Transcript - The 1st Al Jahra Hospital International Conference in

Pneumonias
HAP/HCAP/VAP
Salim A Baharoon MD
Infectious Disease / Critical Care
King Saud Bin Abdulaziz University
Riyadh
DEFINITIONS
• HAP: Pneumonia that occurs 48 hours or more after admission and did not
appear to be incubating at the time of admition.
• Early and Late onset
•
•
VAP: A type of HAP acquired at 48-72 hours after intubation.
•
Early and Late onset
HCAP: Non hospital patient with healthcare contact
•
•
•
•
•
IV therapy, wound care, chemotherapy within 30 days
Nursing home or long term care facility (Nursing Home Pneumonia)
Hospitalization >2 days ore more in past 90 days
Attendance at hospital or HD within 30 days
Family member with a MDR pathogen
ATS/IDSA Am J Respir Crit Care Med. 2005;171: 388-416
DIAGNOSIS
• Progressive infiltrate on lung imaging and clinical characteristics such as:
• Fever
• Purulent sputum
• Leukocytosis
• Decline in oxygenation
• Radiographic findings plus two of the clinical findings.
• 69% sensitivity and 75% specificity for pneumonia (autopsy as reference)
IMPERFECT DIAGNOSTIC TESTS
•
Blood cultures, limited role, sensitivity is only 8% to 20%
•
Sputum neither sensitive, nor specific
•
Tracheo-bronchial aspirates- high sensitivity
• does not differentiate between pathogen and colonizer
• Quantitative cultures increase specificity of the diagnosis of HAP.
•
BAL, PSB’s do not differ from less invasive tests in terms of sensitivity, specificity
or, more importantly, morbidity and mortality.
• Negative lower respiratory tract cultures can be used to stop antibiotic therapy in a
patient who has had cultures obtained in the absence of an antibiotic change in the past
72 hours.
• Role of rapid diagnostic test (PCR) (Multiplex PCR)
EPIDEMIOLOGY
•
•
•
HAP is the second most common
nosocomial infection in the US
Study of 4543 pts. with Culture Positive
Pneumonia: Incidence (%)
HAP increased hospital stay by an
average of 7-9 days per patient
Estimated occurrence of 5-10
cases per 1,000 hospital
admissions
• 0.88 per 1000 patients admission in Taif (19992003)
•
•
0.5 per 1000 patient days of admission in Iran
HAP accounts for up to 25% of all
ICU infections and more than 50%
of antibiotics prescribed
Kolle MH, et al. Epidemiology and outcomes of healthcare
associated pneumonia: results from a large US database of
culture positive pneumonia. Chest 2005;128:3854 62
OUTCOME
•
•
•
•
P<.0001
HAP-associated mortality remains
the leading cause of death among
hospital-acquired infections
Crude mortality of HAP is 30-70%
P>.05
P<.0001
Attributable mortality is 20-50%
Worse outcomes in patients with
bacteremia, medical rather than
surgical illness, ineffective and late
antibiotic therapy.
Kollef MH, et al. Chest. 2005;128:3854-62.
MORTALITY AND TIME OF PRESENTATION OF HAP
P<.001
P<.001
Hospital Mortality (%)
50
P = .504
*
*
40
30
20
*
10
0
*Upper 95% confidence interval
None
Early Onset
Late Onset
Nosocomial Pneumonia
Ibrahim, et al. Chest. 2000;117:1434-1442.
MRSA INFECTION
Crit Care 2006:10(3):R97.
HAP: NON-VENT VS. VENTED PTS.
Pennsylvania study on nosocomial pneumonia, 2009-2011
Davis J. The breath of hospital-acquired pneumonia: nonventilated versus ventilated patients in
Pennsylvania. Focus on Infection Prevention. Pennsylvania Patient Safety Advisory. 2012;9:99-105.
ETIOLOGY
•
Aerobic gram-negative bacteria:
•
•
P. aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Acinetobacter species
Gram-positive cocci
• S. pneumonia.
• H. influenzae
• Staphylococcus aureus (50% in ICU due to MRSA)
• More common in patients with diabetes mellitus, head trauma and those hospitalized in the
ICU.
• Oropharyngeal commensals (viridans group streptococci, coag-negative Staph,
Neisseria species and Corynebacterium) may be relevant in mostly
immunocompromised patients.
