antimicrobial resistance timothy h. dellit, md [email protected] infection control and...
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Antimicrobial Resistance
Timothy H. Dellit, [email protected]
Infection Control and Antimicrobial ManagementHarborview Medical Center
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Gram Positive ResistanceICU 1995-2004
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National Nosocomial Infections Surveillance (NNIS) System
Methicillin-Resistant Staphylococcus aureus
Vancomycin-Resistant Enterococcus
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Gram Negative ResistanceICU 1995-2004
National Nosocomial Infections Surveillance (NNIS) System
3rd Generation Cephalosporin-Resistant Klebsiella pneumoniae
Fluoroquinolone-Resistant Pseudomonas aeruginosa
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Tip of the Iceberg?
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Clinical Culture Surveillance Surveillance, thenClinical Culture
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760 Cases of VRE identified between Jan 1997 – Oct 1999
Clin Infect Dis 2003;37:326-32
86% undetected by clinical specimen alone
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New Resistant Bacteria
Mutations
XX
Susceptible Bacteria
Resistant Bacteria
Resistance Gene Transfer
Emergence of Antimicrobial Resistance
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Resistant StrainsRare
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Resistant Strains Dominant
Antimicrobial Exposure
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Selection for Antimicrobial-Resistant Strains
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Mechanisms of Resistance
• Inactivation of drug– Beta-lactamases
• Alteration of the target– Penicillin binding proteins– Ribosomes
• Decreased permeability• Drug efflux
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R1 C NH HC H2C C
C N C COOH
S
CH3
CH3
O
O
β-lactamase
Site of β-lactamase Activity
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Increased Macrolide Consumption and the Emergence of Resistance
N Engl J Med 1997;337:441-6
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Macrolide Resistance
• Efflux of drug in S. pyogenes, S. pneumoniae– M phenotype encoded by mef gene
• Alteration of 23S rRNA of 50S ribosomal subunit by methylation of adenine– Associated with resistance to macrolides,
lincosamides (clindamycin), and streptogramin type B (MLSB phenotype)
– ermB gene
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Clinical Impact of Resistance
Increasing resistance– Inpatient (MRSA, VRE, Pseudomonas, Acinetobacter)– Outpatient (E. coli, CA-MRSA, S. pneumoniae)
Clinical Condition Mortality RiskMRSA vs. MSSA bacteremia1 1.93MRSA vs. MSSA SSI2 3.4VRE vs. VSE bacteremia3 2.52Emergence of resistant Pseudomonas4 3.0Enterobacter resistant to 3rd gen ceph5 5.02MDR-Acinetobacter vs. non-MDR Acin bacteremia6 4.1
1Clin Infect Dis 2003;36:53-9 4Arch Intern Med 1999;159:1127-322Clin Infect Dis 2003;36:592-8 5Arch Intern Med 2002;162:185-903Clin Infect Dis 2005;41:327-33 6Infect Control Hosp Epidemiol 2007;28:713-9
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Economic Impact of Antimicrobial Resistance
Clinical Condition LOS Attributable CostMRSA in ICU1 $9,275MRSA vs. MSSA bacteremia2 9 vs. 7 d $7,212MRSA vs. MSSA SSI3 $13,901Emergence of resistant Pseudomonas4 OR 1.7Enterobacter resistant to 3rd gen ceph5 OR 1.47 $29,379MDR-Acinetobacter vs. 13.4 more days $3,758 non-MDR Acinetobacter bacteremia6
MDR-Acinetobacter in burn unit7 $98,575
1JAMA 1999;282:1745-1751 5Arch Intern Med 2002;162:185-902ICHE 2005;26:166-174 6ICHE 2007;28:713-9 3Clin Infect Dis 2003;36:592-8 7Am J Infect Control 2004;32:342-44Arch Intern Med 1999;159:1127-32
• Antimicrobials account for upwards of 30% of formulary budgets• 50% of antimicrobial usage is inappropriate
Annual cost of infections due to antimicrobial resistant bacteria estimated to be $4 to $5 billion (IOM 1998)
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Antimicrobials and Animals• 50% of antimicrobials in tonnage used in food-
producing animals and poultry– Disease control and growth promotion
• Paralleled increase in resistance– Salmonella– Campylobacter
• MRSA and pigs• Community-associated VRE and avoparcin
Lancet Infectious Diseases 2001;1:314-25Clin Infect Dis 2007;45:1353-61Emerg Infect Dis 2007;13:1834-9Clin Infect Dis 2008;46:261-3
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Which of the following is CORRECT regarding
S. pneumoniae?
A. The MIC susceptibility breakpoint for penicillin has recently been lowered due to increased clinical failure with penicillin treatment.
