Transcript Selective Pressures- Antimicrobial Use and Resistance

New Antibiotic Availability and
Usage
Lennox K. Archibald, MD, PhD, FRCP, DTM&H
Hospital Epidemiologist
Shands Hospital
University of Florida
Disclosures
None
No conflict of interest
“As we face the new millennium, we must
renew our commitment to the prevention
and control of infectious diseases,
recognizing that the competition between
humans and microbes will continue long
past our lifetimes and those of our
children.”
Jeffrey P. Koplan, Director, CDC
...no man is an island, entire of
itself; every man is a piece of the
continent, a part of the main...
(From “Devotions” by John Donne (15721631)
Antimicrobial Resistance
• World-wide problem
• Major risk factors
–Antimicrobial use (misuse)
–Infection control practices
(non-compliance)
Antimicrobial Resistance:
Vulnerable Patient Populations
• Elderly
• Immunosuppressive Rx
• Organ transplant
• Malignancy
• HIV / AIDS
• Diabetes
• Chronic renal disease
• Pregnant women
• Infants and children
• Alcohol / substance use
• Chronic lung disease
• Chronic heart disease
• Other chronic illnesses
Antimicrobial Resistance
in the U.S.
• >2 million hospitalized patients
•
•
•
affected per year
>90,000 deaths per year
85% bacterial pathogens
70% pathogens resistant to >1
agent
Definition of Emerging Infections
...."Emerging infections are defined as "new, reemerging or drug-resistant infections whose
incidence in humans has increased within the
past two decades or whose incidence threatens
to increase in the near future." A number of
factors were identified as reasons why emerging
infections are a modern-day reality; no one
factor could account for the problem".....
Reference: Lederberg J, Shope RE, Oaks SC, eds. Emerging infections:
microbial threats to health in the United States. Washington, DC: National
Academy Press, 1992
Selective Pressures- Antimicrobial
Use and Resistance
Fruit
Animal
husbandry
Foreign
travel
Outpatient
care
Daycare
Fisheries
Hospitals
Marine
paint
Where do we stand at the
moment?
Rates of Resistance Versus
Rates of Infection
• Over past decade, CDC has documented
downward trend in infection rates in four major
anatomic sites:
– Bloodstream
– Respiratory tract
– Urinary tract
– Wounds
• At same time, infection rates due to resistant
pathogens are increasing
“For as long as CDC has
measured the prevalence of
hospital-acquired infections
caused by multidrug-resistant
organisms, it has been
increasing.”
Muto CA. Infect Control Hospital
Epidemiol 2005; 26:10-12.
Trend in licensed hospital beds,
NNIS Hospitals
P <0.01
Archibald et al.
Clin Infect Dis. 1997 Feb;24(2):211-5.
ICU beds
Hospital
beds
CDC Data
What are the sentinel bugs?
Distribution of the most common HA pathogens isolated from
the four major infection sites, ICU, NNIS hospitals, 1990-1998
16%
13%
12%
10%
9%
40%
18%
17%
11%
7%
5%
42%
Enterococcus sp.
CoNS*
S. aureus
SSI
P. aeruginosa
7%
Enterobacter sp.
Other
OTHER
22%
S. aureus
P. aeruginosa
Enterobacter sp.
K. pneumoniae
Acinetobacter sp.
Other
BSI
17%
UTI
23%
PNEU
31%
*coagulase-negative staphylococcus
37%
14%
13%
5%
5%
26%
CoNS*
Enterococcus sp.
S. aureus
Candida albicans
Enterobacter sp.
Other
18%
16%
14%
11%
6%
35%
Escherichia coli
Candida albicans
Enterococci
P. aeruginosa
K. pneumoniae
Other
Seven Pathogens Associated with 66%
Hospital-Acquired Infections

Increasing resistance over past 20 years
Pathogen
Percentage*
(n=101,821)
Staphylococcus aureus
13
Escherichia coli
12
Coagulase-negative staphylococci
11
 Enterococcus spp.
10
Pseudomonas aeruginosa
9
Enterobacter spp.
