Management of Serious Management of Serious MRSA InfectionsMRSA Infections

DNA

Staphylococcus aureusStaphylococcus aureus

MRSA

mecA gene

Cell Membrane Enzymes: Cell Membrane Enzymes: Abnormal Penicillin Binding Protein (PBP2a) Abnormal Penicillin Binding Protein (PBP2a)

ΒΒ-Lactam -Lactam AntibioticsAntibioticsPenicillins,Penicillins,

(Methicillin)(Methicillin)Cephalosporins,Cephalosporins,Monobactams,Monobactams,Carbapenems, Carbapenems, Staphylococcal Cassette Chromosome

(SCC)

MSSA

Chambers HF. Clin Microbiol Rev. 1997;10:781-791

MSSA

MRSA

PBP2a encoded by a mecA gene

Located in a mobile genetic element, the Staphylococcal Cassette Chromosome mec SCCmec types I, II, III, IV, V

SCCmec types II, III

MSSA

MRSA

1990’s

SCCmec type IV

HA-MRSA CA-MRSA

Genetics of Resistance

Vandenesch F et al. EID.2003; 9:978Jevons MP. Br Med J. 1961;1:124-125 Gillet Y et al. Lancet. 2002;359:753-759

Different genetic backgrounds

PFGE: USA 300 PFGE: USA 100

1960’s

MRSA

MRSA: Resistance MRSA: Resistance

PVL exotoxin

MSSA

MRSA

1960’s

MSSA

MRSA

1990’s

HA-MRSA CA-MRSA

Genetics of Virulence

Vandenesch F et al. EID.2003; 9:978Labandeira-Rey M et al. Science. 2007;315:1130-1133

MRSA: VirulenceMRSA: Virulence

DNA LukSPV andLukFPV genes

mecA gene

PVL (+) strainsMore virulent strains

Genes that encode for Panton-Valentin leukocidin toxin

(PVL)

Catheter Related Bacteremia

Endocarditis

Bone & Joint Infections

Hospital-Acquired Pneumonia

HA-MRSA

Klevens M et al. JAMA. 2007;298:1763-1771

MRSA: Clinical ManifestationsMRSA: Clinical Manifestations

CA-MRSA

Cellulitis Abscess

Necrotizing fasciitis

Necrotizing skin infection

Septic thrombosis

Necrotizing pneumonia

Ventilator-Associated Pneumonia

MRSA Infections

Moellering RC Jr. Ann Intern Med 144:368, 2006

Bone & Joint Infections Catheter Related UTI

UofL Guidelines for HAP/VAP

4. UofL Treatment Pathway 4. UofL Treatment Pathway 4. UofL Treatment Pathway 4. UofL Treatment Pathway

2. De-escalation of Therapy 2. De-escalation of Therapy 2. De-escalation of Therapy 2. De-escalation of Therapy

1. Selection of Empiric Therapy 1. Selection of Empiric Therapy 1. Selection of Empiric Therapy 1. Selection of Empiric Therapy

3. Duration of Therapy 3. Duration of Therapy 3. Duration of Therapy 3. Duration of Therapy

Hospital-Acquired InfectionsHospital-Acquired Infections

P

erce

nt

Mor

tali

ty

0

20

40

60

80

100

Study 1 Study 2 Study 3 Study 4

4. Ibrahim EH et al. Chest. 2000;118:146-155

2.Rello J et al. Am J Respr Crit Care Med. 1997;156:196-200

3. Kollef MH et al. Chest. 1998;113:412-420

1.Luna C et al. Chest. 1997;111:676-685

Appropriate Empiric Therapy

Inappropriate Empiric Therapy

HAP/VAP: Empiric Therapy

* Appropriate empiric therapy on day one* Appropriate empiric therapy on day one * Empiric therapy based on likely organisms* Empiric therapy based on likely organisms

* Appropriate empiric therapy on day one* Appropriate empiric therapy on day one * Empiric therapy based on likely organisms* Empiric therapy based on likely organisms

Correlation of Empiric Therapy with Patient OutcomeCorrelation of Empiric Therapy with Patient Outcome

HAP/VAP: Empiric Therapy

AlveolarAlveolar SpaceSpace

3. Aspiration of gastric content

3. Aspiration of gastric content

2. Inhalation2. Inhalation

4. Hematogenous spread

4. Hematogenous spread

5. Inoculation5. Inoculation

1. Microaspiration1. Microaspiration

The etiology of VAP is closely related to the microbiology of the patient’s oropharynx

The etiology of VAP is closely related to the microbiology of the patient’s oropharynx