B. Levofloxacin is the most active fluoroquinolone against S. pneumoniae
C. The addition of a beta-lactamase inhibitor (ampicillin-sulbactam) can overcome the penicillin resistance.
D. Introduction of the pneumococcal conjugate vaccine has been associated with a reduction in non-penicillin susceptible invasive pneumococcal infections.
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Pneumococcal Conjugate VaccineRate of penicillin-nonsusceptible invasive disease per 100,000
1999 2004All ages 6.3 2.7Children < 2 years of age 70.3 13.1Persons > 65 years of age 16.4 8.4
Serotype 19A 0.3 1.2 Children < 2 years of age 0.8 8.3
Meningitis per 100,000 1994-1999 2001-2004 Children < 2 years of age 7.7 2.6 Persons > 65 years of age 1.2 0.8
N Engl J Med 2006;354:1455-63
Clin Infect Dis 2008;46:1664-72
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S. pneumoniae β-Lactam Resistance
Clin Infect Dis 2009;48:1596-1600
SENTRY surveillance: susceptibility increase from 68% to 93% of isolates
Ceftriaxone Susceptible Intermediate Resistant
Previous < 0.5 1.0 > 2.0
Non-meningitis <1.0 2.0 > 4.0
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S. pneumoniae Resistance
Antimicrobial National Local
Macrolide 29% 25-32%
TMP/SMX 32% 30%
Tetracyclines 16% 17-23%
Fluoroquinolones* 2.3% 0-5%
*21.9% of S. pneumoniae isolates in 2002-2003 had fluoroquinolone mutations in parC and/or gyrA compared to 4.7% in 1997-1998.
Clin Infect Dis 2005;41:139-48
Local Fluoroquinolone SusceptibilityMoxifloxacin: 99-100%Levofloxacin: 95%
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Tetracyclines
• tet efflux genes• Tigecycline is a new glycylcycline derivative
of minocycline– Designed to overcome drug-resistance due to
efflux and ribosomal protection– In vitro activity against PRSP, MRSA, VRE, and
some Acinetobacter, but not Pseudomonas– Emergence of resistance on therapy, particularly
with Acinetobacter
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Fluoroquinolones and AUC:MICD
rug
Con
cent
rati
on
Time
MIC
Peak
Area Under the Curve (AUC)
• Concentration-dependent killing (AUC:MIC)• Fluoroquinolone targets
DNA gyraseTopoisomerase IV
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S. pneumoniae and Fluoroquinolones
Drug MIC90 AUCFree AUC:MICFree
Ciprofloxacin (750 bid) 1.0 28 28Levofloxacin (500 qd) 1.0 34 34Levofloxacin (750 qd) 1.0 70 70Gatifloxacin (400 qd) 0.25 26 106Gemifloxacin (320 qd) 0.03 140-
280Moxifloxacin (400 qd) 0.12 24 200
Cutoff criterion of AUC:MIC >33.7 for gram-positives?
Clin Infect Dis 2005;41:S127-35
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Pseudomonas and Fluoroquinolones
Drug Dose Cmax MIC AUCfree:MIC
Ciprofloxacin 400 q12 4.1 0.125 144
400 q8 4.1 0.125 184
Levofloxacin 750 q24 12.1 0.5 152
Gatifloxacin 400 q12 4.6 1.0 28
Moxifloxacin 400 q24 4.2 2.0 10
IDSA and ATS Guidelines recommend Ciprofloxacin 400mg IV q8hr or Levofloxacin 750 mg qd
Am J Respir Crit Care med 2005;171:388-416
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35 y o man with a history of HIV and methamphetamine use presents to clinic
with a right biceps abscess.
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49 y o man with a 1 week h/o viral syndrome with progressive dyspnea, hypoxia, and hypotension. Sputum,
pleural fluid, and blood cultures with GPC in clusters.
Clin Infect Dis 2005;40:100-7
Chest 2005;128:2732-8
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40 y o man with h/o IDU with heroine presents with fever, chills, cough, and pleuritic chest pain. Doppler demonstrates L common femoral DVT and blood cultures grow GPC with vancomycin MIC 2.0 and remain persistently positive at day 7.
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Which of the following is correct regarding S. aureus resistance?
A. Daptomycin is active against VISA, but not VRSAB. VRSA isolates to date have contained vanBC. Breakpoint for vancomycin susceptibility is 4.0 mcg/mlD. MecA gene encodes PBP2aE. Isolates susceptible to erythromycin should undergo
“D-test” for inducible clindamycin resistanceF. Linezolid resistance is due to drug efflux
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Community-Associated MRSA
• Four pediatric deaths 1997-1999 in Minnesota and North Dakota (MMWR 1999;48:707)
• Clinical manifestations– Predominantly skin and soft tissue
• 59% of purulent SSTI in 11 ED, 78% of S. aureus
– Necrotizing fasciitis– Necrotizing pneumonia
• Different from HA-MRSA– SCCmec type IV– Panton-Valentine Leukocidin exotoxin associated with tissue
necrosis and leukocyte destruction (or other toxin?)
