Methicillin Resistant Methicillin Resistant StaphylococcusStaphylococcus aureus aureus

(MRSA)(MRSA)What is it ?What is it ?

a)a) A A flesh-eatingflesh-eating virus virus

b)b) An Ebola-like pathogenAn Ebola-like pathogen

c)c) The plagueThe plague

d)d) I don’t know, but I don’t want I don’t know, but I don’t want them !them !

e)e) Previously common bacteria Previously common bacteria that have acquired resistance that have acquired resistance genes.genes.

S. aureus

Penicillin

[1950s]

Penicillin-resistant

S. aureus

Evolution of Drug Resistance in Evolution of Drug Resistance in S. S. aureusaureus

Methicillin

[1970s]

Methicillin-resistant S. aureus (MRSA)

Vancomycin-resistant

enterococci (VRE)

Vancomycin

[1990s]

[1997]

Vancomycin

intermediate-resistantS. aureus (VISA)

[ 2002 ]Vancomycin-resistant S.

aureus

0

10

20

30

40

50

60

Per

cen

t R

esis

tan

ceMethicillin-Resistant

Staphylococcus aureus (MRSA)

U.S. Non-Intensive Care

U.S. Intensive Care

The Nebraska Medical Center

Source: National Nosocomial Infections Surveillance (NNIS) System

Grundmann et al. Lancet 2006; 368:874-85.

Worldwide Prevalence of MRSA Among S. aureus IsolatesWorldwide Prevalence of MRSA Among S. aureus Isolates

5

S. aureusS. aureus: A well-armed : A well-armed pathogenpathogen

1) Adherence and colonization

2) Tissue destruction and invasion

3) Toxin production and “disease at a distance”

Virulence under tight regulatory control

Lowy, NEJM 1998

ColonizationColonization 2/3 to 3/4 of humans are 2/3 to 3/4 of humans are colonized by colonized by S. aureusS. aureus at at some point, 20% to 50% some point, 20% to 50% at any given time, 10% - at any given time, 10% - 20% persistently colonized20% persistently colonized

Anterior nares is most Anterior nares is most common site of common site of colonizationcolonization

80% to 90% of strains 80% to 90% of strains causing diseases come causing diseases come from endogenous florafrom endogenous flora

Risk of Infection:Risk of Infection: MSSA 2% - 10%MSSA 2% - 10% MRSA 5% - 30%MRSA 5% - 30%

S. aureusS. aureus Colonization Colonization

National Health and Nutrition Examination Survey 2001-2002 • 32.4% of population (89.4 million persons) nasal colonization by S. aureus• 0.8% MRSA• Burden of MRSA most likely greatly increased since 2001• Nashville: 2001 (0.8%); 2004 (9.2%) (Creech et al, Ped Inf Dis J,

2005) Kuehnert MJ, et al. J Infect Dis, 2006

Beta-lactamase producing and Beta-lactamase producing and methicillin-resistant methicillin-resistant S. aureusS. aureus

Hospital

Community

Hospital

Community

McDonald LC. J Infect Dis, 2006

Community-Acquired MRSACommunity-Acquired MRSA

Community MRSA Throughout the U.S. (2007)Community MRSA Throughout the U.S. (2007)

X

XX

X

X

XX

X

XX

XX

XX

XXX

X

X

X

XX

X

X

X

X

X

X

X

XX

X

XX

XXX

X

XX

X

X

X

Chambers HF. Personal Communication. January 19, 2007

Prevalence of CA-MRSAPrevalence of CA-MRSA

Survey of 11 EDs throughout US in Aug 2004Survey of 11 EDs throughout US in Aug 2004 422 pts with skin & soft tissue infection422 pts with skin & soft tissue infection 320/422 (75%) caused by 320/422 (75%) caused by S. aureusS. aureus MRSA 59% (15% - 74%), USA300 strain 97%MRSA 59% (15% - 74%), USA300 strain 97%

KC 74%; Atlanta 72%, Charlotte NC 68%, New KC 74%; Atlanta 72%, Charlotte NC 68%, New Orleans 67%, Albuquerque 60%, Phoenix 60%, Orleans 67%, Albuquerque 60%, Phoenix 60%, Philadelphia 55%, Portland OR 54%, Los Angeles Philadelphia 55%, Portland OR 54%, Los Angeles 51%, Minneapolis 39%, New York 15%51%, Minneapolis 39%, New York 15%

CA-MRSA: What’s Going On?CA-MRSA: What’s Going On?

