AS Microbiology and Antibiotic Resistance Sep 2012

Report
Antibiotic Resistance and Its
Relationship to Antibiotic Use
Antibiotic Stewardship
Curriculum
Developed by:
Vera P. Luther, M.D.
Christopher A. Ohl, M.D.
Wake Forest School of Medicine
With Support from the Centers for
Disease Control and Prevention
Objectives
1. Define antibiotic susceptibility, antibiotic resistance
and breakpoint
2. List four methods for determining antibiotic
susceptibility
3. Discuss factors that contribute to antibiotic
resistance
4. List five bacterial resistance mechanisms and the
antibiotic classes each affects
5. Understand the clinical implications of antibiotic
resistance for Staphylococcus aureus, Streptococcus
pneumoniae and gram-negative organisms
Outline
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Introduction
Key Terms
Susceptibility Testing Methods
Factors Contributing to Antibiotic Resistance
Mechanisms of Resistance
Clinical Examples
Conclusion
Introduction
• Since the first use of antibiotics in the 1930s
and 1940s, bacteria quickly adapted and
developed mechanisms to escape their effects
• Over the following decades, new antibiotics
were developed to overcome resistance
• Since the 1990s, new antibiotic development
has fallen sharply while bacterial resistance
continues to increase
• Antibiotic resistance is responsible for
countless human deaths and billions of dollars
in healthcare expenses
Introduction
Resistance Beyond Typical Bacteria
• Imidazole-resistant Candida spp.
• Multidrug-resistant tuberculosis
• Multidrug-resistant malaria
• Anti-viral resistant influenza
Outline
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Introduction
Key Terms
Susceptibility Testing Methods
Factors Contributing to Antibiotic Resistance
Mechanisms of Resistance
Clinical Examples
Conclusion
Key Terms
• Antibiotic = A drug that kills or inhibits the growth
of microorganisms
• Resistant = Somewhat arbitrary designation that
implies that an antimicrobial will not inhibit
bacterial growth at clinically achievable
concentrations
• Susceptible = Somewhat arbitrary designation that
implies that an antimicrobial will inhibit bacterial
growth at clinically achievable concentrations
Key Terms
• MIC = Minimal inhibitory concentration. Lowest
concentration of antimicrobial that inhibits growth
of bacteria. Commonly used in clinical lab
• MBC = Minimal bactericidal concentration.
Concentration of an antimicrobial that kills bacteria.
Used clinically only in special circumstances
• Breakpoint = The MIC that is used to designate
between susceptible and resistant. Arbitrarily set by
a committee
Outline
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Introduction
Key Terms
Susceptibility Testing Methods
Factors Contributing to Antibiotic Resistance
Mechanisms of Resistance
Clinical Examples
Conclusion
Minimum Inhibitory Concentration
MIC = 6.25 mcg/mL
Automated Methods
Well Plate for MIC Testing
Many Labs Use
Automated Testing
Other Methods for Determining
Susceptibility
E-test®
Kirby-Bauer
Disk Diffusion
Agar dilution
Concept of Breakpoint to Determine
Susceptibility
EXAMPLE:
Susceptibility
testing for a single
isolate of
Pseudomonas
aeruginosa
-Breakpoint for
intermediate resistance
for meropenem is 4 and
for piperacillin/tazobactam
(pip/tazo) 32
-Pip/tazo is the better
choice between the two
-Ciprofloxacin is a poor
choice even though the
MIC is lowest of the three
Antibiotic
Ampicillin
Gentamicin
Cephalothin
Cefepime
Cefotaxime
Ceftazidime
Aztreonam
Ciprofloxacin
Amp/Sulbactam
Meropenem
Pip/tazo
MIC
>16
2
>16
8
16
2
4
2
>16
4
8
Breakpoint
8
4
N/A
32
16/32
32
16
2
8
4/8
32-64/128
Susceptibility
Resistant
Susceptible
Resistant
Susceptible
Intermediate
Susceptible
Susceptible
Resistant
Resistant
Intermediate
Susceptible
Outline
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Introduction
Key Terms
Susceptibility Testing Methods
Factors Contributing to Antibiotic Resistance
Mechanisms of Resistance
Clinical Examples
Conclusion
Antibiotic Use Leads to
Antibiotic Resistance
Inpatient
Agriculture
Outpatient
Reasons for Antibiotic Overuse :
Conclusions from 8 Focus Groups
Patient Concerns
• Want clear explanation
• Green nasal discharge
• Need to return to work
Physician Concerns
• Patient expects antibiotic
• Diagnostic uncertainty
• Time pressure
Antibiotic Prescription
Barden L.S. Clin Pediatr 1998;37:665
Antibiotic Use Leads to
Antibiotic Resistance
• Resistant bacteria or their
genetic determinates are
selected when colonizing or
infecting bacteria are exposed
to antibiotics
• Resistant bacteria can then be
transmitted between patients
• Highest risk patients:
– Immunocompromised
– Hospitalized
– Invasive devices
(central venous catheters)
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Outline
Introduction
Key Terms
Susceptibility Testing Methods
Factors Contributing to Antibiotic Resistance
Mechanisms of Resistance
– Overview
– Specific Examples
1.