RESULTS, TIME OF INFECTION
• HAP:
• Early onset (0-4 days): S. pneumoniae, H. influenzae
• Late onset (5+ days): oxacillin resistant S. aureus, P. aeruginosa
• VAP:
• Early onset (0-4 days): oxacillin susceptible S. aureus, S.
pneumoniae, Hemophilus sp.
• Late onset (5+ days): Acinetobacter sp. and S. maltophilia
Kollef MH,et al. Chest .2005;128:3854-62.
CAP
HCAP
HAP
VAP
Acinetobacter
spp
Klebsiella
spp
Pseudomonas
spp
Haemophilus
spp
S.pneumo
MRSA
MSSA
0.0
10.0
20.0
Occurrence (%)
30.0
PATHOGENS AMONG PNEUMONIA TYPES
PATHOGENS ASSOCIATED WITH NAP
P = .003
Early-onset NP
Nosocomial Pneumonia (%)
40
Late-onset NP
35
30
P = .408
25
P = .043
20
15
Oxacillin-sensitive
S aureus
ORSA =
Oxacillin-resistant
S aureus
ES =
Enterobacter species
SM =
S marcescens
ES
SM
0
MRSA
OSSA =
P = .144
5
MSSA
P aeruginosa
P = .985
10
PA
PA =
Pathogen
Ibrahim, et al. Chest. 2000;117:1434-1442.
ETIOLOGY
•
•
•
•
Fungal pathogens: most common is Candida and Aspergillus
Most commonly in organ transplant or immunocompromised,
neutropenic patients.
Aspergillus- contaminated air ducts or local construction.
Candida- common airway colonizer and rarely requires
treatment.
ETIOLOGY
•
•
•
Viral Pathogens: low incidence in immunocompetent hosts.
Influenza A is the most common viral cause of HAP and
HCAP in adults.
Risk for secondary bacterial infection “super-infection”
• Streptococcus, H. influenza, Group A Streptococcus, S.
aureus
MDR RISK FACTORS
•
Host risk factors for infection with MDR pathogens include:
Treatment with antibiotics within the preceding 90 days.
Current hospitalization of >4 days
•
•
• High frequency of antibiotic resistance in the community or hospital
unit
• Immunosuppressive disease and/or therapy
• Hospitalization for >/= 2 days within the last 90 days
• Severe illness
• Antibiotic therapy in the past 6 months
• Poor functional status
Colonization
Aspiration
HAP
PATHOGENESIS
• Number and virulence of organisms entering the lower respiratory tract and
response of the host.
•
•
•
•
microaspiration of organisms which have colonized the upper
respiratory/gastrointestinal tract
Hospitalized patients tend to become colonized with organisms in the hospital
environment within 48 hours.
Common mechanisms include: mechanical ventilation, routine nursing care,
lack of hand washing of all hospital personnel.
Disease state also plays a role: alteration in gastric pH due to illness, certain
medications, malnutrition and supplemental feedings.
M
MECHANISMS THAT LEAD TO ORAL AND OROPHARYNGEAL GNR COLONIZATION
Lam OLT, et al. Effectiveness of oral hygiene interventions against oral and oropharyngeal reservoirs
of aerobic and facultatively anaaerobic graminegative bacilli. AJIC 2012;40:175-82.
WHICH PATIENTS ARE AT RISK?
•
Liver disease prior to and during transplantation
•
End-stage renal disease undergoing hemodialysis
•
Cardiovascular disease undergoing surgery
•
Abdominal cancer, head and neck cancer
•
Leukemia
•
COPD
•
Cerebral palsy
•
Asthma, stroke, chronic bronchitis, pharyngitis, HIV infection, diabetes,
alcoholism, Parkinson’s Disease
•
Hospitalized, Institutionalized elderly individuals
MANAGEMENT
HOSPITAL ADMISSION
• Decision to admit remain clinical
• Severity scores can help.
• CURB-65 criteria (>2, more-intensive treatment)
• Confusion
• Urea 7 mmol/L (20 mg/dL)
• Increased respiratory rate >30
• low blood pressure (SBP <90 or DBP <60)
• Pneumonia Severity Index (PSI)
• uses demographics, the coexistence of co-morbid illnesses
findings on physical examination, vital signs and essential
laboratory findings
PSI SCORE
INITIAL APPROPRIATE ANTIBIOTIC THERAPY
A Study by Kollef and Colleagues Evaluating the Impact of Inadequate Antimicrobial Therapy on Mortality
Hospital Mortality (%)
60
*P<.001
52*
50
42*
40
30
24
18
20
10
0
All-Cause Mortality
Inadequate antimicrobial treatment
(n=169)
ATS=American Thoracic Society; IDSA=Infectious Diseases Society of America.
