Management of Serious MRSA Infections. DNA Staphylococcus aureus MRSA mecA gene Cell Membrane...
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Transcript of Management of Serious MRSA Infections. DNA Staphylococcus aureus MRSA mecA gene Cell Membrane...
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