6
 Klebsiella pneumonia
5
Total
Resistance
methicillin
ampicillin
methicillin
vancomycin
imipenem
ceftazidime
ceftazidime
66%
Source: All sites of nosocomial infection, Hospital-wide Component, National
Nosocomial Infection Surveillance System, January to March 1996:
Am J Infect Control 1996:24;380-8
Sentinel Bug/Drug Combinations of
Public Health Significance
(Healthcare Settings)
• Staphylococcus aureus---methicillin
• Enterococcus spp.---vancomycin
• Pseudomonas aeruginosa---3rd generation
cephalosporins (3rd GC)
• Pseudomonas aeruginosa/Imipenem
• Escherichia coli & other GNR/3rd GC
• GNR/Quinolones
Sentinel Bug/Drug Combinations
of Public Health Significance
(Community)
• Staphylococcus aureus/methicillin
group penicillins
• Streptococcus pneumoniae/penicillin
• Salmonella spp./ Quinolones
• Relevant to outpatient, freestanding
centers, LTCF, homecare
Hospital-associated Pneumonia:
Pathogens
•
•
•
•
•
S. aureus:
P. aeruginosa
Enterobacter spp.
K. pneumoniae
Acinetobacter spp.
18%
17%
11%
7%
5%
Methicillin-resistant S. aureus (MRSA)
Infections in NNIS Hospitals, by ICU Status,
1986-1998
60
% resistant
50
> 500 beds
< 500 beds
87
90
40
30
20
10
0
86
88
89
91
92
93
94
95
96
97
98
80
70
60
50
40
30
20
10
0
Year
20
04
20
03
20
02
20
01
20
00
19
99
19
98
19
97
``
19
96
19
95
Percent Resistance
Methicillin (oxacillin)-resistant
Staphylococcus aureus (MRSA) among
ICU patients, 1995-2004
Source: National Nosocomial Infections Surveillance (NNIS)
System
World-wide Prevalence of MRSA by Country
Lancet 2006; 368:876
Vancomycin-resistant Enterococcal
(VRE) Infections in NNIS Hospitals
25
% resistant
20
ICU
Non-ICU
15
10
5
0
89
90
91
92
93
94
95
96
97
98
Vancomycin-resistant Enterococci
among ICU patients,
1995-2004
Percent Resistance
35
30
25
20
15
10
5
20
04
20
03
20
02
20
01
20
00
19
99
19
98
19
97
19
96
19
95
0
Year
Source: National Nosocomial Infections Surveillance (NNIS) System
Independent Predictors* of Vancomycin-Resistant
Enterococci in Adult Intensive Care Units
Change in Predictor
Estimated Change in
Rate of VRE
P-value
Non-ICU VRE rate
+++
0.0001
Cephalosporin use (3rd)
(in all unit types)
++
0.0002
Vancomycin use
++
0.0001
Type of ICU
+
* Preliminary Logistic Regression analysis (n=75) controlling for
each factor, plus ICU “A” or “B”
Source: NNIS/ICARE (preliminary)
0.01
Use of Vancomycin in U.S.*, and VRE
at NNIS** Hospitals
U.S. Hospitals
All NNIS Hospitals
20
100
15
80
60
10
40
5
20
0
% vancomycinresistant
enterococci
Kilograms of
vancomycin (x100)
purchased*
120
0
84 85 86 87 88 89 90 91 92 93 94 95 96 97
Year
* Kirst et al., Historical usage of vancomycin Antimicrob Agents
Chemo 1998:1203-4
** National Nosocomial Infections Surveillance System (CDC)
20
04
20
03
20
02
20
01
20
00
19
99
19
98
19
97
19
96
40
35
30
25
20
15
10
5
0
19
95
Percent Resistance
Fluoroquinolone-resistant
Pseudomonas aeruginosa among ICU
patients, 1995-2004
Year
Source: National Nosocomial Infections Surveillance (NNIS)
System
3rd generation cephalosporin-resistant
Klebsiella pneumoniae among ICU
Patients,1995-2004
Percent Resistance
30
25
20
15
10
5
Year
Source: National Nosocomial Infections Surveillance
(NNIS) System
20
04
20
03
20
02
20
01
20
00
19
99
19
98
19
97
19
96
19
95
0
Extended Spectrum -lactamases (ESBLs)
Risk Factors for Colonization/Infection*
•
•
•
•
•
•
Hospitalization
Nursing home residency
Length of hospital/ICU stay
Severity of illness
Antibiotic exposure (esp. ceftazidime,
aztreonam)
Invasive devices/instrumentation
18
16
14
12
10
8
6
4
2
0
Year
19
97
19
96
19
95
19
94
19
93
19
92
19
91
ICU
19
90
19
89
Percent Resistance
Imipenem-Resistant P. aeruginosa
Infections/10,000 pt-days
6.5
6
5.5
5
4.5
P <.01
4
3.5
3
2.5
1985
Archibald et al.