Adapted from Kollef MH et al. Chest. 1999;115:462-474.
ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.
Infection-Related Mortality
Adequate antimicrobial treatment
(n=486)
Fraction of total patients
EFFECT OF TIMING ON SURVIVAL
Time from hypotension onset (hours)
Crit Care Med 2006;34:1589-96
JAMA 2010
The outcome of patients with sepsis and septic shock presenting to
emergency departments in Australia and New Zealand.
Crit Care Resusc. 2007 Mar;9(1):8-18.
Antipseudomonal cephalosporin
OR
Antipseudomonal carbepenem
OR
β-Lactam/β-lactamase inhibitor
Plus
Antipseudomonal fluoroquinolone
OR
Aminoglycoside
Plus
Sever pneumonia, necrotizing or cavitary
Anti MRSA
infiltrates, empyema
Anti Legionella pneumophila and anti
Viral
INITIAL EMPIRIC THERAPY IN PATIENTS
WITHOUT RISK FACTORS FOR MDR PATHOGENS
Potential Pathogens
Recommended Antibiotic
Streptococcus pneumoniae
H influenzae
Methicillin-sensitive S aureus (MSSA)
Ceftriaxone/Azithromycin
Antibiotic-sensitive, enteric,
gram-negative bacilli
E coli
K pneumoniae (ESBL-)
Enterobacter spp
Proteus spp
Serratia marcescens
or
Levofloxacin, moxifloxacin, or
ciprofloxacin†
or
Ampicillin/sulbactam/Azithromycin
or
Ertapenem/Azithromycin
Adapted from ATS/IDSA. Am J Respir Crit Care Med. 2005;171:401. Table 3.
LINAZOLID VS VANCOMYCIN IN PNEUMONIA
• Retrospective study suggest survival benefit than
vancomycin in MRSA pneumonia (Chest
2003;124;1789-1797.)
• Meta-analysis in MRSA pneumonia: non-inferior than
glycopeptide (2010)
• Latest randomized, double blinded trial suggest better
(non-inferior) clinical success than vancomycin (2010
idsa abstract)
KPC
• Combination therapy
• Synergistic testing
• Suggested regimens include colistine plus tigecycline
plus carbapenem/rifampin
• Other drugs include fosfomycin, aztreonam
PREVENTION
Davis J. The breath of hospital-acquired pneumonia: nonventilated versus ventilated patients in
Pennsylvania. Focus on Infection Prevention. Pennsylvania Patient Safety Advisory. 2012;9:99-105.
ASPIRATION PRECAUTION BUNDLE (APB)
•
Ensure bedside swallow screen completed (if
failed, physician order for speech consult/NPO
status
•
HOB elevated 30 degrees or greater
•
Oral care every 4 hours (brush teeth every 12
hours)
•
No straws
•
Ambulate/up in chair TID and prn
•
Sit upright 90 degrees for meals/snacks
•
Observe patient during meals (check temperature
60 minutes after meal for fever spike)
•
Incentive spirometry (IS), Acapella (preferred) or
PEP therapy
•
Suction set-up in patient room
•
Order Aspiration Precaution on SBAR
Amulti-disciplinary group comprised of
nursing, speech pathology, respiratory therapy and
infection prevention developed an Aspiration Precaution
Bundle (APB).
respiratory therapy and speech therapy participation such
as oral care every four hours,
Acapella or PEP therapy and bedside swallow screening.
In addition, a laminated sign was created to place in the
patient room
SUMMARY
• HAP is a leading infection among all hospital acquired infections
• HAP is associated with high mortality, long hospital stay, high
economic burden
• HAP is still diagnosed with relatively non specific methods
• HAP etiology vary between geographical locations and each region
should have real-time data
• Treatment of MDR organism is posing a very significant problem
• Prevention of HAP through established protocols
Thank you
Questions?
MODIFIABLE RISK FACTORS: INTUBATION AND
MECHANICAL VENTILATION
•
Intubation and mechanical ventilation increase the risk of HAP 6-21 fold.
•
NIPPV, data shows use to avoid reintubation may be associated with more incidence
of HAP.
•
Sedation protocols to accelerate ventilator weaning.
•
Reintubation increases the risk of VAP
•
Oral gastric and tracheal tubes rather than nasal may reduce incidence of sinusitis and
subsequent lower respiratory tract infection (HAP).
