MRSA VAP

Paige Miller, PharmD Candidate 2016

 Patient Case
• LC is a 76 yo WF who presented to Grant Memorial
Hospital on 11/13 with pain in her left hip and a left calf
laceration resulting from a fall earlier that day.
• Patient was hypotensive in the emergency department
with SBPs ranging from 67 to 82 mmHg.
• Calf laceration had moderate bleeding.
• She was taking dabigatran for chronic atrial fibrillation at
home.
• Left hip X-ray revealed a left femur neck fracture.
• Leukocytosis was also noted.
• During transfer to Winchester Medical Center she became
hypotensive and was given norepinephrine.
 Case: Labs on Arrival

11/13 11/13
Blood Pressure (mmHg) 133/103 Sodium (mMol/L) 142
Heart Rate (bpm) 115 Chloride(mMol/L) 108
Respiratory Rate (bpm) 22 BUN (mg/dL) 16
Temperature (°F ) 98.1 Potassium (mMol/L) 4.3
WBC (k/cmm) 35.5 CO2 (mMol/L) 19.1
HGB (gm/dL) 10.2 SCr (mg/dL) 1.20
HCT (%) 30.7 BG (mg/dL) 159

• Height: 5’ • IBW: 45.5 kg

• Weight: 104 kg • DW: 68.9 kg
• CrCl: 75.4 mL/min
 Case
• PMH pertinent for atrial fibrillation, CHF, coronary
artery disease (CAD), myocardial infarction,
diabetes mellitus, ventricular tachycardia and
venous stasis ulcer of lower extremity with
recurrent cellulitis.
• Pertinent Home Medications:
• Atenolol acetaminophen
• Dabigatran • Losartan
• Digoxin • Pravastatin
• Furosemide • Prednisone
• Hydrocodone-
Allergies: baclofen, flu virus vaccine, tape
 Case

• Treated for a urinary tract infection (UTI) on

10/29/15.

• Relevant Home Medication: Amoxicillin-

clavulanate 500-125 mg: 1 tablet PO TID.

• Urine Culture taken on 11/13/15 showed no

growth.
 Case
• Date of Intubation: 11/13/15
• On 11/17 (Day 5 of Hospitalization) LC spiked a
fever and her WBC count started increasing
• Labs began improving on 11/20 before
increasing again on 11/21
• Extubation was attempted on 11/21, she
decompensated and was re-intubation on 11/22
 Case: Relevant Labs
11/17 11/18 11/19
Temperature (°F ) 99 100.7 100.8
WBC (k/cmm) 15.1 17.5 19.6
HGB (gm/dL) 7.8 7.1 9.0
HCT (%) 22.4 20.9 26.2
Platelet count (K/cmm) 132 149 154
Lymphocytes (%) 9.0 7.0 13.0
Bands (%) 2 5 3
Creatinine (mg/dL) 0.73 0.72 0.66
BP (mmHg) 107/52 122/47 114/45
 Case: Microbiology
• Respiratory Culture (from endotracheal aspirate)
• Positive for Methicillin Resistant Staphylococcus aureus
(MRSA) on 11/17, 11/21 and 11/23
• Susceptible to : Linezolid (2), Rifampin (≤ 0.5), Tetracycline
(≤1), Trimeth/Sulfa (≤ 10), Vancomycin (1)
• Resistant to: Nafcillin, Clindamycin
• Moderate growth Candida albicans on 11/17

• Blood Cultures (11/13, 11/18, 11/20, 12/01), Urine Cultures

(11/13, 11/18, 11/23,12/01 ) and Fugal Culture (11/20) all
showed no growth
• Vancomycin Trough 11/16 was 10.09 mg/L
 Patient Case: Problem
List
• Suspected sepsis with a hospital acquired
organism
• Circulatory shock
• Acute-on-chronic respiratory failure
• Atrial fibrillation
• Acute post hemorrhagic anemia
• Lactic acidosis
• Acute-on-chronic systolic congestive heart failure (CHF)
• Comminuted fracture of the left hip
 Case
Current Inpatient Antibiotics Medications
Antibiotics Dose Frequency Start Date Stop Date
Linezolid 600 mg IV BID 11/21 Current

Previous Inpatient Antibiotics Medications

Antibiotics Strength Frequenc Started Stopped Days of Therapy
y
Cefepime 2g IV Q12H 11/13 11/19 7
Vancomycin 1000 mg IV Q24H 11/13 11/17 -
1250 mg IV Q24H 11/18 11/21 9
Zosyn 3.375 mg IV Q8H 11/19 11/29 11
ext. infusion
 Case
• Assessment:

1. Fever

2. Increasing WBC count

3. Intubated for ≥ 72 hours

4. Respiratory Culture positive for MRSA

Ventilator Associated Pneumonia (VAP)1

VAP: pneumonia that develops more than 48-72 hours

after endotracheal intubation1

• Common Causes1 • Signs and Symptoms1

• Aerobic gram-negative • Fever > 38° C (100.4°F),
bacilli • Leukocytosis or leukopenia
• P. aeruginosa, Escherichia • Purulent secretions
coli, Klebsiella pneumoniae,
and Acinetobacter species.
• Gram-positive cocci
• Staphylococcus aureus
 VAP: Diagnosis1

• On Mechanical Ventilation for ≥ 48 to 72 hours +

• New or progressive radiographic infiltrate in the lung
• Clinical Finding Suggestive of Infection:
• Fever
• Purulent Sputum
• Leukocytosis
• Decline in Oxygenation
• Positive Respiratory Tract Cultures (options:
endotracheal aspirates, bronchoalveolar lavage [BAL] or
protected specimen brush [PSB])
 Initial Empiric VAP Treatment1
• Typically Cover for:
• Streptococcus pneumoniae, Haemophilus influenzae,
Methicillin-sensitive Staphylococcus aureus, Sensitive
gram negative bacilli (E. coli, K. pneumoniae,
Enterobacter species, Proteus species, Serratia
marcescens)

• If Concerned about MDR Pathogens cover for:

• Pseudomonas aeruginosa, Klebsiella pneumoniae
(ESBL), Acinetobacter species, Legionella pneumophila
and all previously listed bacteria
 Initial Empiric VAP Treatment1
• Use:
• Antipseudomonal cephalosporin or Antipseudomonal
carbepenem or β-lactam/β-lactamase inhibitor
• Plus Antipseudomonal fluoroquinolone or Aminoglycoside

• If risk factors for MRSA present add Linezolid or

Vancomycin

• Reassess need for Empiric Therapy at (or before) Day 3

 Treatment after
Cultures Return
Positive for MRSA VAP
 VAP MRSA Treatment2
• Vancomycin: 15-20 mg/kg/dose IV every 8-12 hours
• Goal Trough for pneumonia: 15-20 mg/L
• Monitor: renal function (SCr), trough, CBC with differential
• AE: red man syndrome, ototoxicity, nephrotoxicity,
phlebitis

• Linezolid: 600 mg PO/IV every 12 hours

• Monitor: CBC with differential
• AE: myelosuppression, visual impairment / changes,
serotonin syndrome, neuropathy
 VAP MRSA Treatment2
• Treat for 7-21 days

• Monitor resolution of infection:

• Fever
• CBC with differential
• Chest X-ray
• Cultures
Studies
Hamilton LA, et al. Treatment of methicillin-resistant
Staphylococcus aureus ventilator-associated pneumonia
with high-dose vancomycin or linezolid. J Trauma Acute
Care Surg. 2012;72(6): 1478-83.

• Purpose: to determine the clinical success rate of high-

dose vancomycin for the treatment of methicillin-
resistant Staphylococcus aureus (MRSA) ventilator-
associated pneumonia (VAP) in critically ill trauma
patients.

• Retrospective, observational review of MRSA VAP

patients seen in the ICU (trauma patients only) from
January 1997 to December 2008 in Memphis, TN

• Demographics: age 41 ± 21, mainly male and Caucasian

with APACHE II median score at admission = 18
Treatment of methicillin-resistant
Staphylococcus aureus ventilator-associated
pneumonia with high-dose vancomycin or
linezolid.
• Results: 125 patients with 141 episodes
• 76 treated with vancomycin
• 10 treated with linezolid
• 55 switched from vancomycin to linezolid

• Clinical success was achieved in 88% (125 of 131)

• 68/76 patients treated with Vancomycin only
• 47/55 patients treated with Linezolid and Vancomycin

• VAP related mortality was 10% (12 of 125)

• Conclusion: High dose vancomycin effective option for
the treatment of MRSA VAP in trauma ICU patients
Wunderink RG, et al. Linezolid in Methicillin-Resistant
Staphylococcus aureus Nosocomial Pneumonia: A
Randomized, Controlled Study. Clinical Infectious
Diseases. 2012;54:621-9.

• Purpose: To provide a prospective analysis of the

efficacy and safety of linezolid, compared with a dose-
optimized vancomycin regimen, for the treatment of
MRSA nosocomial pneumonia.

• Patients enrolled from October 2004 to January 2010.

• General hospital patients

• Randomized into two groups for 7 – 14 days treatment:

• 1) IV linezolid 600 mg Q12H
• 2) IV vancomycin 15mg/kg Q12H (adjusted based on
trough levels)
 Linezolid in Methicillin-Resistant Staphylococcus
aureus Nosocomial Pneumonia: A Randomized,
Controlled Study.
• Randomized: 1225 people
• Allocated to linezolid: 618  mITT: 224  PP population:
172
• Allocated to vancomycin: 607  mITT: 224  PP
population: 176

• VAP patients: 221 of 348 (63.5%)

• Linezolid 104 of 172
• Vancomycin 117 of 176

• In the PP patients treated with linezolid 57.6% were

clinically cured at the end of the study, compared to
46.6% in the vancomycin treatment group (P=0.042)
 Linezolid in Methicillin-Resistant Staphylococcus
aureus Nosocomial Pneumonia: A Randomized,
Controlled Study.

