Antimicrobial Resistance

Timothy H. Dellit, MDthdellit@u.washington.edu

Infection Control and Antimicrobial ManagementHarborview Medical Center

Gram Positive ResistanceICU 1995-2004

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National Nosocomial Infections Surveillance (NNIS) System

Methicillin-Resistant Staphylococcus aureus

Vancomycin-Resistant Enterococcus

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

New Resistant Bacteria

Mutations

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Susceptible Bacteria

Resistant Bacteria

Resistance Gene Transfer

Emergence of Antimicrobial Resistance

Resistant StrainsRare

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Resistant Strains Dominant

Antimicrobial Exposure

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Selection for Antimicrobial-Resistant Strains

Mechanisms of Resistance

• Inactivation of drug– Beta-lactamases

• Alteration of the target– Penicillin binding proteins– Ribosomes

• Decreased permeability• Drug efflux

R1 C NH HC H2C C

C N C COOH

S

CH3

CH3

O

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β-lactamase

Site of β-lactamase Activity

Increased Macrolide Consumption and the Emergence of Resistance

N Engl J Med 1997;337:441-6

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

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

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)

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

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.

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

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

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%

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

Fluoroquinolones and AUC:MICD

rug

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Time

MIC

Peak

Area Under the Curve (AUC)

• Concentration-dependent killing (AUC:MIC)• Fluoroquinolone targets

DNA gyraseTopoisomerase IV

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

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

35 y o man with a history of HIV and methamphetamine use presents to clinic

with a right biceps abscess.

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

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.

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

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

Washington State MRSA TrendAntibiotic Resistance Sentinel Network

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All isolates

Outpatient isolates

MRSA Resistance to Beta-Lactams

Beta-Lactam

Modified from David Spach, MD

Cell WallCell Membrane

Alternative Penicillin Binding Protein PBP2a

DNA

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

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)

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

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

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.

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

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All Infections Excluding TV Endocarditis

Vancomycin

TMP-SMX

Clin

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p < 0.02 p = 0.06

*All patients with MRSA were cured

May not be effective against -hemolytic streptococci (ie Group A strep)

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

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

Vancomycin MIC and Clinical Outcome

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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

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age

Arch Intern Med 2006;166:2138-2144

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

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

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

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

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

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

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

New Antibacterial Drugs Approved By FDA

Linezolid 2000

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

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