JID 2005
1990
1995
Year
2000
20
04
20
03
20
02
20
01
20
00
19
99
19
98
19
97
19
96
40
35
30
25
20
15
10
5
0
19
95
Percent Resistance
Fluoroquinolone-resistant Pseudomonas
aeruginosa among ICU patients,
1995-2004
Year
Source: National Nosocomial Infections Surveillance (NNIS) System
3rd generation cephalosporin-resistant
Klebsiella pneumoniae Among ICU
Patients,1995-2004
Percent Resistance
30
25
20
15
10
5
20
04
20
03
20
02
20
01
20
00
19
99
19
98
19
97
19
96
19
95
0
Year
Source: National Nosocomial Infections Surveillance
(NNIS) System
Rate of Antimicrobial Use in Adult Intensive Care Unit
(ICU) Areas (n=108) and non-ICU Areas (n=40)
Defined Daily Doses/1000
patient-days
180
Non-ICU inpatient
160
ICU
140
120
P <0,05
Wilcoxon rank
sum
100
80
60
40
20
0
3G
C
Source: ICARE Phase 2
VA
NC
O
PIP
IMI
FQ
NL
Hospital-Associated
Pneumonia
• Leading cause of ICU antimicrobial
prescribing
Resistant Pathogens
Community-acquired
•
•
•
•
•
•
•
•
•
Streptococcus pneumoniae
Salmonella
Shigella
Gonococci
Haemophilus influenzae
Mycobacterium tuberculosis
Staphylococcus aureus
***HIV***
Malaria
The Reality?
The Best of Times
• Over 100 antimicrobial agents available
in the U.S.
• New antifungals and antivirals
• DNA probes and PCR provide
accurate laboratory diagnosis of
infections in hours
However…
• No new classes of agents 1968-2000
• Since 2000, only 3 new classes
approved by FDA—effective largely
against MRSA &VRE: streptogramins,
linezolid, daptomycin
• Apart from tigecycline, no new class of
agents against Gram-negative
organisms
The Worst of Times
• New pathogens continue to emerge
• Resistance continues to increase: bacteria,
fungi, viruses, and parasites
• Reports of MRSA from community settings
• Pressures to reduce laboratory costs are
curtailing diagnostic services
• Not much new for gram negative infections
Other Emerging Gram-negative
pathogens
• Acinetobacter spp.
• Stenotrophomonas spp.
• Extended spectrum beta-lactamase
producing pathogens:
– Enterobacter cloacae
– Klebsiella pneumoniae
• Carbapenemase-producing Klebsiella
pneumoniae
Resistant Pathogens
Community-acquired
•
•
•
•
•
•
•
•
•
Streptococcus pneumoniae
Salmonella
Shigella
Gonococci
Haemophilus influenzae
Mycobacterium tuberculosis
Staphylococcus aureus
***HIV***
Malaria
Emergence of Multidrug Resistance
in S. pneumoniae
• 1930s:
• 1940s:
Sulfonamide / sulfa drugs discovered & used
PCN introduced for Rx
• 1943:
• 1967:
First sulfa-resistant clinical isolate reported
First PCN-resistant clinical isolate reported
(New Guinea)
• 1977:
Outbreak of multi-drug resistant
pneumococci
(South Africa)
• 1990s: Global spread of resistant pneumococci
Gram-negative Pathogens
• 1986 through 2003: 65% of pneumonia
episodes
• Proportion of Acinetobacter spp.
pneumonias increased from 4% in 1986
to >7.0% in 2003
Why Are Gram-negative Infections
Increasing?
• Adhere to host tissue via microbial
adhesions
• Interact with receptors on mucosal
surfaces
• Adhesin/receptor interactions define
bacterial populations
Why Are Gram-negative Infections
Increasing?
• Changes in adhesins associated with
resistant microorganisms or their
interactions
• Hence the underlying role of antimicrobial
use!!
