
Infection Prevention and Control
• Goal: Reduce the risk of transmission of pathogens from
both recognized and unrecognized sources
• Unrecognized carriers of resistant organisms are the
most common source of patient-to-patient transmission
in the hospital
15
Infection Prevention and Control
• Goal: Reduce the risk of transmission of pathogens from
both recognized and unrecognized sources
• Unrecognized carriers of resistant organisms are the
most common source of patient-to-patient transmission
in the hospital
Infection Prevention and Control
• Goal: Reduce the risk of transmission of pathogens from
both recognized and unrecognized sources
• Unrecognized carriers of resistant organisms are the
most common source of patient-to-patient transmission
in the hospital
• Prevention and control requires a comprehensive
program:
– Assess risk of infection
– Establish hospital guideline policies
– Monitor compliance
– Enforce policies
Antimicrobial Stewardship
17
• Antibiotic stewardship in the hospital setting is necessary
to (1) prevent the overuse of antibiotics, (2) inappropriate
treatment of infected patients, and (3) selection of
antibiotic resistant bacteria
Antimicrobial Stewardship
17
• Antibiotic stewardship in the hospital setting is necessary
to (1) prevent the overuse of antibiotics, (2) inappropriate
treatment of infected patients, and (3) selection of
antibiotic resistant bacteria
• Antibiotic resistance is increasing in an era when
alternative drugs are not available and relatively few are
in development
Antimicrobial Stewardship
17
• Antibiotic stewardship in the hospital setting is necessary
to (1) prevent the overuse of antibiotics, (2) inappropriate
treatment of infected patients, and (3) selection of
antibiotic resistant bacteria
• Antibiotic resistance is increasing in an era when
alternative drugs are not available and relatively few are
in development
• Traditional manual and automated antibiotic
susceptibility tests may be inadequate in detecting all
resistant organisms (e.g., resistance to carbapenems
and colistin)
Antimicrobial Stewardship
17
• Antibiotic stewardship in the hospital setting is necessary
to (1) prevent the overuse of antibiotics, (2) inappropriate
treatment of infected patients, and (3) selection of
antibiotic resistant bacteria
• Antibiotic resistance is increasing in an era when
alternative drugs are not available and relatively few are
in development
• Traditional manual and automated antibiotic
susceptibility tests may be inadequate in detecting all
resistant organisms (e.g., resistance to carbapenems
and colistin)
• Rapid molecular tests can provide sensitive methods for
detecting colonized patients.
Antimicrobial Stewardship
17
Antimicrobial Stewardship Program – collaborative,
coordinated program of intervention designed to improve
antimicrobial prescribing (right drug, dose, duration and
route of administration) to optimize clinical outcomes while
minimizing unintended consequences of antimicrobials
such as toxicity, selection of pathogenic organisms, and
emergence of resistance.
19
Antibiotic Stewardship Guidelines: 2016 A focused Approach
19
Antibiotic Stewardship Guidelines: 2016 A focused Approach
• Targeted antibiotics such as those that treat emerging
drug-resistant bacterial infections, should require
preauthorization.
19
Antibiotic Stewardship Guidelines: 2016 A focused Approach
• Targeted antibiotics such as those that treat emerging
drug-resistant bacterial infections, should require
preauthorization.
• Syndrome-specific interventions – focused multifaceted
interventions for the treatment of specific syndromes,
rather than trying to improve treatment of all infections.
19
Antibiotic Stewardship Guidelines: 2016 A focused Approach
• Targeted antibiotics such as those that treat emerging
drug-resistant bacterial infections, should require
preauthorization.
• Syndrome-specific interventions – focused multifaceted
interventions for the treatment of specific syndromes,
rather than trying to improve treatment of all infections.
• Rapid diagnostic testing – rapid testing of blood cultures or
respiratory cultures can lead to specific, directed therapy.