•
Limiting use of sedative and paralytic agents that depress cough.
•
Keep endotracheal cuff to >20 cm H2O
MODIFIABLE RISK FACTORS
•
Strict infection control
•
Alcohol-based hand disinfection
•
Microbiologic surveillance with timely data on local MDR pathogens
•
Removal of invasive devices
•
Programs to reduce or alter antibiotic-prescribing practices
MODIFIABLE RISK FACTORS: MODULATION OF
COLONIZATION: ORAL ANTISEPTICS AND
ANTIBIOTICS
•
Oropharyngeal colonization is an independent risk factor for ICU-acquired HAP
by enteric gram-negative bacteria and P. aeruginosa
•
Oral antiseptic chlorhexidine significantly reduced rates of nosocomial infection
in post-operative patients and is routinely used in the ICU as part of “oral care”.
•
Selective decontamination fo the digestive tract (SDD): using non-absorbable
antibiotics either orally or through GT has shown benefit in reducing HAP/VAP.
However not widely used in the US due to risk for drug resistance.
MDR: STRESS BLEEDING PROPHYLAXIS,
TRANSFUSION, AND GLUCOSE CONTROL
•
H2 blockers have shown an increased risk for VAP, risk vs. benefit for stress
bleeding should be considered
•
Multiple studies have identified allogeneic blood products as a risk factor for
post-operative pneumonia, and the time length of blood storage as another risk
factor. Blood transfusion is usually limited to Hb <7 in the patient who has no
active bleeding.
•
Hyperglycemia is an additional risk for blood stream infection, increased
duration of mechanical ventilation increasing risk for HAP/VAP.
FOUR MAJOR PRINCIPLES UNDERLIE THE MANAGEMENT
•
Avoid untreated or inadequately treated HAP, VAP or HCAP, failure to
do so is a consistent factor associated with increased mortality.
•
Recognize the variability of bacteriology from one hospital to another,
one department from another and one time period to another.
•
Avoid the overuse of antibiotics by focusing on accurate diagnosis,
tailoring therapy and limit duration of therapy to the minimal effective
period.
•
Apply prevention strategies aimed at modifiable risk factors.
VAP VS. HAP FLORA
• Study of VAP and HAP pathogens for purposes of optimizing
therapy
• University of North Carolina Hospitals study conducted system wide,
2000-2003
• Used definitions as described by ATS
• Did not include CAP or HCAP
• Specimens obtained via bronchoscopy, expectorated sputum, or
tracheal aspirates
Weber DJ, et al. Microbiology of ventilator associated pneumonia compared with that of hospital acquired pneumonia. Infect Control Hosp
Epidemiol 2007;28:825 31
RESULTS, EPIDEMIOLOGY
588 LOWER RESPIRATORY THERAPY TRACT INFECTIONS IN 556 PATIENTS
INCIDENCE OF PNEUMONIA: 0.37%
Assessment of Non-Responders
Wrong Organism
Wrong Diagnosis
Drug-resistant Pathogens:
(Bacteria, Mycobacteria, Virus, Fungus)
Inadequate Antimicrobial Therapy
Atelectasis
Pulmonary Embolism
ARDS
Pulmonary Hemorrhage
Underlying Decease
Neoplasm
Complications
Empyema or Lung Abscess
Clostridium Difficile Colitis
Occult Infection
Drug Fever
RESULTS, PATHOGENS
PATHOGENS ISOLATED FROM 92.4% OF PATIENTS WITH VAP AND 76.6% FROM HAP
PATIENTS
RESULTS, TIME OF INFECTION
• Pathogens statistically associated with VAP:
• Early onset (0-4 days): oxacillin susceptible S. aureus, S.
pneumoniae, Hemophilus sp.
• Late onset (5+ days): Acinetobacter sp. and S. maltophilia
• HAP:
• Early onset (0-4 days): only S. pneumoniae.
• Late onset (5+ days): oxacillin resistant S. aureus and
P.aeruginosa
VAP etiology
Other
Staph areus
Pseudomonas
PATHOGENS CAUSING NOSOCOMIAL PNEUMONIA (TRENDS OVER TIME)
NATIONAL NOSOCOMIAL INFECTIONS SURVEILLANCE SYSTEM
30
25
S aureus
20
P aeruginosa
Enterobacter spp.