SCCmec I-V, mecIV is most commonly found in CA-MRSA; 25 KB, mobile

What’s different about CA-What’s different about CA-MRSA?MRSA?

SCCmec IV (V) is mobile and in variety SCCmec IV (V) is mobile and in variety of background strainsof background strains

Replicate more rapidly than HA-MRSA Replicate more rapidly than HA-MRSA (23 min vs 46 min) – More fit than HA-(23 min vs 46 min) – More fit than HA-MRSAMRSA

MW2 sequence vs 5 HA-MRSA reveal 19 MW2 sequence vs 5 HA-MRSA reveal 19 putative virulence genes: 4 putative virulence genes: 4 Enterotoxins, 11 exotoxins (PVL), Enterotoxins, 11 exotoxins (PVL), collagen adhesin, etc. More virulent?collagen adhesin, etc. More virulent?

LD is 5x less than HA-MRSA (no single LD is 5x less than HA-MRSA (no single gene appears responsible)gene appears responsible)

What is PVL (Panton-Valentine What is PVL (Panton-Valentine Leukocidin)?Leukocidin)?

11stst described in 1932 described in 1932 Bicomponent synergistic membrane-Bicomponent synergistic membrane-

tropic toxintropic toxin Encoded by lukS-PV and lukF-PV genesEncoded by lukS-PV and lukF-PV genes Assembled as hetero-oligimers that Assembled as hetero-oligimers that

synergistically act to form pores in cell synergistically act to form pores in cell membranes (lysis) of pmns and membranes (lysis) of pmns and monocytes/macrophagesmonocytes/macrophages

Associated with necrotizing skin and Associated with necrotizing skin and soft tissue infections and pneumonia soft tissue infections and pneumonia

S. aureusS. aureus Today Today

Most common cause of endocarditis (38%) Most common cause of nosocomial

infection (13%) Most common cause of SSI (20%) Most common cause of cellulitis,

osteomyelitis, septic arthritis Common cause of bacteremia, nosocomial

pneumonia, foodborne disease, implant infection, abscess, etc

Staphylococcal Skin & Soft Tissue Staphylococcal Skin & Soft Tissue InfectionsInfections

Cellulitis

Staphylococcal Disease due to Metastatic Seeding

Staphylococcal Disease due to Metastatic Seeding

Staphylococcal Disease due to Metastatic Seeding: Endocarditis

Staphylococcal Staphylococcal Toxin-Mediated Toxin-Mediated DiseasesDiseases

Toxic Shock Syndrome

Staphylococcal Scalded Skin Syndrome

Staphylococcal Toxin-Staphylococcal Toxin-Mediated Diseases: Mediated Diseases: Food PoisoningFood Poisoning

Clinical Presentation of CA-Clinical Presentation of CA-MRSAMRSA

Clinical Presentation of CA-Clinical Presentation of CA-MRSAMRSA

Clinical Disease due to CA-Clinical Disease due to CA-MRSA MRSA

PyomyositisPurpura fulminans, Necrotizing fasciitis

Necrotizing Pneumonia

The distinction between CA and The distinction between CA and HA is blurring!HA is blurring!

Characterized 132 cases of MRSA BSI in AtlantaCharacterized 132 cases of MRSA BSI in Atlanta 34% of MRSA were USA 30034% of MRSA were USA 300

28% of pts with HA BSI factors28% of pts with HA BSI factors 20% of pts with nosocomial BSI 20% of pts with nosocomial BSI

0%

20%

40%

60%

80%

100%

Total (n=116) HA (n=107) Noso (n=49)

USA800

USA500

USA100

USA300

Seybold U, et al. Seybold U, et al. Clin Infect Dis, Clin Infect Dis, 20062006

Methicillin ResistantMethicillin Resistant Staphylococcus aureusStaphylococcus aureus

(MRSA)(MRSA)

Who usually gets infected with Who usually gets infected with MRSA?MRSA?

a)a) ID PhysiciansID Physicians

b)b) Family members of those who have Family members of those who have been previously diagnosed.been previously diagnosed.

c)c) Hospital personnel, especially NP’sHospital personnel, especially NP’s

d)d) Residents of extended care Residents of extended care facilitiesfacilities

e)e) Patients hospitalized for other Patients hospitalized for other medical reasons.medical reasons.

