Transcript Slide 1

Management of Serious
MRSA Infections
Staphylococcus aureus
MSSA
MRSA
Cell Membrane Enzymes:
Abnormal Penicillin Binding Protein (PBP2a)
mecA gene
DNA
Staphylococcal Cassette Chromosome
(SCC)
Β-Lactam
Antibiotics
Penicillins,
(Methicillin)
Cephalosporins,
Monobactams,
Carbapenems,
MRSA: Resistance
Genetics of Resistance
MSSA
MSSA
MRSA
PBP2a encoded by a mecA gene
1960’s
Located in a mobile genetic element, the
Staphylococcal Cassette Chromosome mec
SCCmec types I, II, III, IV, V
SCCmec types II, III
SCCmec type IV
PFGE: USA 100
PFGE: USA 300
MRSA
HA-MRSA
1990’s
MRSA
Different genetic
backgrounds
Jevons MP. Br Med J. 1961;1:124-125
Gillet Y et al. Lancet. 2002;359:753-759
CA-MRSA
Chambers HF. Clin Microbiol Rev. 1997;10:781-791
Vandenesch F et al. EID.2003; 9:978
MRSA: Virulence
Genetics of Virulence
MSSA
MSSA
mecA gene
DNA
LukSPV and
LukFPV genes
1990’s
1960’s
Genes that encode for
Panton-Valentin
leukocidin toxin
(PVL)
MRSA
HA-MRSA
PVL (+) strains
More virulent strains
PVL
exotoxin
MRSA
CA-MRSA
Labandeira-Rey M et al. Science. 2007;315:1130-1133
Vandenesch F et al. EID.2003; 9:978
MRSA: Clinical Manifestations
MRSA Infections
HA-MRSA
CA-MRSA
Hospital-Acquired Pneumonia
Necrotizing skin infection
Ventilator-Associated Pneumonia
Cellulitis Abscess
Catheter Related Bacteremia
Necrotizing fasciitis
Catheter Related UTI
Bone & Joint Infections
Bone & Joint Infections
Necrotizing pneumonia
Endocarditis
Klevens M et al. JAMA. 2007;298:1763-1771
Septic thrombosis
Moellering RC Jr. Ann Intern Med 144:368, 2006
UofL Guidelines for HAP/VAP
1. Selection of Empiric Therapy
2. De-escalation of Therapy
3. Duration of Therapy
4. UofL Treatment Pathway
HAP/VAP: Empiric Therapy
100
Hospital-Acquired Infections
Appropriate Empiric Therapy
0
Percent Mortality
80
60
40
20
Inappropriate Empiric Therapy
Study 1
Study 2
Study 3
Study 4
1.Luna C et al. Chest. 1997;111:676-685 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
4. Ibrahim EH et al. Chest. 2000;118:146-155
HAP/VAP: Empiric Therapy
Correlation of Empiric Therapy with Patient Outcome
* Appropriate empiric therapy on day one
* Empiric therapy based on likely organisms
HAP/VAP: Etiology
Likely Organisms
1. Microaspiration
The etiology of VAP
is closely related to
the microbiology
of the patient’s
5. Inoculation oropharynx
Alveolar
Space
4. Hematogenous
spread
2. Inhalation
3. Aspiration of
gastric content
HAP/VAP: Etiology
Microbiology of the Oropharynx
Normal
Community
Flora
Shift
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
HAP/VAP: Etiology
HAP/VAP: Likely Organisms
Group 1
Core
Organisms
Group 2
Core Plus
Resistant Organisms
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
ATS/IDSA. Am J Respr Crit Care Med. 2005;171:388
HAP/VAP: Etiology
HAP/VAP: Likely Organisms
Group 1
Core
Organisms
*Streptococcus pneumoniae
*Methicillin-sensitive
Staphylococcus aureus
*Haemophilus influenzae
*Moraxella catarrhalis
*Escherichia coli
*Klebsiella pneumoniae
Group 2
Core Plus
Resistant Organisms
*Methicillin-resistant
Staphylococcus aureus
*Pseudomonas aeruginosa
*Acinetobacter species
*Citrobacter freundii
*Enterobacter cloacae
*Morganella morganii
ATS/IDSA. Am J Respr Crit Care Med. 2005;171:388