2.
3.
4.
Antibiotic Degrading Enzymes
Decreased Permeability
Efflux Pumps
Target Alterations
• Clinical Examples
• Conclusion
Cycle of Antibiotic
Resistance Acquisition:
Bacterial Selection
Under increasing antibiotic
selection pressure:
1. Bacteria resistant to a
particular drug are
selected and replicate
2. Different antibiotics
select different
bacteria but can select
resistant phenotypes
to other drugs as well
3. This results in
multidrug-resistant
(MDR) organisms and
increases their total
number
R
Selection by Drug X
Replication
Selection by Drug Y
Replication
Resistance to:
Drug X
Drug Y
Drug Z
Antibiotic Mechanism of Action
Linezolid
Daptomycin
Daptomycin
Linezolid
Daptomycin
Mechanisms Of Antibiotic Resistance
• Bacteria are capable of
becoming resistant through
several mechanisms
• One or many mechanisms
may exist in an organism
• Multidrug-resistant bacteria
often have multiple
mechanisms
• Genes encoding resistance
may exist on plasmid or
chromosome
Decreased
Permeability
Alteration in
Target
Molecule
Mechanisms of Resistance
Antibiotic Degrading Enzymes
• Sulfonation, phosphorylation, or esterifictation
– Especially a problem for aminoglycosides
• β-lactamases
– Simple, extended spectrum β-lactamases (ESBL),
cephalosporinases, carbapenemases
– Confer resistance to some, many, or all beta-lactam
antibiotics
– May be encoded on chromosome or plasmid
– More potent in gram-negative bacteria
– Examples: S. aureus, H. influenzae, N. gonorrhoeae, E.
coli, Klebsiella sp., Enterobacter sp., Serratia sp., other
enteric bacteria, anaerobes
Extended Spectrum -lactamases
• -lactamases capable of hydrolysing extended
spectrum cephalosporins, penicillins, and aztreonam
• Most often associated with E. coli and Klebsiella
pneumoniae but spreading to other bacteria
• Usually plasmid mediated
• Aminoglycoside, ciprofloxacin and trimethoprimsulfamethoxazole resistance often encoded on same
plasmid
• Has become a significant resistance determinate in
acute and long-term care facility enteric pathogens
Class A Carbapenemases
• Most common in Klebsiella pneumoniae (KPC)
• Also seen in E. coli, Enterobacter, Citrobacter,
Salmonella, Serratia, Pseudomonas and Proteus spp.
• Very often with multiple other drug resistance
mechanisms, resistance profile similar to ESBL but
also carbapenem resistant
• Became problem in New York City first in 2002-2003
and is being increasingly recognized in Mid-Atlantic
US.
• Spreading across species to other gram-negatives and
enterobacteriaceae
• Emerging in long-term care facilities
Mechanisms of Resistance
Decreased Permeability
• Pseudomonas spp.
• Affects many antibiotics including carbapenems
Efflux Pumps
• Pseudomonas spp. (multiple antibiotics)
• Tetracyclines
• Macrolides
Mechanisms of Resistance
Target Alteration
• DNA gyrase
• Fluoroquinolones
• Many gram-negatives, S. pneumoniae
• Penicillin-binding protein
• Methicillin-resistant S. aureus (MRSA)
• Penicillin-resistant S. pneumoniae
• Gram positive cell wall
• Vancomycin
• Enterococcus spp.
Mechanisms of Resistance
Target Alteration (cont’d)
• Ribosome
• Tetracyclines
• Macrolides
• S. pneumoniae, Staphylococcus sp., N.