15
E coli
K pneumoniae
10
Serratia marcescens
Acinetobacter spp
5
0
19751
1992–19982
20031
1. Gaynes R, et al. Clin Infect Dis .2005; 41:848-54. NNIS system report. Am J Infect Control. 2000; 28(6):429-48.
2. Richards MJ, et al. Infect Control Hosp Epidemiol. 2000; 21:510-5.
Lung Penetration Concentration vs MIC90 of Linezolid
Against Gram-Positive Organisms
• Plasma and pulmonary
epithelial lining fluid
(ELF) linezolid
concentrations
exceeded MIC90 for
staphylococci and
streptococci through
the dosing interval
Plasma
MIC90 S aureus
Concentration (µg/L)
• 5 doses of linezolid
600 mg q12h were
administered orally to
25 healthy volunteers
Epithelial lining fluid
MIC90=minimum concentration needed to inhibit 90% of organisms.
Adapted from Conte JE Jr et al. Antimicrob Agents Chemother. 2002;46:1475-1480.
MIC90 Enterococcus spp
MIC90 S pneumoniae
Time After Last Dose (h)
PHARMACOKINETIC CHARACTERISTICS OF
LINEZOLID IN ADULTS
Parameter
Effect
Oral bioavailability
100%
Ingestion of food
No dose adjustment
Volume of distribution
Total body water, 40 L to 50 L
Dosage formulations
IV, tablets, oral suspension (PO)
Distribution
Readily distributes into well-perfused
tissues
Protein binding
31%, independent of drug concentration
LINEZOLID PHARMACOKINETICS IN VAP
 16 critical-care patients with
late-onset VAP (≥5 days on
the ventilator)
 Pharmacokinetic profile was
evaluated after 2 days of
linezolid (600 mg q12h IV)
therapy. ELF samples were
collected by mini-BAL brush
Steady State Concentrations in 16 VAP Patients
Peak
Trough
Plasma (mg/L)
17.7±4
2.4±1.2
ELF (mg/L)
14.4±5.6
2.6±1.7
Boselli E et al. Crit Care Med. 2005;33:1520-1533.
FIRST PROSPECTIVE COMPARISON OF LINEZOLID VS
VANCOMYCIN FOR EMPIRIC TREATMENT OF NOSOCOMIAL
PNEUMONIA (NP)
A randomized, double-blind, multicenter, multinational, comparator-controlled
trial to compare the safety and efficacy of linezolid versus vancomycin for NP
Clinical Cure (%)
70
60
53
58
55
52
50
46
50
40
30
20
10
86/161 74/142
31/56
19/41
18/31
10/20
0
Intent-to-treat (ITT)
S aureus NP
Linezolid 600 mg q12h IV
MRSA NP
Vancomycin 1 g q12h IV
Safety and efficacy of linezolid versus vancomycin were compared in 402 patients with NP, including VAP;
398 patients received at least 1 dose of study medication. Patients were treated for 7 to 21 days, with
optional aztreonam 1 g to 2 g q8h. Clinical cure rates were assessed 12 to
28 days after end of therapy.
Rubinstein E et al. Clin Infect Dis. 2001;32:402-412.
Data on file. Pfizer Inc.
SECOND PROSPECTIVE COMPARISON OF
LINEZOLID VS VANCOMYCIN FOR EMPIRIC
TREATMENT OF NP
A randomized, double-blind, multicenter, multinational, comparator-controlled
trial to compare the safety and efficacy of linezolid versus vancomycin for NP.
Clinical Cure (%)
70
60
60
53
52
50
49
42
40
29
30
20
10
0
135/256 128/245
ITT
40/81
40/95
S aureus NP
Linezolid 600 mg q12h IV
18/30
12/41
MRSA NP
Vancomycin 1 g q12h IV
The safety and efficacy of linezolid IV versus vancomycin IV were compared in 623 patients with NP, including VAP. Patients were treated for 7
to 21 days, with optional aztreonam 1 g to 2 g q8h. Clinical cure rates were assessed 15 to 21 days after end of therapy.
Wunderink RG et al. Clin Ther. 2003;25:980-992.
Data on file. Pfizer Inc.
LINEZOLID DEMONSTRATES EXCELLENT EFFICACY IN A
RETROSPECTIVE ANALYSIS OF TWO PROSPECTIVE CLINICAL TRIALS
A retrospective analysis of the combined results from the 2 prospective,
identical design trials in 1019 patients with NP including ventilator-associated
pneumonia (VAP)
Clinical Cure (%)
70
60
59
53
52
52
50
43
36
40
30
20
10
221/417 202/387
70/136 59/136
ITT
S aureus NP
36/61
22/62
0
Linezolid 600 mg q12h IV
Linezolid was equally effective in the ITT and S aureus NP populations (P=NS).