• Thus, control must include control of
antimicrobial use in ICUs
Antimicrobial Resistance Issues in
Developing Countries
• Unnecessary intensive care units
• Indiscriminate antimicrobial use
– Blind empiricism
– Unnecessary prophylaxis
• Inability to detect true resistance
– Enhancement of laboratory capacity
– Quality assurance (costly)
The Action of Antimicrobial
Drugs
Figure 20.2
Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis
• Penicillins
• Cephalosporins
–2nd, 3rd, and 4th generation
–Generally more effective against gramnegatives
• Vancomycin (glycopeptide): important "last
line" against antibiotic resistant S. aureus
Antibacterial Antibiotics
Inhibitors of Protein Synthesis
•
•
•
•
Chloramphenicol
Aminoglycosides
Tetracyclines
Macrolides (erythromycin)
Antibacterial Antibiotics
Injury to the Plasma Membrane
• Polymyxin B
–Topical
–Combined with bacitracin and neomycin
in over-the-counter preparation
Antibacterial Antibiotics
Inhibitors of Nucleic Acid Synthesis
• Quinolones and fluoroquinolones
• Ciprofloxacin
Antibacterial Antibiotics
Competitive Inhibitors
• Sulfonamides (Sulfa drugs)
• Inhibit folic acid synthesis
• Broad spectrum
Figure 5.7
Linezolid
Linezolid (I)
• Oxazolidinone—synthetic
• FDA approval—April 2000
• Unique mechanism of action—
inhibition of bacterial ribosome RNA
assembly complex
• No other agent inhibits this process
• No cross-resistance with other
antibiotics
Linezolid (II)
• All major pathogenic gram-positive
bacteria susceptible in vitro
• Development of resistance rare but
has occurred in pts who received longterm therapy
• 2001: Staphylococcus aureus
resistance reported
Linezolid (III)
• FDA approval:
–VRE bacteremias, community and
healthcare-associated pneumonias,
infections of the skin
Daptomycin
Daptomycin (I)
• New lipopeptide agent
• FDA approval—2003
• Distinct mechanism of action—
disrupts multiple aspects of bacterial
cell membrane function
Daptomycin (II)
• Binds to membrane and causes rapid
depolarization, leading to inhibition of
protein, DNA, and RNA synthesis
• Active against gram-positive
microorganisms
• Bactericidal
• Resistance rare (no cross resistance)
Tigecycline
Tigecycline (I)
• Novel glycylcycline—related to
tetracycline
• FDA approval: 2005
• Binds to bacterial ribosomes that
produce cell’s proteins
• Active against gram-positive and
gram-negative microorganisms
Tigecycline (II)
• Prevents multiplication but does not kill
the bacterium—bacteriostatic
• Active against some strains of
Acinetobacter
• Not active against Pseudomonas or
Proteus
• Licensed for skin, soft tissue, and intraabdominal infections
Synercid
Streptogramins (I)
• Quinopristin-dalfopristin—a 30/70 drug
combination of two semisynthetic
derivatives of pristinamycin
• Dalfopristin inhibits the early phase of
protein synthesis in the bacterial ribosome
and quinupristin inhibits the late phase
• Combination of the two components acts
synergistically
Streptogramins (I)
• 2000: first agent approved by FDA for
treatment of patients with serious VRE
infections
• Toxic—used less frequently today
Streptogramins (II)
• Bactericidal for streptococci and
staphylococci
• Inhibitory for enterococcus
• Resistance common—up to 30%
patients with Enterococcus faecium
infection
• Not effective against E. faecalis
Antimicrobial Use
• Prophylaxis
• Empiric
• Definitive
Prophylaxis
• Medical
– Exposure to virulent pathogen
– Endocarditis (dental)
– Immunocompromised
– HIV with CD4 < 200
– Asplenia
– Neutropenia
• Surgical (emergency and elective
procedures)
Duration of Therapy
• Not well defined!
– Usually less than 14 days!
– Longer for endocarditis, osteomyelitis,
• Prostatitis (varies by bug & drugs)
• Endometritis: until afebrile 24-48 hrs
• Track number of days of therapy in progress
notes & set endpoint!
• Prolonged unnecessary therapy increases risk
of resistance, adverse effects, and cost!
What do we do?
Prevention and Control Strategies
for the New Millennium
 Hand hygiene
 Aggressive infection
control
 Antimicrobial Use
Strategies to Optimize Antimicrobial
Use in Hospitals







Education of prescribers
Guidelines
Antimicrobial formulary restrictions
Pharmacy justification
Formulary substitution or switch (IV to oral)
Computer surveillance
Multidisciplinary approach
Reality
• Decades of discussing control of
antimicrobial-resistant nosocomial
pathogens
• Little evidence of control in most
healthcare facilities
• Myriad articles published: have helped
explain this failure
Why Spiraling out of Control?
• Variation in surveillance activities
• Inconsistent use of effective control
measures—e.g., surveillance
cultures not being performed
• Frequent failure of hospitals to use
effective measures---reasons??
Why Spiraling out of Control?