CDC Guidance on Antimicrobial Stewardship
20
CDC Guidance on Antimicrobial Stewardship
20
1. Leadership commitment – antibiotic stewardship involves many –
physicians, pharmacists, nurses, and administrators
CDC Guidance on Antimicrobial Stewardship
20
1. Leadership commitment – antibiotic stewardship involves many –
physicians, pharmacists, nurses, and administrators
2. Accountability – a single leader must be responsible for program
outcomes
CDC Guidance on Antimicrobial Stewardship
20
1. Leadership commitment – antibiotic stewardship involves many –
physicians, pharmacists, nurses, and administrators
2. Accountability – a single leader must be responsible for program
outcomes
3. Drug expertise – a single pharmacist must be appointed to lead
initiatives to improve antibiotic use among patients
CDC Guidance on Antimicrobial Stewardship
20
1. Leadership commitment – antibiotic stewardship involves many –
physicians, pharmacists, nurses, and administrators
2. Accountability – a single leader must be responsible for program
outcomes
3. Drug expertise – a single pharmacist must be appointed to lead
initiatives to improve antibiotic use among patients
4. Action – implement at least 1 recommended action with the goal of
improving antimicrobial use
CDC Guidance on Antimicrobial Stewardship
20
1. Leadership commitment – antibiotic stewardship involves many –
physicians, pharmacists, nurses, and administrators
2. Accountability – a single leader must be responsible for program
outcomes
3. Drug expertise – a single pharmacist must be appointed to lead
initiatives to improve antibiotic use among patients
4. Action – implement at least 1 recommended action with the goal of
improving antimicrobial use
5. Tracking – monitor antibiotic resistance and antibiotic prescribing
patterns
CDC Guidance on Antimicrobial Stewardship
20
1. Leadership commitment – antibiotic stewardship involves many –
physicians, pharmacists, nurses, and administrators
2. Accountability – a single leader must be responsible for program
outcomes
3. Drug expertise – a single pharmacist must be appointed to lead
initiatives to improve antibiotic use among patients
4. Action – implement at least 1 recommended action with the goal of
improving antimicrobial use
5. Tracking – monitor antibiotic resistance and antibiotic prescribing
patterns
6. Reporting – regular reports of information on antibiotic resistance
and prescribing practices
CDC Guidance on Antimicrobial Stewardship
20
1. Leadership commitment – antibiotic stewardship involves many –
physicians, pharmacists, nurses, and administrators
2. Accountability – a single leader must be responsible for program
outcomes
3. Drug expertise – a single pharmacist must be appointed to lead
initiatives to improve antibiotic use among patients
4. Action – implement at least 1 recommended action with the goal of
improving antimicrobial use
5. Tracking – monitor antibiotic resistance and antibiotic prescribing
patterns
6. Reporting – regular reports of information on antibiotic resistance
and prescribing practices
7. Education – educate physicians about resistance and optimal
prescribing
Diagnostic Test Stewardship
21
• Selection of empiric antimicrobial therapy is associated
with increased costs and poor patient outcomes.
Diagnostic Test Stewardship
21
• Selection of empiric antimicrobial therapy is associated
with increased costs and poor patient outcomes.
• Directed therapy requires guidance with timely, accurate
diagnostic tests.
Diagnostic Test Stewardship
21
• Selection of empiric antimicrobial therapy is associated
with increased costs and poor patient outcomes.
• Directed therapy requires guidance with timely, accurate
diagnostic tests.
• An accurate test requires collection of the right
specimen, rapid transit to the laboratory, and skilled
processing of the culture or other diagnostic test.
Diagnostic Test Stewardship
21
• Selection of empiric antimicrobial therapy is associated
with increased costs and poor patient outcomes.
• Directed therapy requires guidance with timely, accurate
diagnostic tests.
• An accurate test requires collection of the right
specimen, rapid transit to the laboratory, and skilled
processing of the culture or other diagnostic test.
• It is important for the laboratory to adopt workflow
practices that ensure accurate diagnostic testing and
timely communication of results
Diagnostic Test Stewardship
21
• Evaluated 70 clinical trials that assessed mortality in patients receiving antibiotic therapy for sepsis
• 46.5% of the patients received inappropriate therapy and 36% of these patients died
• There was more than a 2-fold increased risk of mortality with inappropriate therapy
22
• Meta-analysis of 60 publications assessing the impact of antibiotic therapy on gram-negative sepsis
• Inappropriate therapy was associated with 3.3-fold increased risk of mortality and higher costs including longer hospitalization and increased antibiotic usage
Barriers Contributing to Under-utilization
of Diagnostic Tests
Barriers Contributing to Under-utilization
of Diagnostic Tests
• Lack of timely reporting of diagnostic test results
• Over the counter access to antimicrobials
• Diagnostics not consistently used to modify
empiric therapy
• Labs fail to use best diagnostic practices such
as 2-3 blood culture sets.
Barriers Contributing to Under-utilization
of Diagnostic Tests
• Lack of timely reporting of diagnostic test results
• Over the counter access to antimicrobials
• Diagnostics not consistently used to modify
empiric therapy
• Labs fail to use best diagnostic practices such
as 2-3 blood culture sets.
• Value of diagnostics may not be appreciated by
health care systems
– Inadequate laboratory budget
– Difficulty in quantitating patient benefits and
hospital financial savings
– Lack of reimbursement
US National Action Plan
Goal 1. Slow the Emergence and Prevent the Spread of
Resistant Bacteria
Goal 2. Strengthen National One-Health Surveillance Efforts to
Combat Resistance
Goal 3. Advance Development and Use of Rapid and Innovative
Diagnostic Tests
Goal 4. Accelerate Research and Development for New
Antibiotics, Other Therapeutics, and Vaccines
Goal 5. Improve International Collaboration and Capacities for
Antibiotic Resistance Prevention, Surveillance, and Control
Goals of the US National Action Plan
26
Goal 1. Slow the Emergence and Prevent the Spread of
Resistant Bacteria
1. Implement programs that advance antibiotic-resistance
prevention and foster antibiotic stewardship in healthcare
settings and community
2. Eliminate the use of medically important antibiotics for growth
promotion in food-producing animals and provide oversight
for in-feed and in-water uses of antibiotic
3. Identify and implement measures to foster stewardship of
antibiotics in animals
Goals of the National Action Plan
27
• In 2015, 21,000 tons of antibiotics were used in the United
States.