The outcome difference in the MRSA NP subgroup is provided as a descriptive measure only.
No further inference should be drawn due to the retrospective nature of the analysis (P<.01).
MRSA NP
Vancomycin 1 g q12h IV
Wunderink RG et al. Chest. 2003;124:1789-1797.
Data on file. Pfizer Inc.
LINEZOLID DEMONSTRATES EXCELLENT EFFICACY IN A
RETROSPECTIVE ANALYSIS OF TWO PROSPECTIVE CLINICAL TRIALS
A retrospective analysis of 544 patients with VAP from the two prospective,
identical design trials in 1019 patients with NP.
80
Clinical Cure (%)
70
62
60
50
49
45
37
40
35
30
21
20
10
103/227
76/207
43/88
32/91
23/37
7/33
0
ITT
S aureus NP
Linezolid 600 mg q12h IV
Linezolid was equally effective in the ITT and S aureus NP populations (P=NS).
The outcome difference in the MRSA NP subgroup is provided as a descriptive measure only.
No further inference should be drawn due to the retrospective nature of the analysis (P<.01).
MRSA NP
Vancomycin 1 g q12h IV
Kollef MH et al. Intens Care Med. 2004;30:388-394.
Wunderink RG et al. Chest. 2003;124:1789-1797.
Data on file. Pfizer Inc.
VANCOMYCIN FAILURE DESPITE
ADEQUATE MIC IN MRSA BACTEREMIA
* P = .01
100%
9
80%
21
60%
40%
56
20%
10
0%
MIC ≤ 0.5
Sakoulas G, et al. J Clin Microbiol 2004;42:2398 – 402
MIC 1-2
Failure
Success
HIGHER VANCOMYCIN MICS ASSOCIATED WITH HIGHER
MORTALITY RATES
• Relationship of vancomycin MIC to mortality in patients with
MRSA HAP, VAP and HCAP. Chest 2010 June 17.
• An increase of 1 Vancomycin MIC leads to odds ratio of
death as 2.97 folds.
Inadequate Antimicrobial Therapy
Vancomycin for MRSA NP/VAP
•
•
•
40% failure rate for MRSA NP with vancomycin at
standard dosing (1 g q12h)
Despite appropriate therapy with glycopeptides,
mortality in VAP with MRSA > VAP without MRSA
In VAP / severe sepsis  underdosing
•
•
•
Enhance renal blood flow
Increase volume of distribution (hyperdynamic)
Suggest a higher dose (trough 15-20 mg/L) than traditional
dosage (5-15 mg/L)
ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.
Craven DE et al. Infect Dis Clin N Am. 2004;18:939-962.
Rello J, et al. Crit Care Med 2005; 33:1983–7.
HETERORESISTANCE
•
Etest Macromethod: using a higher
inoculum to detect the presence of a less
susceptible subpopulation
•
J Clin Microbiol 2007;45:329-32.
The annals of pharmacotherapy 2010;44:844-850.
POTENTIAL BENEFIT OF LINEZOLID
SUMMARY OF CLINICAL TRIALS FOR NOSOCOMIAL
PNEUMONIA DUE TO MRSA
LINEZOLID 600 MG IV Q12H VS VANCOMYCIN 1 G IV Q12H
Trials
Clinical
response (ITT)
Microbiological
eradication
Survival
Rubinstein,
CID 2001
Prospective
RCT, N=396
53% vs 52%
(p = 0.79)
67% vs 71%
(p = 0.69)
-
Wunderink,
52% vs 52%
(p = NS)
61% vs 53%
(p = NS)
-
Clin Ther 2003
Prospective
RCT, N=623
Wunderink,
Chest 2003
Retrospective
N=1019
MRSA
59% vs 35%
(p < 0.01)
-
MRSA
80% vs 63%
(p = 0.03)
Kollef,
ICM 2004
Retrospective
N=544
MRSA
62% vs 21%
(p = 0.001)
MRSA
60% vs 22%
(p = 0.001)
MRSA:
84% vs 61%
(p = 0.02)
LINEZOLID VS VANCOMYCIN IN
NOSOCOMIAL PNEUMONIA
(EMPIRICAL)
Linezolid vs Vancomycin Chest 2003;124;1789-1797.
LINEZOLID VS VANCOMYCIN IN
NOSOCOMIAL PNEUMONIA
(EMPIRICAL)
Linezolid vs Vancomycin. Chest 2003;124:1789-1797.