Likely Organisms

HAP/VAP: Etiology

Microbiology of the Oropharynx

Normal Community Flora

Resistant Nosocomial Flora

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Days after hospitalization

Shift

HAP/VAP: Etiology

Normal Community Flora

Resistant Nosocomial Flora

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Days after hospitalization

Shift

HAP/VAP: Etiology

ATS/IDSA. Am J Respr Crit Care Med. 2005;171:388

HAP/VAP: Likely Organisms

Group 1 Core

Organisms

Group 2 Core Plus

Resistant Organisms

HAP/VAP: Etiology

ATS/IDSA. Am J Respr Crit Care Med. 2005;171:388

HAP/VAP: Likely Organisms

Group 1 Core

Organisms

Group 2 Core Plus

Resistant Organisms

*Streptococcus pneumoniae *Methicillin-sensitive Staphylococcus aureus*Haemophilus influenzae*Moraxella catarrhalis *Escherichia coli*Klebsiella pneumoniae

*Pseudomonas aeruginosa*Acinetobacter species *Citrobacter freundii*Enterobacter cloacae*Morganella morganii

*Methicillin-resistant Staphylococcus aureus

Normal Community Flora

Resistant Nosocomial Flora

Shift

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Days after hospitalization

Microbiology of the Oropharynx

HAP/VAP: Etiology

Late OnsetEarly Onset

Risk Factors for Resistant Organisms

Group 1: Core Organisms

Group 1: Core Organisms

Group 2: Core plus MDR

Group 2: Core plus MDR

2. Prolonged Hospitalization ( > 7 days)

Risk Factors for Resistant Organisms

3. Prolonged Ventilation (> 3 days)

4. Prior Antibiotic Use ( > 3 days)

5. Immunosuppression

1. Documented MDR colonization

No

No

No

No

Yes Yes

Yes

Yes

No

Yes

ATS/IDSA. Am J Respr Crit Care Med. 2005;171:388

HAP/VAP: Etiology

Group 1: Patient with no RFRO

Focus Antibiotic Therapy

HAP/VAP: Empiric Therapy

*Streptococcus pneumoniae *Methicillin-sensitive Staphylococcus aureus

*Haemophilus influenzae*Moraxella catarrhalis *Escherichia coli*Klebsiella pneumoniae

* Cephalosporins 3rd Generation: Ceftriaxone

* Penicillin/B-lactamase inhibitor: Ampicillin-sulbactam

Group 2: Patient with RFRO

ATS/IDSA. Am J Respr Crit Care Med. 2005;171:388

Broad Spectrum Antibiotic Therapy

Vancomycin vs Linezolid

Monotherapy vs Combination

HAP/VAP: Empiric Therapy

*Pseudomonas aeruginosa*Acinetobacter species *Citrobacter freundii*Enterobacter cloacae*Morganella morganii

*Methicillin-resistant Staphylococcus aureus

Days0 10 20 30 40 50

NAP due to NAP due to S. aureusS. aureus: Kaplan-Meier Survival Curve: Kaplan-Meier Survival Curve

Surv

ival

(pe

rcen

tage

of

pat

ien

ts)

Surv

ival

(pe

rcen

tage

of

pat

ien

ts)

100 %

0 %

Vancomycin

Linezolid

ITT S. aureus (n = 339)

P = 0.131

Wunderink R et al. Chest. 2003;124:1789-1797

VAP: Empiric Therapy

OR (95% CI)OR (95% CI)

Age < 65 yrAge < 65 yr

APACHE II score < 20APACHE II score < 20

Single-lobe NAPSingle-lobe NAP

1.7 (1.0-2.9)1.7 (1.0-2.9)

3.7 (2.0-6.9)3.7 (2.0-6.9)

1.7 (1.0-2.9)1.7 (1.0-2.9)

0.0810.081

0.0010.001

0.0720.072

PredictorsPredictors P valueP value

Linezolid therapyLinezolid therapy 1.7 (1.0-2.9)1.7 (1.0-2.9) 0.0680.068

Logistic Regression Analysis for SurvivalLogistic Regression Analysis for Survival

Days0 10 20 30 40 50

Su

rviv

al (

perc

enta

ge o

f p

atie

nts

) Su

rviv

al (

perc

enta

ge o

f p

atie

nts

)

100 %

0 %

Vancomycin

Linezolid

ITT MRSA (n = 160)

P = 0.025

Wunderink R et al. Chest. 2003;124:1789-1797

NAP due to MRSA: Kaplan-Meier Survival CurveNAP due to MRSA: Kaplan-Meier Survival Curve

VAP: Empiric Therapy

PredictorsPredictors OR (95% CI)OR (95% CI) P valueP value

Logistic Regression Analysis for SurvivalLogistic Regression Analysis for Survival