Treatment of CA-MRSATreatment of CA-MRSA

Most disease is skin & soft tissue (75% - Most disease is skin & soft tissue (75% - 80%)80%)

Data suggests that many cases can be Data suggests that many cases can be treated with I&D without Abxtreated with I&D without Abx 73% of pts in one study received antibiotics 73% of pts in one study received antibiotics

to which the organisms was resistant. No to which the organisms was resistant. No difference in number of follow-up visits, difference in number of follow-up visits, subsequent need for I&D, or change in subsequent need for I&D, or change in antibiotic therapy (Fridkin, NEJM, 2005)antibiotic therapy (Fridkin, NEJM, 2005)

Recurrent FurunculosisRecurrent Furunculosis

Very little data indicating Very little data indicating long-termlong-term benefit of benefit of decolonization regimens. decolonization regimens. Toxicity/cost/resistanceToxicity/cost/resistance

Combination of topical, mucosal, and systemic Combination of topical, mucosal, and systemic antibiotics:antibiotics: Oral TMP-SMX, nasal mupirocin, chlorhexidine Oral TMP-SMX, nasal mupirocin, chlorhexidine

showers x 5dshowers x 5d Bleach baths (1 teaspoon of bleach per gallon of Bleach baths (1 teaspoon of bleach per gallon of

water) x 10 minutes 2 times/wkwater) x 10 minutes 2 times/wk Environmental cleaning (bedclothes, towels, surfaces)Environmental cleaning (bedclothes, towels, surfaces)

Close contacts? Pets? Environment? Close contacts? Pets? Environment?

0 4 8 12 24 36 48102

103

104

105

106

107

108

109

1010

Ba

cte

ria [C

FU

/mL

]

Time (hours)

Linezolid Rifampin SXT SXT+Rifampin Clindamycin Minocycline Control

Time-kill curves for all isolates of Methicillin Time-kill curves for all isolates of Methicillin ResistantResistant Staphylococcus Aureus (12) Staphylococcus Aureus (12)

Kaka, et al IDSA, 2005

Inducible Clindamycin Inducible Clindamycin ResistanceResistance

Vancomycin Treatment of Vancomycin Treatment of MRSAMRSA

0

1

2

3

4

5

6

7

8

0 2h 4 8 12 18 24lo

g10 C

FU

Nafcillin Vancomycin

• Time-kill assays vancomycin Time-kill assays vancomycin kills kills S. aureusS. aureus more slowly than more slowly than beta-lactam antibioticsbeta-lactam antibiotics• Vancomycin treatment of R-Vancomycin treatment of R-sided endocarditis is assoc with sided endocarditis is assoc with failure in 15% - 33% vs. 5% for failure in 15% - 33% vs. 5% for nafcillinnafcillin• Bacteremia lasts a median of 7-9 Bacteremia lasts a median of 7-9 days with vancomycin treatment days with vancomycin treatment vs. 3-5 days with nafcillinvs. 3-5 days with nafcillin

Small and Chambers, AAC 1990; Korzeniowski Small and Chambers, AAC 1990; Korzeniowski et al, Ann Intern Med 1982;Levine et al, Ann et al, Ann Intern Med 1982;Levine et al, Ann Intern Med 1991; Chambers et al Ann Intern Intern Med 1991; Chambers et al Ann Intern Med 1988Med 1988

Vanc vs B-lactam for MSSA

FAQ Re: Treatment of FAQ Re: Treatment of MRSAMRSA What is role of aminoglycosidesWhat is role of aminoglycosides??

Gentamicin (in combination with B-lactam Gentamicin (in combination with B-lactam or Vanc) results in more rapid killing and or Vanc) results in more rapid killing and clearance of blood cultures and clearance of blood cultures and defervescence of fever. Goal peak of 3-5 defervescence of fever. Goal peak of 3-5 ug/mL, 3-5 days. ug/mL, 3-5 days. May be assoc with May be assoc with renal toxicityrenal toxicity (particularly in elderly) (particularly in elderly)

What is role of RifampinWhat is role of Rifampin?? Rifampin (in combination with B-lactam or Rifampin (in combination with B-lactam or

vanc) can result in indifference, vanc) can result in indifference, antagonism, or synergism. Rifampin in antagonism, or synergism. Rifampin in combination with FQ yields synergism.combination with FQ yields synergism.