• Moderate compliance with goals to
optimize antimicrobial use, and to
detect, report, and control the
spread of antimicrobial resistant
pathogens
• Efforts to control antimicrobial use
insufficient in many U.S. hospitals
i.e., no man is an island!
Active Surveillance
• Active surveillance cultures for VRE and
MRSA in ICUs with isolation of persons
colonized—highly effective strategy
• Isolation purely on the basis of history of
previous detection of VRE or MRSA appears to
be of little benefit
• Standard precautions and isolation of
occasional patient recognized to be colonized
through routine clinical cultures are minimally
effective
CDC has not provided any evidencebased data that show standard
precautions and passive surveillance
will suddenly start controlling the spread
of MRSA, VRE, and other nosocomial
pathogens
Optimizing Use and Reducing
Resistance
“National
guidelines seldom are studied
thoroughly by physicians, and, if they
are read, they rarely are incorporated
into everyday practice”
• Goldman, Weinstein, Wenzel et al., Strategies to prevent
and control the emergence and spread of antimicrobial
resistant microorganisms in hospitals. A challenge to
hospital leadership. JAMA 1996;275:234-240
Optimizing Use and Reducing
Resistance
“Success depends on the hospital
leadership ---members of the board, the
executive administrative staff, and
physician opinion leaders --- making the
campaign against antimicrobial resistance
a strategic priority… under the aegis of the
hospital’s overall efforts to improve quality”
– Goldman, Weinstein, Wenzel et al, JAMA
1996;275:234-240
Optimal Antimicrobial Use
 “Appropriate antimicrobial stewardship that
includes optimal selection, dose, and
duration of treatment, as well as control of
antibiotic use, will prevent or slow the
emergence of resistance among
microorganisms”
- SHEA/IDSA Guidelines. Infect Control
Hosp Epidemiol 1997;18:275-91
Antimicrobial Stewardship
What is the role of the ICP?
• Sharing epidemiologic data
• Area of institution on which to focus
• Establishing outcomes following
interventions
• What about cycling of antimicrobials?
• Use of antimicrobials as growth
promoters in animals (chicken and
pork colonized with VRE)?
• Agricultural produce (e.g.,
Enterococcus spp. with multiple-drugresistance patterns isolated from
fresh produce)?
What about Routine Cycling?
• Insufficient study to determine any
meaningful impact on resistance
• Mathematical models question
usefulness of cycling in infection control
• Crit Care Med 2004; 32:2450-56. Warren
et al showed that cycling did not result in
significant change in enteric acquisition of
Gram-negative bacteria in ICU patients
What About Antimicrobial Growth
Promoters (AGP)?
• EU has withdrawn as AGP some
compounds that remain in use in the US
• This difference in availability allows
comparisons to be made of AR outcomes
with and without use of AGP
• Thus far, little apparent benefit to human
health resulting from EU removal of AGP
acquisition of GN bacteria in ICU patients
Fresh Agricultural Produce?
The role of foods in the transmission
of antibiotic-resistant strains to
human populations in the US is yet
to be elucidated
Take Home Message
• Much published data on infections due to
antimicrobial-resistant pathogens carried out in
hospitals with:
– Untried control programs
– Substantially ineffective programs
• Lack of gold standard evidence to support
controlled trials of interventions
• Growing evidence that programs described in
SHEA Guidelines are effective and costeffective
McGeer A. ICHE 2004; 25:97-98
Take Home Message
• In North America, we don’t pay attention
to new approaches (c.f. Europe)
• Healthcare professionals and healthcare
administrators unwilling to invest
intelligently in prevention
• Death and morbidity often regarded as
unavoidable
McGeer A. ICHE 2004; 25:97-98
Take Home Message
• Infection control practitioners need to play
a greater role on antimicrobial stewardship
programs
– Areas to focus
– Compliance
– Outcomes
– Epidemiologic data
Thank you!
“Learning is like rowing upstream; not to
advance is to fall back” (Chinese Proverb)
"Knowing is not enough; we must apply.
Willing is not enough; we must do."
—Johann Wolfgang von Goethe, German poet
(1749-1832)
Thank you
[email protected]
Questions?
Lennox K. Archibald, MD, PhD, FRCP, DTM&H
[email protected]
So, how do we address these emerging
Gram-negative pathogens?
• Acinetobacter spp.
• Stenotrophomonas spp.
• Extended spectrum beta-lactamase
producing pathogens:
– Enterobacter cloacae
– Klebsiella pneumoniae
• Carbapenemase-producing Klebsiella
pneumoniae