Antimicrobial Resistance Fellows 2009

8/12/2019 Antimicrobial Resistance Fellows 2009

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Antimicrobial Resistance

Timothy H. Dellit, MD

[email protected] Control and Antimicrobial Management

Harborview Medical Center


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Gram Positive ResistanceICU 1995-2004

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60

70

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

Year

PercentResistance

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5

10

15

20

25

30

35

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

Year

PercentResistance

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

0

5

10

15

20

25

30

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

Year

PercentRes

istance

0

5

10

15

20

25

30

35

40

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

Year

PercentRes

istance


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Tip of the Iceberg?

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100

Clinical Culture Surveillance Surveillance, then

Clinical Culture

Perce

ntofCasesId

entified

760 Cases of VRE identified between Jan 1997Oct 1999

Clin Infect Dis 2003;37:326-32

86% undetected

by clinicalspecimen alone


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New Resistant Bacteria

Susceptible Bacteria

Resistant Bacteria

Resistance Gene Transfer

Emergence of AntimicrobialResistance


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Resistant StrainsRare

Resistant StrainsDominant

AntimicrobialExposure

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

CH3O

O

-lactamase

Site of -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 ribosomalsubunit by methylation of adenine

Associated with resistance to macrolides,lincosamides (clindamycin), and streptogramin type

B (MLSBphenotype) 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 resistantPseudomonas4 3.0Enterobacter resistant to 3rdgen ceph5 5.02

MDR-Acinetobactervs. 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;162:185-903


Infect 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 $13,901

Emergence of resistant Pseudomonas4 OR 1.7Enterobacter resistant to 3rd gen ceph5 OR 1.47 $29,379MDR-Acinetobactervs. 13.4 more days $3,758

non-MDRAcinetobacterbacteremia6

MDR-Acinetobacterin burn unit7 $98,575

1JAMA 1999;282:1745-1751 5Arch Intern Med 2002;162:185-902ICHE 2005;26:166-174 6ICHE 2007;28:713-93Clin Infect Dis 2003;36:592-8 7Am J Infect Control 2004;32:342-4

4Arch 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 resistantbacteria 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 regardingS. pneumoniae?

A. The MIC susceptibility breakpoint for penicillin hasrecently been lowered due to increased clinical failurewith penicillin treatment.

B. Levofloxacin is the most active fluoroquinolone againstS. pneumoniae

C. The addition of a beta-lactamase inhibitor (ampicillin-sulbactam) can overcome the penicillin resistance.

D. Introduction of the pneumococcal conjugate vaccine hasbeen associated with a reduction in non-penicillinsusceptible invasive pneumococcal infections.


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Pneumococcal Conjugate Vaccine

Rate of penicillin-nonsusceptible invasive disease per 100,000

1999 2004All ages 6.3 2.7Children < 2 years of age 70.3 13.1

Persons > 65 years of age 16.4 8.4

Serotype 19A 0.3 1.2Children < 2 years of age 0.8 8.3

Meningitis per 100,000 1994-1999 2001-2004Children < 2 years of age 7.7 2.6Persons > 65 years of age 1.2 0.8

N Engl J Med 2006;354:1455-63



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S. pneumoniae-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 4.0


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S. pneumoniaeResistance

Antimicrobial National Local

Macrolide 29% 25-32%

TMP/SMX 32% 30%

Tetracyclines 16% 17-23%

Fluoroquinolones* 2.3% 0-5%

*21.9% of S. pneumoniaeisolates in 2002-2003 had fluoroquinolone

mutations inparC and/or gyrAcompared to 4.7% in 1997-1998.


Local Fluoroquinolone SusceptibilityMoxifloxacin: 99-100%Levofloxacin: 95%


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Tetracyclines

tetefflux genes

Tigecycline is a new glycylcycline derivativeof minocycline

Designed to overcome drug-resistance due toefflux and ribosomal protection

In vitro activity against PRSP, MRSA, VRE, andsomeAcinetobacter, but not Pseudomonas

Emergence of resistance on therapy, particularlywithAcinetobacter


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Fluoroquinolones and AUC:MIC

Dr

ugConcentra

tion

Time

MIC

Peak

Area Under the Curve

(AUC)

Concentration-dependent killing (AUC:MIC)Fluoroquinolone targets

DNA gyraseTopoisomerase IV


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S. pneumoniaeand Fluoroquinolones

Drug MIC90 AUCFree AUC:MICFree

Ciprofloxacin (750 bid) 1.0 28 28

Levofloxacin (500 qd) 1.0 34 34Levofloxacin (750 qd) 1.0 70 70

Gatifloxacin (400 qd) 0.25 26 106

Gemifloxacin (320 qd) 0.03 140-280

Moxifloxacin (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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Pseudomonasand Fluoroquinolones

Drug Dose Cmax MIC AUCfree:MICCiprofloxacin 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 Ciprofloxacin400mg 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 clinicwith a right biceps abscess.


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49 y o man with a 1 week h/o viral syndrome withprogressive dyspnea, hypoxia, and hypotension. Sputum,

pleural fluid, and blood cultures with GPC in clusters.