JAMA 2003;290:2976-2984
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Washington State MRSA TrendAntibiotic Resistance Sentinel Network
0%
10%
20%
30%
40%
50%
1999 2000 2001 2002 2003 2004
All isolates
Outpatient isolates
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MRSA Resistance to Beta-Lactams
Beta-Lactam
Modified from David Spach, MD
Cell WallCell Membrane
Alternative Penicillin Binding Protein PBP2a
DNA
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Nasal Carriage of S. aureus
Increased rates– IDDM– HD/CAPD– IDU– HIV
MRSA– Healthcare contact
• Surgery• Dialysis• Indwelling devices
– Long-term care facilities– IDU (Clin Infect Dis 2002;34:425-33)– Correction facilities (Clin Infect Dis
2003;37:1384-8)– MSM (Clin Infect Dis 2005;40:1529-34)– Tattoo (MMWR 2006;55(24):677-9)– Native Americans, Pacific Islanders– Other close contact
• Athletic (N Engl J Med 2005;352:468-75)
– “Spider bite”
Clin Microbiol Rev 1997;10:505-520
20-40% of people colonized with S. aureus–20% persistent, 30% intermittent, 50% never
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Prevalence of MRSA Colonization
• 2003-2004 National Health and Nutrition Examination Survey (NHANES) 9004 persons (J Infect Dis 2008;197:1226-34)
– 1.5% vs. 0.8% MRSA colonization in 2001-2002
• >10 fold increase in healthy children from 2001 to 2004, with MRSA colonization rate of 9.2% (Pediatr Infect Dis J 2005;24:617-21)
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2008 MRSA Susceptibilities
Clindamycin*
Levofloxacin
Tetracycline
TMP/SMX
Vancomycin
Harborview UW
71% 60%
21% 27%
95% 94%
91% 95%
100% 100%
*D-zone test should be done to look for inducible resistance to clindamycin9% at HMC and 13% at UWMC
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Staphylococcus aureus and Inducible Resistance to Clindamycin
• Test for inducible resistance to clindamycin using D test in erythromycin resistant isolates
• Methylation of an adenine residue of bacterial 23S rRNA (MLSB
phenotype, ermB)• Effective in treatment of CA-MRSA
in the absence of inducible resistance
Clin Infect Dis 2003;37:1257-60 Pediatr Infect Dis J 2003;22:593-8
Pediatr Infect Dis J 2002;21:530-4
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Treatment Options for MRSA Infections
• Vancomycin*• Linezolid*• Daptomycin*• Tigecycline*• Quinupristin/dalfopristin*
• TMP-SMX• Minocycline/Doxy• Clindamycin**• Fluoroquinolone• Linezolid*
Intravenous Oral
*FDA approved for MRSA
**test for inducible resistance if erythromycin–R and clindamycin-S
• Rifampin should not be routinely used in combination for SSTI and NEVER alone due to rapid emergence of resistance.
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Trimethoprim-Sulfamethoxazole and Staphylococcus aureus
• Randomized study comparing TMP-SMX and vancomycin in 101 IDU’s with S. aureus infections
• Clinical characteristics– 47% of isolates were MRSA – 65% of patients were
bacteremic– 32% with skin and soft
tissue infections
Ann Intern Med 1992;117:390-398
0
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All Infections Excluding TV Endocarditis
Vancomycin
TMP-SMX
Clin
ical
Cur
e R
ate*
p < 0.02 p = 0.06
*All patients with MRSA were cured
May not be effective against -hemolytic streptococci (ie Group A strep)
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IDSW, WA DOH, King and Pierce County Health Departments
• Incorporation of MRSA risk factor assessment• Importance of Incision & Drainage• Emphasize culture and susceptibility testing• Empiric outpatient or discharge regimens to
include trimethoprim-sulfamethoxazole, minocycline or doxycycline, or clindamycin
• Judicial use of linezolid and daptomycin
Outpatient Management of SSTI
http://www.doh.wa.gov/Topics/Antibiotics/MRSA.htm
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Vancomycin MIC Creep
• Association between increasing MIC and clinical failure, particularly prolonged bacteremia – Breakpoint lowered to < 2 mcg/ml
• Trough of 15-20 mcg/ml recommended in endocarditis, osteomyelitis, and ventilator-associated pneumonia
Clin Infect Dis 2006;42:S51-7
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Vancomycin MIC and Clinical Outcome
0
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Clinical Response Mortality
MIC < 1.0MIC > 1.5Prospective study of 95
patients with MRSA infections