Linezolid therapyLinezolid therapy 2.2 (1.0-4.8)2.2 (1.0-4.8) 0.0500.050

C

lini

cal C

ure

(Per

cent

of

Pat

ient

s)

LinezolidLinezolid LinezolidLinezolid VancomycinVancomycinVancomycinVancomycin

Patient Population

VAP(n=434)

4537

62

21

Clinical Cure Rates for Patients with VAP Clinical Cure Rates for Patients with VAP

0

20

40

60

80

Kollef MH et al. Intensive Care Med. 2004;30:388-394

G+ VAP (n=214)

Sa VAP (n=179)

MRSA VAP (n=70)

P = 0.07 54

38

P = 0.02

49

35

P = 0.06

P = 0.001

HAP/VAP: Empiric Therapy

Vancomycin & MRSA: “S” “I” “R”

MRSA: Treatment ConsiderationsMRSA: Treatment Considerations

Moise-Broder PA et al. Clin Infect Dis. 2004;38:1700-1705.

Clinical and Laboratory Standards Institute (CLSI); 2006.

MIC ≤ 2

MIC 4-8

MIC ≥ 16

Susceptible (VS-MRSA)

Intermediate (VISA or GISA)

Resistant (VRSA)

Vancomycin Susceptibility

Vancomycin & MRSA: “S” “I” “R”

MRSA: Treatment ConsiderationsMRSA: Treatment Considerations

“R” VRSA

“I” VISA (GISA)

“S” hVISA

“S” MIC 2 ug/ml

“S” MIC 1 ug/ml

“S” MIC ≤ 0.5 ug/ml

MIC ≥ 16

MIC 4-8

Allen M et al. IDSA Meeting 2008.

HA-MRSA

1 2 4

21%

75%

CA-MRSA65%

1 2 4

35%

4%

Vancomycin & MRSA: “S” “I” “R”

MRSA: Treatment ConsiderationsMRSA: Treatment Considerations

“R” VRSA

“I” VISA (GISA)

“S” hVISA

“S” MIC 2 ug/ml

“S” MIC 1 ug/ml

“S” MIC 0.5 ug/ml

Vancomycin MIC0.5 1 2

Tre

atm

ent

Fai

lure

22%

37%

63%

MIC ≥ 16

MIC 4-8

MRSA HAP/VAPMRSA HAP/VAP

Zervos M et al. IDSA Meeting 2008.

Group 2: Patient with RFRO

ATS/IDSA. Am J Respr Crit Care Med. 2005;171:388

Broad Spectrum Antibiotic Therapy

Vancomycin vs Linezolid

Monotherapy vs Combination

HAP/VAP: Empiric Therapy

*Pseudomonas aeruginosa*Acinetobacter species *Citrobacter freundii*Enterobacter cloacae*Morganella morganii

*Methicillin-resistant Staphylococcus aureus

Gram (-) rods: Combination Therapy

To obtain synergy

To prevent development of resistance

To provide a broad-spectrum empiric regimen

HAP/VAP: Empiric Therapy

*Anti-Pseudomonal Beta-lactam: Cefepime, Piperacillin-tazobactam,

* Aminoglycoside: Tobramycin

*Quinolone: Cipro/Levo

PLUS 2nd Antipseudomonal Agent

OR

Meta-analysis: Monotherapy is not inferior to combination therapy in the empirical treatment of VAP

Aarts MA. Crit Care Med. 2008 Jan;36(1):108-17

Group 2: Patient with RFRO

*Anti-Pseudomonal Beta-lactam: Cefepime, Piperacillin-tazobactam,

*Glycopeptide: Vancomycin

*Oxazolidins: Linezolid

PLUS Anti-MRSA Therapy

* Aminoglycoside: Tobramycin

*Quinolone: Cipro/Levo

(+/-) 2nd Antipseudomonal Agent

OR

OR

HAP/VAP: Empiric Therapy

Broad Spectrum Antibiotic Therapy

UofL Guidelines for HAP/VAP

4. UofL Treatment Pathway 4. UofL Treatment Pathway 4. UofL Treatment Pathway 4. UofL Treatment Pathway

2. De-escalation of Therapy 2. De-escalation of Therapy 2. De-escalation of Therapy 2. De-escalation of Therapy

1. Selection of Empiric Therapy 1. Selection of Empiric Therapy 1. Selection of Empiric Therapy 1. Selection of Empiric Therapy