– 17,200 tons (81.7%) were used in animals
– The bulk of antibiotics were put into food and water to
prevent disease and promote growth; only a small
portion was used to treat disease
– Most antibiotics used in animals are purchased over-
the-counter
Antibiotic Use and Resistance
28
• In 2014, USDA issued their action plan to address antimicrobial resistance
Antibiotic Use and Resistance
29
• In 2014, USDA issued their action plan to address antimicrobial resistance
– Objective 1: Determine and model patterns, purposes, and impacts of antibiotic use in food-producing animals
– Objective 2: Monitor antibiotic drug susceptibilities of selected bacterial organisms in food-producing animals
– Objective 3: Identify feasible management practices, alternatives to antibiotic use, and other mitigations to reduce AMR associated with food-producing animals and their production environments
Antibiotic Use and Resistance
29
• In 2014, USDA issued their action plan to address antimicrobial resistance
– Objective 1: Determine and model patterns, purposes, and impacts of antibiotic use in food-producing animals
– Objective 2: Monitor antibiotic drug susceptibilities of selected bacterial organisms in food-producing animals
– Objective 3: Identify feasible management practices, alternatives to antibiotic use, and other mitigations to reduce AMR associated with food-producing animals and their production environments
• In 2017, the FDA ban use of antibiotics for growth promotion and placed all other use of antibiotics (disease prevention, disease treatment) under the guidance of a veterinarian.
Antibiotic Use and Resistance
29
Goal 2. Strengthen National One-Health Surveillance Efforts to
Combat Resistance
1. Create a regional public health laboratory network to strengthen
national capacity to detect resistant strains, and create a specimen
repository
2. Expand public health surveillance and data reporting, and provide
incentives for reporting of antibiotic-resistance and antibiotic use in
all healthcare settings
3. Develop, expand, and maintain capacity in veterinary and food
safety laboratories to conduct antibiotic susceptibility testing and
characterize zoonotic and animal pathogens
4. Enhance monitoring of antibiotic-resistance patterns, as well as
antibiotic sales, usage, and management practices in the
production chain for food animals and retail meat
Goals of the National Action Plan
30
CDC Antibiotic Resistance (AR) Lab Network
31
National targets for 2020:
• Reduce by 50% the incidence of C. difficile infections compared to 2011
• Reduce by 60% carbapenem-resistant Enterobacteriaceae infections during hospitalization
• Reduce by 35% multidrug-resistant Pseudomonas infections compared to 2011
• Reduce by 50% MRSA bloodstream infections compared to 2011
• Reduce by 25% multidrug-resistant nontyphoidal Salmonella infections compared to 2011
• Reduce by 15% multidrug-resistant M. tuberculosis infections
National Action Plan for Combating Antibiotic-Resistant Bacteria
32
Summary
Summary
• Antimicrobial resistance poses a major global healthcare
problem that will impact on the viability of the healthcare system.
Summary
• Antimicrobial resistance poses a major global healthcare
problem that will impact on the viability of the healthcare system.
• Each country must develop a National Action Plan consisting of:
– Education
– Surveillance
– Infection prevention and control
– Antibiotic stewardship
– Diagnostic stewardship
Summary
• Antimicrobial resistance poses a major global healthcare
problem that will impact on the viability of the healthcare system.
• Each country must develop a National Action Plan consisting of:
– Education
– Surveillance
– Infection prevention and control
– Antibiotic stewardship
– Diagnostic stewardship
• The components of the plan are inter-dependent so they must
be developed in a coordinated way rather than sequential.
Summary
• Antimicrobial resistance poses a major global healthcare
problem that will impact on the viability of the healthcare system.
• Each country must develop a National Action Plan consisting of:
– Education
– Surveillance
– Infection prevention and control
– Antibiotic stewardship
– Diagnostic stewardship
• The components of the plan are inter-dependent so they must
be developed in a coordinated way rather than sequential.
• Each component should be focused on specific identified
problems associated with the development and spread of AMR.
Summary
• Antimicrobial resistance poses a major global healthcare
problem that will impact on the viability of the healthcare system.
• Each country must develop a National Action Plan consisting of:
– Education
– Surveillance
– Infection prevention and control
– Antibiotic stewardship
– Diagnostic stewardship
• The components of the plan are inter-dependent so they must
be developed in a coordinated way rather than sequential.
• Each component should be focused on specific identified
problems associated with the development and spread of AMR.
• The success of the program should be measured by specific
metrics including patient outcomes and hospital costs.