gonorrhoeae, enteric gram-negative rods
Outline
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•
•
•
•
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Introduction
Key Terms
Susceptibility Testing Methods
Factors Contributing to Antibiotic Resistance
Mechanisms of Resistance
Clinical Examples
– Staphylococcus aureus
– Streptococcus pneumoniae
– Escherichia coli
• Conclusion
Illustrative Case 1
• A 50 y.o. female with type 2 diabetes mellitus
was admitted for an elective total knee
replacement. Postoperative day 4: fever to
39ºC and a gray, purulent wound discharge
• Gram stain of the exudate showed neutrophils
and gram positive cocci in clusters
• She was started on IV cefazolin. After two
days of therapy she remained febrile and her
wound showed little improvement
Case 1
Gram
Stain
Illustrative Case 1 (cont’d)
• Wound cultures yielded S. aureus resistant to
penicillin, methicillin, all cephalosporins,
erythromycin, tetracycline, gentamicin and
ciprofloxacin
• The wound was débrided and she was started on
IV vancomycin with improvement
• After 4 days of vancomycin she was discharged on
oral trimethoprim/sulfamethoxazole for 2 weeks
• 3 months later she experienced a recurrence of
symptoms after initial improvement and was
diagnosed as having a deep prosthetic joint
infection due to MRSA
Increase in MRSA Prevalence in US
Comparison to Other Drug-Resistant Organisms
Wenzel et. al. ICHE 2008;29;1012
Surgical Site Infections
Impact of Resistance on Clinical Outcomes
MSSA
(N=165)
MRSA
(N=121)
P Value
6.7%
20.7%
P<.001
After surgery
14 (7-25)
23 (12-38)
P<.001
After infection
10 (4-17)
15 (7-30)
P=.001
Unadjusted
Mortality, 90-day
Length of stay:
median days
Adjusted* mortality for MRSA (P=0.003)
*Adjusted for other predictors of mortality: age, physical status, duration of surgery.
Engemann JJ, et al. Clin Infect Dis. 2003;36:592-598.
Glycopeptide Resistant S.aureus
• Glycopeptide Intermediate Resistance:
–
–
–
–
First reported in Japan
Vancomycin MIC 8μg/mL
Still uncommon
All with prolonged vancomycin use due to persistent S.aureus
infections
• Glycopeptide High Level Resistance:
–
–
–
–
First report in Michigan in June 2002
Vancomycin MIC >128 ug/ml
Diabetic with peripheral vascular disease and chronic renal failure
Resistance determinant acquired from Vancomycin-resistant
Enterococcus (VRE)
– Very uncommon
MMWR 2002; 51:565-7
MMWR 2000;48:1165-7
Smith TL et al. NEJM 1999;340:493-501
Illustrative Case 2
• 67 y.o. man with chronic lymphocytic leukemia
admitted with sudden onset high fever, rigors,
pleuritic chest pain and productive cough
• Physical exam and chest x-ray confirmed
pneumonia
• Started on IV azithromycin
Illustrative Case 2 (cont)
• Gram stain showed numerous
neutrophils and sheets of lancet
shaped gram positive diplococci
• After 48 hours the patient was
still febrile and developed
progressive respiratory tract
failure
• Blood culture from admission
yielded S. pneumoniae resistant
to penicillin, ceftriaxone,
erythromycin and clindamycin
Gram stain
2009 S. pneumoniae Susceptibility
CDC ABC surveillance Network
Invasive Isolates (Meningitis, bacteremia, etc.)
http://www.cdc.gov/abcs/reports-findings/survreports/spneu09.pdf
Macrolide-Resistant S. pneumoniae
Prevalence is Increasing in US
Jenkins S. et al Emerg Infect Dis. 2009;5:1260
Hicks L et. Al. Emerg Infect Dis. 2010;16:896
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
15 - 64 y.o
6
> 64 y.o
# of Rx/100 persons
5
4
3
2
1
# of Prescriptions / 100 Persons
S. pneumo. with Reduced
Susceptibility to Fluoroquinolones (%)
Decreased Susceptibility of S. pneumoniae to
Fluoroquinolones (FQRSP) in Canada
Relationship of Resistance to Antibiotic Use
0
1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998
Chen et. al., NEJM 1999;341:233-9
Illustrative Case 3
• 45 y.o. female seen in clinic for urinary urgency,
frequency and dysuria. Her urinalysis is positive
for leukocyte esterase and 31-40 white blood
cells. A urine gram stain was performed and
showed 2+ white blood cells and many gramnegative rods
• Urine culture reveals E. coli, which is resistant to
ciprofloxacin and trimethoprim-sulfamethoxazole,
but is sensitive to ceftriaxone
Community-Acquired Resistant
E. Coli
• Mostly UTIs
• Young healthy women in
addition to the elderly
• 10-20% now resistant to
fluoroquinolones
• 30-50% resistant to
trimethoprimsulfamethoxazole
• CTX-M β-lactamases
becoming more common
– Cause cephalosporin resistance
Outline
•
•
•
•
•
•
•
Introduction
Key Terms
Susceptibility Testing Methods
Factors Contributing to Antibiotic Resistance
Mechanisms of Resistance
Clinical Examples
Conclusion
Conclusion
• Inappropriate and excessive use of antibiotics
is a major factor contributing to emerging
antibiotic resistance
• Determinants of resistance are selected for by
antibiotic use
• Multiple mechanisms exist for bacteria to
become resistant to antibiotics
• Antibiotic resistance is a problem in outpatient
and inpatient settings and is a factor in a wide
variety of infections
• Antibiotic resistance continues to emerge as a
serious threat to public health

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