HAP/VAP: Etiology
Microbiology of the Oropharynx
Normal
Community
Flora
Early Onset
Shift
Resistant
Nosocomial
Flora
Late Onset
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
Risk Factors for Resistant Organisms
HAP/VAP: Etiology
Risk Factors for Resistant Organisms
1. Documented MDR colonization
No
Yes
No
2. Prolonged Hospitalization ( > 7 days)
Yes
No
3. Prolonged Ventilation (> 3 days)
Yes
No
4. Prior Antibiotic Use ( > 3 days)
Yes
No
5. Immunosuppression
Yes
Group 1:
Core Organisms
Group 2:
Core plus MDR
ATS/IDSA. Am J Respr Crit Care Med. 2005;171:388
HAP/VAP: Empiric Therapy
Group 1: Patient with no RFRO
*Streptococcus pneumoniae
*Methicillin-sensitive
Staphylococcus aureus
*Haemophilus influenzae
*Moraxella catarrhalis
*Escherichia coli
*Klebsiella pneumoniae
Focus Antibiotic Therapy
* Cephalosporins 3rd Generation: Ceftriaxone
* Penicillin/B-lactamase inhibitor: Ampicillin-sulbactam
HAP/VAP: Empiric Therapy
Group 2: Patient with RFRO
*Methicillin-resistant
Staphylococcus aureus
Vancomycin vs
Linezolid
*Pseudomonas aeruginosa
*Acinetobacter species
*Citrobacter freundii
*Enterobacter cloacae
*Morganella morganii
Monotherapy vs
Combination
Broad Spectrum Antibiotic Therapy
ATS/IDSA. Am J Respr Crit Care Med. 2005;171:388
VAP: Empiric Therapy
NAP due to S. aureus: Kaplan-Meier Survival Curve
ITT S. aureus (n = 339)
Survival (percentage of patients)
100 %
Linezolid
P = 0.131
Vancomycin
Logistic Regression Analysis for Survival
Predictors
OR (95% CI)
P value
APACHE II score < 20
3.7 (2.0-6.9)
0.001
Age < 65 yr
1.7 (1.0-2.9)
0.081
Single-lobe NAP
1.7 (1.0-2.9)
0.072
Linezolid therapy
1.7 (1.0-2.9)
0.068
0%
0
10
20
30
40
50
Days
Wunderink R et al. Chest. 2003;124:1789-1797
VAP: Empiric Therapy
NAP due to MRSA: Kaplan-Meier Survival Curve
ITT MRSA (n = 160)
Survival (percentage of patients)
100 %
Linezolid
P = 0.025
Vancomycin
Logistic Regression Analysis for Survival
Predictors
OR (95% CI)
P value
Linezolid therapy
2.2 (1.0-4.8)
0.050
0%
0
10
20
30
40
50
Days
Wunderink R et al. Chest. 2003;124:1789-1797
HAP/VAP: Empiric Therapy
Clinical Cure Rates for Patients with VAP
Linezolid
Vancomycin
Clinical Cure
(Percent of Patients)
80
P = 0.001
P = 0.02
60
P = 0.07
45
40
37
P = 0.06
54
49
38
35
21
20
0
62
VAP
(n=434)
G+ VAP
(n=214)
Sa VAP
(n=179)
MRSA VAP
(n=70)
Patient Population
Kollef MH et al. Intensive Care Med. 2004;30:388-394
MRSA: Treatment Considerations
Vancomycin & MRSA: “S” “I” “R”
Vancomycin Susceptibility
MIC ≥ 16
Resistant (VRSA)
MIC 4-8
Intermediate (VISA or GISA)
MIC ≤ 2
Susceptible (VS-MRSA)
Clinical and Laboratory Standards Institute (CLSI); 2006.
Moise-Broder PA et al. Clin Infect Dis. 2004;38:1700-1705.
MRSA: Treatment Considerations
Vancomycin & MRSA: “S” “I” “R”
MIC ≥ 16
“R” VRSA
MIC 4-8
“I” VISA (GISA)
75%
HA-MRSA
“S” hVISA
“S” MIC 2 ug/ml
21%
1
4%
4
2
65%
CA-MRSA
“S” MIC 1 ug/ml
“S” MIC ≤ 0.5 ug/ml
35%
1
2
4
Allen M et al. IDSA Meeting 2008.
MRSA: Treatment Considerations
Vancomycin & MRSA: “S” “I” “R”
MIC ≥ 16
“R” VRSA
MIC 4-8
“I” VISA (GISA)
Treatment Failure
MRSA HAP/VAP
“S” hVISA
63%
37%
22%
0.5
1
2
Vancomycin MIC
“S” MIC 2 ug/ml
“S” MIC 1 ug/ml
“S” MIC 0.5 ug/ml
Zervos M et al. IDSA Meeting 2008.