• Elderly population, 64% in SNF, 77% with PNA or bacteremia
• 51/95 (54%) with strains having MIC > 1.5 mcg/ml
Per
cent
age
Arch Intern Med 2006;166:2138-2144
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Impact of Vancomycin MIC
1.0 1.5 2.0 Total
MRSA 21 (39%) 19 (35%) 14 (26%) 54
MSSA 19 (41%) 10 (22%) 17 (37%) 46
Vancomycin MIC Mortality OR P
1.0 1
1.5 2.86 0.08
2.0 6.39 <0.001
414 Episodes of MRSA Bacteremia
Clin Infect Dis 2008;46:193-200
Harborview Sample MICs for first blood isolate
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Vancomycin Resistance• Binds to cell wall precursors ending in D-
Ala-D-Ala and prevents their incorporation into cell wall synthesis
• Vancomycin-intermediate resistant S. aureus (VISA)– First documented in Japan 1996, US in 1997– Increased cell wall thickness limiting
glycopeptide access to site of cell wall synthesis
• Vancomycin-resistant S. aureus (VRSA)– Isolated in June 2002– Contained vanA resistance gene identical to
vanA gene in patient’s vancomycin-resistant Enterococcus faecalis
– van genes encode for precursors with alternative termini that have low affinity for vancomycin (eg. vanA encodes D-Ala-D-Lac)
VISA
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Reduced Susceptibility to Vancomycin Associated with Reduced Susceptibility to
Daptomycin in S. aureus
No. (%) of IsolatesVancomycin Daptomycin DaptomycinMIC, mcg/ml MIC < 1 mcg/ml MIC > 2 mcg/ml
< 2 812 (97) 30 (3)4 11 (20) 43 (80)8-16 1 (7) 15 (93)> 32* 5 (100) 0 (0)
* vanA mediated resistance
Clin Infect Dis 2006;42:1652-3
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So what are non-vanco options?Linezolid
• Pros– 100% oral bioavailability– Benefit in MRSA PNA?– Protein synthesis inhibitor
• Cons– Static drug– Limited data in bacteremia and
endocarditis– Adverse events
• Marrow suppression • Serotonin syndrome • Lactic acidosis• Optic neuritis, peripheral
neuropathy, Bell’s palsy
– Cost
Daptomycin• Pros
– Cidal drug– Approved for bacteremia and
right sided endocarditis
• Cons– Not active in the lung– Parenteral only– Decreased susceptibility to
vancomycin associated with decreased susceptibility to daptomycin
– Emergence of resistance on therapy
– Cost
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35 y o woman develops a catheter-related bloodstream infection with Enterobacter.
Monotherapy with which of the following antibiotics would be LEAST preferred even though the organism is susceptible to all three?
A. Ceftazidime
B. Cefepime
C. Imipenem
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25 y o man with a h/o MVA develops ventilator-associated pneumonia with quantitative BAL culture growing 50,000 cfu Klebsiella pneumonia reported as producing an extended-spectrum beta-lactamase (ESBL). Which of the following antibiotics is the best choice?
A. CeftriaxoneB. CeftazidimeC. CefepimeD. Imipenem
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ESBL AmpC
Bugs E. coli, Klebsiella SPICEM organisms (Serratia, Pseudomonas, Providencia, Indole-pos Proteus, Citrobacter, Enterobacter, Morganella
Genetics Plasmid Chromosome or plasmid
Inducible Resistance No Yes*
Most stable β-lactams Carbapenem Carbapenem or cefepime
*Monotherapy with penicillin or 3rd generation cephalosporin may be associated with inducible resistance
Problematic β-lactamases
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New Antibacterial Drugs Approved By FDA
Linezolid 2000
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Bad Bugs, No Drugs
• Gram-positive bacteria– MRSA and VRE– Emergence of vancomycin-resistant S. aureus and
linezolid-resistant Enterococcus– Decreased S. aureus susceptibility to vancomycin
associated with decreased susceptibility to daptomycin
• Gram-negative bacteria– Pan-resistant Acinetobacter and Pseudomonas
• Colistin/Polymixin E– nephrotoxicity 20-30%– neurotoxicity 7%
– Extended-spectrum β-lactamase organisms
Clin Infect Dis 2006;42:657-68
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Summary
• Development of antimicrobial resistance is directly related to antimicrobial usage, especially inappropriate usage
• Understanding antimicrobial pharmocokinetics/dynamics and resistance mechanisms can help guide appropriate usage
• Knowledge of local susceptibility patterns is essential
• Paucity of new antimicrobial agents in pipeline