LINEZOLID VS VANCOMYCIN IN
NOSOCOMIAL PNEUMONIA
(EMPIRICAL)
• Reason for improved survival: poor penetration of
vancomycin into the lungs
• Mean concentration of vancomycin in lung tissue VS
serum
• 1h: 9.6 mg/kg vs 40.6mg/L
• 12h: 2.8 mg/kg vs 6.7mg/L
• Mean concentration of linezolid in ELF vs plasma
• 4h: 64.3 ug/ml vs 7.3 ug/ml
• 23h: 24.3 ug/ml vs 7.6 ug/ml
Linezolid vs Vancomycin. Chest 2003;124:1789-1797.
THE RECOMMENDATION FOR USING LINEZOLID
IN MRSA PNEUMONIA
• Linezolid is an alternative
to vancomycin, and
unconfirmed, preliminary
data suggest it may have
an advantage for proven
VAP due to MRSA.
Am J Respir Crit Care Med 2005. 171(4): 388-416.
LIMITATION OF THE RETROSPECTIVE STUDY
•
Post hoc analysis
•
Subgroup analysis is not randomized.
Chest 2004:126(1):314-316.
•
Chest 2004:125(6):2370-2371.
•
Chest 2005:127(6):2298-2301.
LIMITATION OF THE PHARMACOKINETICS
STUDY
•
Vancomycin level study: study in patients without pneumonia.
Cruciani M. J antimicrob chemother 1996:38(5): 865-869.
•
Other study in pneumonia patients did not show sub-therapeutic lung concentration.
Lamer C. Antimicrob agents chemother 1993. 37(2): 281-286.
LATEST EVIDENCE FOR LINEZOLID
USE
META-ANALYSIS
META-ANALYSIS
Target population
Comparator
Primary end-point
Walkey AJ, et al.
Chest 2010
Suspected MRSA
nosocomial
pneumonia
Linezolid vs
glycopeptide
Clinical success
Kalil AC, et al.
Crit Care Med 2010
Nosocomial
pneumonia
Linezolid vs
glycopeptide
Clinical cure
Linezolid vs
Vancomycin
Treatment success
Beibei L, et al.
Gram-positive
International journal bacterial infections
of antimicrobial
agents 2010
LINEZOLID VS GLYCOPEPTIDE FOR THE
TREATMENT OF SUSPECTED MRSA
NOSOCOMIAL PNEUMONIA
Walkey AJ, et al. Chest. E-publish Sep 23, 2010
LINEZOLID VS GLYCOPEPTIDE FOR THE
TREATMENT OF SUSPECTED MRSA
NOSOCOMIAL PNEUMONIA
Walkey AJ, et al. Chest. E-publish Sep 23, 2010
LINEZOLID VS GLYCOPEPTIDE FOR THE
TREATMENT OF SUSPECTED MRSA
NOSOCOMIAL PNEUMONIA
Walkey AJ, et al. Chest. E-publish Sep 23, 2010
LINEZOLID VS GLYCOPEPTIDE FOR THE
TREATMENT OF SUSPECTED MRSA
NOSOCOMIAL PNEUMONIA
Risk of thrombocytopenia: no significantly 2.97 times higher
in linezolid group (95% CI: 0.81-10.94. P=0.10)
Risk of renal impairment: no significantly difference (RR:
1.09, 95% CI: 0.35-3.38, P=0.89)
Walkey AJ, et al. Chest. E-publish Sep 23, 2010
II. LINEZOLID VS VANCOMYCIN OR
TEICOPLANIN FOR NOSOCOMIAL
PNEUMONIA
Kalil AC, et al. Crit care Med 2010;38(9); 1802-1808.
II. LINEZOLID VS VANCOMYCIN OR
TEICOPLANIN FOR NOSOCOMIAL
PNEUMONIA
Clinical cure: RR 1.01 (0.93-1.10), P=0.83
Kalil AC, et al. Crit care Med 2010;38(9); 1802-1808.
II. LINEZOLID VS VANCOMYCIN OR
TEICOPLANIN FOR NOSOCOMIAL
PNEUMONIA
For MRSA pneumonia:
RR: 1.10 (0.83-1.38), P=0.44
Kalil AC, et al. Crit care Med 2010;38(9); 1802-1808.
II. LINEZOLID VS VANCOMYCIN OR
TEICOPLANIN FOR NOSOCOMIAL
PNEUMONIA
GI events
Thrombocytopenia
Kalil AC, et al. Crit care Med 2010;38(9); 1802-1808.
