1. Management of Serious MRSA Infections

2. Staphylococcus aureus
MSSA
MRSA
Cell Membrane Enzymes:
Abnormal Penicillin Binding Protein (PBP2a)
Β-Lactam
Antibiotics
Penicillins,
(Methicillin)
Cephalosporins,
Monobactams,
Carbapenems,
mecA gene
DNA
Staphylococcal Cassette Chromosome
(SCC)

3. MRSA: Resistance Genetics of Resistance MSSA MSSA MRSA MRSA HA-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
1990’s
1960’s
SCCmec types II, III
SCCmec type IV
PFGE: USA 100
PFGE: USA 300
MRSA
MRSA
Different genetic
backgrounds
HA-MRSA
CA-MRSA
Jevons MP. Br Med J. 1961;1:
Chambers HF. Clin Microbiol Rev. 1997;10:
Gillet Y et al. Lancet. 2002;359:
Vandenesch F et al. EID.2003; 9:978

4. MRSA: Virulence Genetics of Virulence MSSA MSSA MRSA MRSA HA-MRSA
mecA gene
DNA
LukSPV and
LukFPV genes
1990’s
1960’s
Genes that encode for
Panton-Valentin
leukocidin toxin
(PVL)
PVL
exotoxin
MRSA
MRSA
PVL (+) strains
More virulent strains
HA-MRSA
CA-MRSA
Labandeira-Rey M et al. Science. 2007;315:
Vandenesch F et al. EID.2003; 9:978

5. 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
Septic thrombosis
Klevens M et al. JAMA. 2007;298:
Moellering RC Jr. Ann Intern Med 144:368, 2006

6. UofL Guidelines for HAP/VAP
1. Selection of Empiric Therapy
2. De-escalation of Therapy
3. Duration of Therapy
4. UofL Treatment Pathway

7. HAP/VAP: Empiric Therapy
Hospital-Acquired Infections
Appropriate Empiric Therapy
Inappropriate Empiric Therapy
Percent Mortality
Study 1
Study 2
Study 3
Study 4
1.Luna C et al. Chest ;111:
2.Rello J et al. Am J Respr Crit Care Med. 1997;156:
3. Kollef MH et al. Chest ;113:
4. Ibrahim EH et al. Chest ;118:

8. HAP/VAP: Empiric Therapy
Correlation of Empiric Therapy with Patient Outcome
* Appropriate empiric therapy on day one
* Empiric therapy based on likely organisms

9. HAP/VAP: Etiology Likely Organisms 1. Microaspiration 2. Inhalation
The etiology of VAP
is closely related to
the microbiology
of the patient’s
oropharynx
3. Aspiration of
gastric content
5. Inoculation
Alveolar
Space
4. Hematogenous
spread

10. HAP/VAP: Etiology Microbiology of the Oropharynx Resistant Normal
Nosocomial
Flora
Normal
Community
Flora
Shift
Days after hospitalization

11. HAP/VAP: Etiology HAP/VAP: Likely Organisms Resistant Normal
Group 1
Core
Organisms
Group 2
Core Plus
Resistant Organisms
Resistant
Nosocomial
Flora
Normal
Community
Flora
Shift
Days after hospitalization
ATS/IDSA. Am J Respr Crit Care Med. 2005;171:388

12. HAP/VAP: Etiology HAP/VAP: Likely Organisms Group 1 Core Organisms
Core Plus
Resistant Organisms
*Streptococcus pneumoniae
*Methicillin-sensitive
Staphylococcus aureus
*Methicillin-resistant
Staphylococcus aureus
*Pseudomonas aeruginosa
*Acinetobacter species
*Citrobacter freundii
*Enterobacter cloacae
*Morganella morganii
*Haemophilus influenzae
*Moraxella catarrhalis *Escherichia coli
*Klebsiella pneumoniae
ATS/IDSA. Am J Respr Crit Care Med. 2005;171:388

13. HAP/VAP: Etiology Microbiology of the Oropharynx Resistant Normal
Nosocomial
Flora
Normal
Community
Flora
Shift
Early Onset
Late Onset
Days after hospitalization
Risk Factors for Resistant Organisms

14. HAP/VAP: Etiology Risk Factors for Resistant Organisms Group 1:
1. Documented MDR colonization No
Yes
2. Prolonged Hospitalization ( > 7 days) No
Yes
3. Prolonged Ventilation (> 3 days) No
Yes
4. Prior Antibiotic Use ( > 3 days) No
Yes
5. Immunosuppression No
Yes
Group 1:
Core Organisms
Group 2:
Core plus MDR
ATS/IDSA. Am J Respr Crit Care Med. 2005;171:388