Chest 2005;128:2732-8


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40 y o man with h/o IDUwith heroine presents withfever, chills, cough, andpleuritic chest pain.

Doppler demonstrates Lcommon femoral DVT andblood cultures grow GPCwith vancomycin MIC 2.0and remain persistently

positive at day 7.


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Which of the following is correct

regarding S. aureusresistance?

A. Daptomycin is active against VISA, but not VRSA

B. VRSA isolates to date have contained vanBC. Breakpoint for vancomycin susceptibility is 4.0 mcg/ml

D. MecAgene encodes PBP2a

E. Isolates susceptible to erythromycin should undergoD-test for inducible clindamycin resistance

F. Linezolid resistance is due to drug efflux


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Community-Associated MRSA

Four pediatric deaths 1997-1999 in Minnesota andNorth 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*

LevofloxacinTetracycline

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 clindamycin

9% at HMC and 13% at UWMC


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Staphylococcus aureusandInducible Resistance to Clindamycin

Test for inducible resistance toclindamycin using D test inerythromycin resistant isolates

Methylation of an adenine residueof bacterial 23S rRNA (MLSBphenotype, ermB)

Effective in treatment of CA-MRSA

in the absence of inducibleresistance

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 erythromycinR 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-Sulfamethoxazoleand Staphylococcus aureus

Randomized studycomparing TMP-SMX andvancomycin in 101 IDUs

with S. aureusinfections Clinical characteristics

47% of isolates were MRSA

65% of patients were

bacteremic 32% with skin and softtissue infections

Ann Intern Med 1992;117:390-398

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All Infections Excluding TV Endocarditis

Vancomycin

TMP-SMX

ClinicalCureRate*

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 PierceCounty Health Departments

Incorporation of MRSA risk factor assessment

Importance of Incision & Drainage

Emphasize culture and susceptibility testing

Empiric outpatient or discharge regimens toinclude 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

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Clinical Response Mortality

MIC < 1.0

MIC > 1.5Prospective study of 95patients with MRSA infections

Elderly population, 64%in SNF, 77% with PNA orbacteremia

51/95 (54%) with strainshaving MIC > 1.5 mcg/ml

Percentage

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


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Vancomycin Resistance

Binds to cell wall precursors ending in D-Ala-D-Ala and prevents theirincorporation into cell wall synthesis

Vancomycin-intermediate resistant S.aureus (VISA)

First documented in Japan 1996, US in 1997 Increased cell wall thickness limitingglycopeptide access to site of cell wallsynthesis

Vancomycin-resistant S. aureus(VRSA) Isolated in June 2002

Contained vanA resistance gene identical tovanA gene in patients vancomycin-resistantEnterococcus faecalis

vangenes encode for precursors withalternative termini that have low affinity forvancomycin (eg. vanA encodes D-Ala-D-Lac)

VISA


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Reduced Susceptibility to VancomycinAssociated with Reduced Susceptibility to

Daptomycin in S. aureusNo. (%) of Isolates

Vancomycin 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)

* vanAmediated resistance



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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 bacteremiaand endocarditis

Adverse events Marrow suppression Serotonin syndrome Lactic acidosis Optic neuritis, peripheral

neuropathy, Bells palsy

Cost

Daptomycin

Pros Cidal drug

Approved for bacteremiaand right sided endocarditis

Cons Not active in the lung

Parenteral only

Decreased susceptibility tovancomycin associatedwith decreasedsusceptibility to daptomycin

Emergence of resistanceon therapy

Cost


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35 y o woman develops a catheter-relatedbloodstream infection with Enterobacter.

Monotherapy with which of the followingantibiotics would be LEAST preferred even

though the organism is susceptible to all three?

A. Ceftazidime

B. CefepimeC. Imipenem


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25 y o man with a h/o MVA develops ventilator-associated pneumonia with quantitative BALculture growing 50,000 cfu Klebsiella pneumoniareported as producing an extended-spectrumbeta-lactamase (ESBL). Which of the following

antibiotics is the best choice?

A. Ceftriaxone

B. Ceftazidime

C. CefepimeD. Imipenem


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ESBL AmpCBugs 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 -lactams Carbapenem Carbapenem or cefepime

*Monotherapy with penicillin or 3rdgeneration cephalosporin may be

associated with inducible resistance

Problematic -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. aureusandlinezolid-resistant Enterococcus

Decreased S. aureus susceptibility to vancomycinassociated with decreased susceptibility to daptomycin

Gram-negative bacteria Pan-resistantAcinetobacterand Pseudomonas

Colistin/Polymixin E nephrotoxicity 20-30%

neurotoxicity 7%

Extended-spectrum -lactamase organisms



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Summary

Development of antimicrobial resistance isdirectly related to antimicrobial usage, especiallyinappropriate usage

Understanding antimicrobialpharmocokinetics/dynamics and resistancemechanisms can help guide appropriate usage

Knowledge of local susceptibility patterns isessential

Paucity of new antimicrobial agents in pipeline

Documents

Antimicrobial Resistance Fellows 2009