HAP/VAP: Empiric Therapy
Group 2: Patient with RFRO
*Methicillin-resistant
Staphylococcus aureus
Vancomycin vs
Linezolid
*Pseudomonas aeruginosa
*Acinetobacter species
*Citrobacter freundii
*Enterobacter cloacae
*Morganella morganii
Monotherapy vs
Combination
Broad Spectrum Antibiotic Therapy
ATS/IDSA. Am J Respr Crit Care Med. 2005;171:388
HAP/VAP: Empiric Therapy
Gram (-) rods: Combination Therapy
To obtain synergy
To prevent development of resistance
To provide a broad-spectrum empiric regimen
*Anti-Pseudomonal Beta-lactam:
Cefepime, Piperacillin-tazobactam,
PLUS 2nd Antipseudomonal Agent
* Aminoglycoside:
Tobramycin
OR
*Quinolone:
Cipro/Levo
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
HAP/VAP: Empiric Therapy
Group 2: Patient with RFRO
*Anti-Pseudomonal Beta-lactam:
Cefepime, Piperacillin-tazobactam,
(+/-) 2nd Antipseudomonal Agent
* Aminoglycoside:
Tobramycin
OR
*Quinolone:
Cipro/Levo
PLUS Anti-MRSA Therapy
*Glycopeptide:
Vancomycin
OR
*Oxazolidins:
Linezolid
Broad Spectrum Antibiotic Therapy
UofL Guidelines for HAP/VAP
1. Selection of Empiric Therapy
2. De-escalation of Therapy
3. Duration of Therapy
4. UofL Treatment Pathway
De-Escalation of Therapy
De-escalation of
Therapy
Initial Empiric
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
Clinical Improvement
4. Discontinuation of combination anti-pseudomonal therapy
5. Switch to oral antibiotic therapy
De-Escalation of Therapy
Initial Empiric
Therapy
De-escalation of
Therapy
Patients treated for HAP/VAP
280 Patients
Empiric therapy for HAP/VAP
233 Patients
Candidates for de-escalation
198 Patients
85%
UofL Guidelines for HAP/VAP
1. Selection of Empiric Therapy
2. De-escalation of Therapy
3. Duration of Therapy
4. UofL Treatment Pathway
Duration of Therapy
Hospital-Acquired Pneumonia
Short-course empiric antibiotic therapy for
patients with pulmonary infiltrates in the
intensive care unit
Clinical pulmonary infection score (CPIS)
Singh N et al. Am J Respr Crit Care Med. 2000;162:505-511
NAP: Short Course Therapy
Clinical Pulmonary Infection Score (CPIS)
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
NAP: Short Course Therapy
Clinical Pulmonary Infection Score (CPIS)
CPIS equal or < 6
ATB x 3 days
CPIS ≤ 6
CPIS > 6
Short Course
Standard Care
3 days / $259
10 days / $640
LOS in ICU
9 days
15 days
.04
Superinfection
14 %
38 %
.01
ATB Use/Cost
Mortality
13 % (30 days)
31 % (30 days)
.0001
.06
Singh N et al. Am J Respr Crit Care Med. 2000;162:505-511
HAP: Duration of Therapy
Short Course Therapy
280 Patients
CPIS < 6 on day 0 and day 3
Yes
No immunosuppression
No severe sepsis or shock
No bacteremia
No other site of infection
16 Patients
Candidate for Short
Course Therapy
HAP: Duration of Therapy
Recommendations
4 days?
Total duration of therapy of 4 days for
patients that are candidates for short course
therapy
8 days?
10 days?
For other patients consider discontinuation
of antibiotics once documented clinical
improvement
14 days?
21 days?
Total duration of therapy of +/- 14 days for
HAP/VAP due to Pseudomonas or
Acinetobacter or MRSA
UofL Guidelines for HAP/VAP
1. Clinical Diagnosis
2. Selection of Empiric Therapy
3. De-escalation of Therapy
4. Duration of Therapy
5. UofL Treatment Pathway
HAP/VAP: UofL Treatment Pathway
Day 0: Evaluation for “Empiric Therapy”
Cultures
Evaluate RFRO
Calculate CPIS
Start ATB: Group 1 Focus therapy vs Group 2 broad spectrum
Day 2/3: Evaluation for “De-escalation of Therapy”
Results of cultures and sensitivity
Pathogen directed
therapy
according to C&S
Discontinue MRSA
therapy if cultures
(-) for MRSA
Discontinue combination
therapy if cultures are
(-) for Pseudomonas
Day ≥4: Evaluation for “Duration of Therapy”
Candidate for short
course therapy:
4 days
Pseudomonas, MRSA,
Acinetobacter:
+/- 14 days
Other patients:
duration of therapy
based on clinical response