• No difference between groups in development of anemia

or thrombocytopenia or IT group 60 day mortality
• Nephrotoxicity more common in vancomycin treatment
18.2% compared to 8.4% in the linezolid treatment group
(based on laboratory evidence)

• Conclusion: Clinical response at the end of study was

better with linezolid than vancomycin for the treatment of
nosocomial pneumonia due to MRSA however there were
no statistically significant differences in mortality between
the two groups
Peyrani P, et al. Higher clinical success in patients with ventilator-
associated pneumonia due to methicillin-resistant
Staphylococcus aureus treated with linezolid compared with
vancomycin: results from the IMPACT-HAP study. Critical Care.
2014;18:R118.

• Purpose: Compare clinical success rates of

patients treated with linezolid versus vancomycin
for MRSA VAP.
• Secondary Objective: Compare mortality, safety, and
resource utilization between the two groups
• Mortality: all cause 14-day mortality after VAP diagnosis
• Safety: Thrombocytopenia, Anemia, Nephrotoxicity
• Resource Utilization: days on mechanical ventilation,
length of stay (LOS) in the ICU, LOS in the hospital

• Retrospective, observational study in ICU patients

 Higher clinical success in patients with ventilator-
associated pneumonia due to methicillin-resistant
Staphylococcus aureus treated with linezolid compared
with vancomycin: results from the IMPACT-HAP study.

• Included in the analysis: 188 patients diagnosed with MRSA

VAP
• Linezolid: 101
• Vancomycin: 87

• Clinical success reached in 85% of linezolid treated patients,

69% in vancomycin treated patients (p=0.009)
• Linezolid patients were 24% more likely to experience treatment
success (p = 0.018)
• No difference in mortality (at 14 days), safety events or resource
utilization between groups
• Conclusion: Patients with MRSA VAP are more likely to respond
favorably to treatment with linezolid compared to those treated
with vancomycin
 Opinion
• Patients treated with linezolid have better clinical
response than those treated with vancomycin

• Mortality benefit has yet to be seen in patients

with an improved clinical response to linezolid

• Cost6
Dose Unit Size AWP One Dose
Linezolid 600 mg IV 300 mL $750 $75
Vancomycin 1000 mg IV 150 mL $86.98 $12.42

• Vancomycin Trough Level = ~ $1007

 Case
11/30 12/1 12/2
Temperature (°F ) 98.2 97.3 100.2
WBC (k/cmm) 13.8 13.8 13.5
HGB (gm/dL) 9.6 9.6 9.6
HCT (%) 29.6 29.4 29.4
Platelet count (K/cmm) 272 274 244
Lymphocytes (%) 9.0 19.6 16.8
Bands (%) None reported None reported None reported
Creatinine (mg/dL) 0.80 0.80 0.77

• Extubated on 11/28.
• Plan:
• Continue Linezolid for 30 days (currently on Day 14).
• Discharge tentatively planned for 12/5.
 References
1. American Thoracic Society; Infectious Disease Society of America. Guideline for the
management of adults with hospital-acquired, ventilator-associated, and healthcare-
associated pneumonia. Am J Respir Crit Care Med. 2005; 171:388-416. DOI:
10.1164/rccm.200405-644ST.
2. Lou C, Bayer A, Cosgrove SE, et al. Clinical practice guideline by the Infectious diseases
society of America for the treatment of methicillin-resistant staphylococcus aureus
infections in adults and children. Clinical Infectious Diseases. 2011; 52:285-92.
DOI:10.1093/cid/ciq146.
3. Hamilton LA, Wood CG, Magnotti LJ, et al. Treatment of methicillin-resistant
Staphylococcus aureus ventilator-associated pneumonia with high-dose vancomycin or
linezolid. J Trauma Acute Care Surg. 2012;72(6):1478-83.
4. Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in Methicillin-Resistant
Staphylococcus aureus Nosocomial Pneumonia: A Randomized, Controlled Study. Clinical
Infectious Diseases. 2012;54(5):621-9.
5. Peyrani P, Wiemken TL, Kelley R, et al. Higher clinical success in patients with ventilator-
associated pnuemonia due to methicillin-resistant Staphylococcus aureus treated with
linezolid compared with vancomycin: results from the IMPACT-HAP study. Critical Care.
2014;18:R118.
6. Red Book. Montvale, N.J.: Medical Economics Data; 2015. Micromedex.
7. James CW and Gurk-Turner CG. Recommendations for monitoring serum vancomycin
concentrations. Proc (Bayl Univ Med Cent). 2001;14(2):189-90.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1291340/.