3. Duration of Therapy 3. Duration of Therapy 3. Duration of Therapy 3. Duration of Therapy

De-escalation of Therapy

Initial Empiric Therapy

De-Escalation of TherapyDe-Escalation of Therapy

Positive Culture

1. Pathogen directed therapy according to C&S

Negative Culture

2. No MRSA: Discontinuation of anti-MRSA therapy

3. No Pseudomonas: Discontinuation of combination therapy

5. Switch to oral antibiotic therapy

4. Discontinuation of combination anti-pseudomonal therapy

Clinical Improvement

De-escalation of Therapy

Initial Empiric Therapy

De-Escalation of TherapyDe-Escalation of Therapy

280 PatientsPatients treated for HAP/VAP

233 PatientsEmpiric therapy for HAP/VAP

198 PatientsCandidates for de-escalation 85%

UofL Guidelines for HAP/VAP

4. UofL Treatment Pathway 4. UofL Treatment Pathway 4. UofL Treatment Pathway 4. UofL Treatment Pathway

2. De-escalation of Therapy 2. De-escalation of Therapy 2. De-escalation of Therapy 2. De-escalation of Therapy

1. Selection of Empiric Therapy 1. Selection of Empiric Therapy 1. Selection of Empiric Therapy 1. Selection of Empiric Therapy

3. Duration of Therapy 3. Duration of Therapy 3. Duration of Therapy 3. Duration of Therapy

Hospital-Acquired Pneumonia

Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit

Singh N et al. Am J Respr Crit Care Med. 2000;162:505-511

Duration of TherapyDuration of Therapy

Clinical pulmonary infection score (CPIS)

Clinical Pulmonary Infection Score (CPIS)

NAP: Short Course Therapy NAP: Short Course Therapy

1. Temperature: 0 to 2 points

2. Blood Leukocytes: 0 to 1 point

3. Tracheal secretions: 0 to 2 points

4. Oxygenation, PaO2/FIO2: 0 to 2 points

5. Pulmonary radiography: 0 to 2 points

6. Progression of pulmonary infiltrate: 0 to 2 points

7. Culture of tracheal aspirate: 0 to 2 points

Clinical Pulmonary Infection Score (CPIS)

CPIS equal or < 6

ATB x 3 days

CPIS > 6 CPIS ≤ 6

Singh N et al. Am J Respr Crit Care Med. 2000;162:505-511

NAP: Short Course Therapy NAP: Short Course Therapy

ATB Use/Cost

Superinfection

LOS in ICU

Mortality

3 days / $259 10 days / $640

9 days 15 days

14 % 38 %

13 % (30 days) 31 % (30 days)

.0001

.04

.01

.06

Short Course Standard Care

Candidate for Short Course Therapy

Candidate for Short Course Therapy

CPIS < 6 on day 0 and day 3

Short Course Therapy

No severe sepsis or shock

No immunosuppression

Yes

HAP: Duration of Therapy

No bacteremia

No other site of infection

16 Patients

280 Patients

HAP: Duration of Therapy

8 days?

14 days?

21 days?

10 days?

4 days?

For other patients consider discontinuation of antibiotics once documented clinical improvement

Total duration of therapy of +/- 14 days for HAP/VAP due to Pseudomonas or Acinetobacter or MRSA

Total duration of therapy of 4 days for patients that are candidates for short course therapy

Recommendations

UofL Guidelines for HAP/VAP

5. UofL Treatment Pathway 5. UofL Treatment Pathway 5. UofL Treatment Pathway 5. UofL Treatment Pathway

3. De-escalation of Therapy 3. De-escalation of Therapy 3. De-escalation of Therapy 3. De-escalation of Therapy

2. Selection of Empiric Therapy 2. Selection of Empiric Therapy 2. Selection of Empiric Therapy 2. Selection of Empiric Therapy

4. Duration of Therapy 4. Duration of Therapy 4. Duration of Therapy 4. Duration of Therapy

1. Clinical Diagnosis 1. Clinical Diagnosis 1. Clinical Diagnosis 1. Clinical Diagnosis

Day 2/3: Evaluation for “De-escalation of Therapy”

Results of cultures and sensitivity

Discontinue MRSA therapy if cultures

(-) for MRSA

Discontinue combination therapy if cultures are (-) for Pseudomonas

Day 0: Evaluation for “Empiric Therapy”

Cultures Calculate CPIS Evaluate RFRO

Start ATB: Group 1 Focus therapy vs Group 2 broad spectrum

Day ≥4: Evaluation for “Duration of Therapy”

Pathogen directed therapy

according to C&S

Candidate for short course therapy:

4 days

Pseudomonas, MRSA, Acinetobacter:

+/- 14 days

Other patients: duration of therapy

based on clinical response

HAP/VAP: UofL Treatment Pathway HAP/VAP: UofL Treatment Pathway