Newer Agents to Treat Newer Agents to Treat MRSAMRSA

Quinupristin/Dalfopristin (Synercid)Linezolid (Zyvox)Daptomycin (Cubicin)Tigecycline (Tygacil)Investigational Agents

Oxazolidinones:Oxazolidinones:Linezolid (Zyvox®, 2000)Linezolid (Zyvox®, 2000)

Mechanism: Interferes with formation of protein synthesis initiation complexPharmacokinetics: Essentially 100% bioavailable (IV or oral), Peak level ~ 15, ½ life 5 hours (BID dosing)

Quinupristin/DalfopristinQuinupristin/Dalfopristin

SynercidSynercid (1999) (1999) Combination of quinupristin/dalfopristin, Combination of quinupristin/dalfopristin,

cidal for susceptible strains; static for cidal for susceptible strains; static for MLSMLSBB(+) strains(+) strains

CostCost IV route, phlebitisIV route, phlebitis Myalgias/arthralgiasMyalgias/arthralgias Cytochrome p450 (CYP3A4) metabolismCytochrome p450 (CYP3A4) metabolism

Adverse Events Associated with Adverse Events Associated with LinezolidLinezolid

Drug WarningDrug Warning:: Reversible myelosuppressionReversible myelosuppression

associated with linezolid therapy associated with linezolid therapy (particularly > 2 wks)(particularly > 2 wks)

Serotonin SyndromeSerotonin Syndrome Reported in pts on SSRI with Reported in pts on SSRI with

underlying hepatic, pulmonary, underlying hepatic, pulmonary, or cardiovascular dzor cardiovascular dz

HTN, agitation, tremors, fatigue, HTN, agitation, tremors, fatigue, palpitations (Raad et al, CID palpitations (Raad et al, CID 2003)2003)

NeuropathyNeuropathy Peripheral and Optic (Lee, et al, Peripheral and Optic (Lee, et al,

CID 2003)CID 2003) ResistanceResistance

Increasing reports of resistant Increasing reports of resistant staphylococci and enterococcistaphylococci and enterococci

Vaculated erythroblasts in subject receiving Linezolid x 4 mo

(Green, et al. JAMA 2001)

Baltz RH. In: Strohl WR, ed. Biotechnology of Antibiotics. 1997;415-435.

NH

HN

NH

OHN

CONH2

OCO2H

NH

O

O

NH

O

HN

HN

O

HO2C

NH

ONH2

O

HN

OHO2C

HN

O

NH

O

HN

HO O

NH

HO2C

O

O NH2

OO

(CH2)8CH3

Daptomycin Daptomycin (2003)(2003)

Lipopeptide Lipopeptide antibioticantibiotic

Fermentation Fermentation product of product of Streptomyces Streptomyces roseosporusroseosporus

Water solubleWater soluble StableStable

Bacteremia/Endocarditis Study Outcomes Bacteremia/Endocarditis Study Outcomes (ITT)(ITT)

56.3 55.2

43.337.7

42.1 43.8

11.1

22.2

0

10

20

30

40

50

60

Succ

ess

Rat

e (%

)

UncompBact

CompBact

R-endocard

L-endocard

DaptoComp

MRSA Study Outcomes at 6 weeks MRSA Study Outcomes at 6 weeks (ITT)(ITT)

44.4

32.6

60

45.5 45.5

27.3

50 50

0 00

10

20

30

40

50

60

Succ

ess

Rat

e (%

)

Overall Uncomp Bact Comp Bact R-Endocard L-Endocard

DaptoComp

Decreased Renal FunctionDecreased Renal Function

11

26.3

0

5

10

15

20

25

30

%

DaptoComp

Tigecycline (Tygacil)Tigecycline (Tygacil)

FDA Approval FDA Approval June 2005June 2005 Complicated skin Complicated skin

and skin structure and skin structure infections; infections; Complicated intra-Complicated intra-abdominal abdominal infectionsinfections

In-vitro activity vs. In-vitro activity vs. MRSA & VREMRSA & VRE

0102030405060708090

100

Tigecycline Vanc/ Az

Clinical Cure M-ITT, SSTI, N= 1057

Investigational Anti-Investigational Anti-Staphylococcal AntibioticsStaphylococcal Antibiotics

GlycopeptidesGlycopeptides Ortivancin (Intermune)Ortivancin (Intermune) Dalbovancin (Vicuron)Dalbovancin (Vicuron) Telavancin (Theravance)Telavancin (Theravance)

DHFR inhibitorDHFR inhibitor Iclaprim (Arpida)Iclaprim (Arpida)