Renal failure
III. LINEZOLID VS VANCOMYCIN FOR THE
TREATMENT OF GRAM-POSITIVE BACTERIAL
INFECTIONS
International journal of antimicrobial agents. 2010;35: 3-12.
III. LINEZOLID VS VANCOMYCIN FOR THE
TREATMENT OF GRAM-POSITIVE BACTERIAL
INFECTIONS
International journal of antimicrobial agents. 2010;35: 3-12.
III. LINEZOLID VS VANCOMYCIN FOR THE
TREATMENT OF GRAM-POSITIVE BACTERIAL
INFECTIONS
International journal of antimicrobial agents.
2010;35: 3-12.
Beibei L, et al.
III. LINEZOLID VS VANCOMYCIN FOR THE
TREATMENT OF GRAM-POSITIVE BACTERIAL
INFECTIONS
International journal of antimicrobial agents. 2010;35: 3-12.
III. LINEZOLID VS VANCOMYCIN FOR THE
TREATMENT OF GRAM-POSITIVE BACTERIAL
INFECTIONS
International journal of antimicrobial agents. 2010;35: 3-12.
III. LINEZOLID VS VANCOMYCIN FOR THE
TREATMENT OF GRAM-POSITIVE BACTERIAL
INFECTIONS
International journal of antimicrobial agents. 2010;35: 3-12.
META-ANALYSIS
Target population
Comparator
Primary end-point
Walkey AJ, et al.
Chest 2010
Suspected MRSA
nosocomial
pneumonia
Linezolid vs
glycopeptide
Clinical success at
the test of cure
(TOC) among
clinically evaluable
subjects
Kalil AC, et al.
Crit Care Med 2010
Nosocomial
pneumonia
Linezolid vs
glycopeptide
Clinical cure
Linezolid vs
Vancomycin
Treatment success
Beibei L, et al.
Gram-positive
International journal bacterial infections
of antimicrobial
agents 2010
RANDOMIZED CONTROLLED STUDY
RANDOMIZED, DOUBLE BLINDED
TRIAL
phase 4 study: nosocomial pneumonia due to proven MRSA
compared the efficacy and safety of Zyvox with vancomycin
Zyvox IV 600 mg every 12 hours or
Vancomycin 15 mg/kg every 12 hours over the course of 7 to 14
days;
• vancomycin doses could be titrated at the investigator’s
discretion based on creatinine clearance and vancomycin trough
levels
•
•
•
•
48th Annual Meeting of the Infectious Diseases Society of America
RANDOMIZED, DOUBLE BLINDED
TRIAL
• 156 centers worldwide in 2004-2010
• randomized 1,225 patients
• 448 patients had proven MRSA nosocomial
pneumonia (modified intent-to-treat group)
• 339 patients also met key protocol criteria at the end of
study (per-protocol group) (> 5 days treatment)
RANDOMIZED, DOUBLE BLINDED
TRIAL
•
Clinical success rates at the end of study (study 7-30 days post end of treatment) , perprotocol analysis
• 57.6 % (95/165) in Zyvox group
• 46.6 % (81/174) in Vancomycin group
• 95 % CI for the difference in response rates: 0.5%-21.6%
• p=0.042
RANDOMIZED, DOUBLE BLINDED TRIAL: SAFETY
• Intent-to-treat analysis: 1184 patients
Linezolid
%
vancomyci
n
%
diarrhea
3.7
diarrhea
4.3
rash
2.7
nausea
1.9
constipation
1.0
rash
1.7
nausea
1.0
anemia
1.4
Acute renal
failure
1.4
• No statistical significance in the risk of
thrombocytopenia
RANDOMIZED CONTROLLED STUDY
SUMMARY
LINEZOLID IN MRSA INFECTION
• MRSA has high prevalence in nosocomial infection
• Lead to catastropic results in patients
• Fair treatment response to tranditional antimicrobials
• Increasing MIC of vancomycin and hetero-resistance
• Potential side effect while increasing trough
LINEZOLID IN MRSA INFECTION
•
Retrospective study suggest survival benefit than vancomycin in MRSA pneumonia (Chest
•
Meta-analysis in MRSA pneumonia: non-inferior than glycopeptide (2010)
•
Latest randomized, double blinded trial suggest better (non-inferior) clinical success than
vancomycin (2010 idsa abstract)
2003;124;1789-1797.)