15. 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

16. 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

17. VAP: Empiric Therapy NAP due to S. aureus: Kaplan-Meier Survival Curve
ITT S. aureus (n = 339)
100 %
Linezolid
P = 0.131
Vancomycin
Age < 65 yr
APACHE II score < 20
Single-lobe NAP
1.7 ( )
3.7 ( )
0.081
0.001
0.072
Predictors
P value
Linezolid therapy
0.068
Logistic Regression Analysis for Survival
OR (95% CI)
Survival (percentage of patients)
0 %
Days
Wunderink R et al. Chest ;124:

18. VAP: Empiric Therapy NAP due to MRSA: Kaplan-Meier Survival Curve
ITT MRSA (n = 160)
100 %
Linezolid
P = 0.025
Vancomycin
Survival (percentage of patients)
Predictors
OR (95% CI)
P value
Logistic Regression Analysis for Survival
Linezolid therapy
2.2 ( )
0.050
0 %
Days
Wunderink R et al. Chest ;124:

19. HAP/VAP: Empiric Therapy
Clinical Cure Rates for Patients with VAP
Linezolid
Vancomycin 80
P = 0.001 54 38
P = 0.02 62 49 35
P = 0.06 60
P = 0.07 45
(Percent of Patients)
Clinical Cure 40 37 21 20
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:

20. Vancomycin Susceptibility
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:

21. MRSA: Treatment Considerations
Vancomycin & MRSA: “S” “I” “R”
MIC ≥ 16
“R” VRSA
MIC 4-8
“I” VISA (GISA)
HA-MRSA 1 2 4
21%
75%
CA-MRSA
65%
35% 4%
“S” hVISA
“S” MIC 2 ug/ml
“S” MIC 1 ug/ml
“S” MIC ≤ 0.5 ug/ml
Allen M et al. IDSA Meeting 2008.

22. MRSA: Treatment Considerations
Vancomycin & MRSA: “S” “I” “R”
MIC ≥ 16
“R” VRSA
MIC 4-8
“I” VISA (GISA)
MRSA HAP/VAP
“S” hVISA
63%
“S” MIC 2 ug/ml
Treatment Failure
37%
“S” MIC 1 ug/ml
22%
“S” MIC 0.5 ug/ml
0.5 1 2
Vancomycin MIC
Zervos M et al. IDSA Meeting 2008.

23. 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

24. 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
*Quinolone:
Cipro/Levo OR
Meta-analysis: Monotherapy is not inferior to combination therapy
in the empirical treatment of VAP
Aarts MA. Crit Care Med Jan;36(1):108-17

25. HAP/VAP: Empiric Therapy
Group 2: Patient with RFRO
*Anti-Pseudomonal Beta-lactam:
Cefepime, Piperacillin-tazobactam,
(+/-) 2nd Antipseudomonal Agent
* Aminoglycoside:
Tobramycin
*Quinolone:
Cipro/Levo OR
PLUS Anti-MRSA Therapy
*Glycopeptide:
Vancomycin
*Oxazolidins:
Linezolid OR
Broad Spectrum Antibiotic Therapy

26. UofL Guidelines for HAP/VAP
1. Selection of Empiric Therapy
2. De-escalation of Therapy
3. Duration of Therapy
4. UofL Treatment Pathway

27. De-Escalation of Therapy
Initial Empiric
Therapy
De-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
Clinical Improvement
4. Discontinuation of combination anti-pseudomonal therapy
5. Switch to oral antibiotic therapy

28. De-Escalation of Therapy
Initial Empiric
Therapy
De-escalation of
Therapy
280 Patients
Patients treated for HAP/VAP
233 Patients
Empiric therapy for HAP/VAP
198 Patients
85%
Candidates for de-escalation

29. UofL Guidelines for HAP/VAP
1. Selection of Empiric Therapy
2. De-escalation of Therapy
3. Duration of Therapy
4. UofL Treatment Pathway

30. Hospital-Acquired Pneumonia
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:

31. 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

32. 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
ATB Use/Cost
3 days / $259
10 days / $640
.0001
LOS in ICU
9 days
15 days
.04
Superinfection
14 %
38 %
.01
Mortality
13 % (30 days)
31 % (30 days)
.06
Singh N et al. Am J Respr Crit Care Med. 2000;162:

33. 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

34. HAP: Duration of Therapy
Recommendations
Total duration of therapy of 4 days for patients that are candidates for short course therapy
4 days?
8 days?
For other patients consider discontinuation of antibiotics once documented clinical improvement
10 days?
14 days?
Total duration of therapy of +/- 14 days for HAP/VAP due to Pseudomonas or Acinetobacter or MRSA
21 days?

35. 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

36. 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