Novel B-lactamsNovel B-lactams CeftobiproleCeftobiprole BMS-247243, RWJ 54428, CB-181963, BAL BMS-247243, RWJ 54428, CB-181963, BAL

5788, S-35785788, S-3578

Other Potential Anti-Other Potential Anti-Staphylococcal AgentsStaphylococcal Agents

Capsule 5/8 Vaccine (NABI): - Capsule 5/8 Vaccine (NABI): - FDA fast tracked FDA fast tracked announced 10/12/04; Halt in development 11/05 announced 10/12/04; Halt in development 11/05

Staph capsule IG (NABI & Biosynexus) Staph capsule IG (NABI & Biosynexus) (Halt (Halt 11/05)11/05)

Lysostaphin (Biosynexus)Lysostaphin (Biosynexus) Aurexis (Inhibitex) anti-ClfAAurexis (Inhibitex) anti-ClfA Veronate (Inhibitex) Adhesin Ab (neonates)Veronate (Inhibitex) Adhesin Ab (neonates) Aurograb (NeuTec) Ab vs ABC transporterAurograb (NeuTec) Ab vs ABC transporter Peptide deformylase inhibitorsPeptide deformylase inhibitors

Methicillin Resistant Methicillin Resistant Staphylococcus Staphylococcus aureusaureus (MRSA) (MRSA)

How can we protect How can we protect our patients, our patients, ourselves ?ourselves ?

MRSA MRSA precautionsprecautions

Handwashing Handwashing ComplianceCompliance

AuthorAuthor Clinical SettingClinical Setting Rate of Compliance, Rate of Compliance, %%

Preston et al.Preston et al. Open wardOpen ward

ICUICU1616

3030

Albert et alAlbert et al ICUsICUs

ICUsICUs4141

2828

LarsonLarson All wardsAll wards 4444

DonowitzDonowitz PICUPICU 3030

GrahamGraham ICUICU 3232

Dubbert et alDubbert et al ICUICU 8181

Pettinger et alPettinger et al SICUSICU 5151

Larson et alLarson et al NICU/othersNICU/others 2929

Doebbeling et alDoebbeling et al ICUsICUs 4040

Zimakoff et alZimakoff et al ICUsICUs 4040

Meengs et alMeengs et al Emergency departmentEmergency department 3232

Pittet et alPittet et al All wardsAll wards 4848Boyce JM. Boyce JM. Clin Infect Dis.Clin Infect Dis. 2001;33:S135. 2001;33:S135.

Infection Control:Infection Control:Conflicting ApproachesConflicting Approaches

““Search and Destroy” Search and Destroy” Universal application of active Universal application of active

surveillance cultures and rigorous surveillance cultures and rigorous enforcement of contact isolationenforcement of contact isolation

DecolonizationDecolonization Laissez-Faire Laissez-Faire

No cultures, No isolation for pts No cultures, No isolation for pts colonized or infected with MRSAcolonized or infected with MRSA

Numerous reports of control of MRSA, Numerous reports of control of MRSA, primarily in short-term outbreak setting primarily in short-term outbreak setting through application of contact isolation through application of contact isolation and surveillance culturesand surveillance cultures

Experience in Netherlands and Northern Experience in Netherlands and Northern EuropeEurope

ICHE 2003

Strategies to Reduce Transmission of Strategies to Reduce Transmission of Antimicrobial Resistant Bacteria in the Antimicrobial Resistant Bacteria in the ICU (STAR-ICU)ICU (STAR-ICU)

Huskins, et al. SHEA 2007Huskins, et al. SHEA 2007. . Prospective, cluster-Prospective, cluster-randomized study of Std Precautions vs Intense randomized study of Std Precautions vs Intense Control StrategyControl Strategy

10 ICUs in ICS vs 9 ICUs in Std precautions10 ICUs in ICS vs 9 ICUs in Std precautions All pts at admit in ICS had surveillance cx for All pts at admit in ICS had surveillance cx for

MRSA and VRE, In ICS unit pts placed in MRSA and VRE, In ICS unit pts placed in universal glove use until Cx knownuniversal glove use until Cx known

5434 pts in ICS ICUs vs 3705 pts in Std ICUs5434 pts in ICS ICUs vs 3705 pts in Std ICUs No differences in pt populations re: comorbidity, No differences in pt populations re: comorbidity,

Severity of illness, LOS, devices, antibiotics, Severity of illness, LOS, devices, antibiotics, ~90% compliance with cultures~90% compliance with cultures

Life Goes On!