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:

Radiographic findings plus two of the clinical findings.

Fever
Purulent sputum
Leukocytosis
Decline in oxygenation
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, PSBs 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

Study of 4543 pts. with Culture Positive Pneumonia:

Incidence (%)

nosocomial infection in the US

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 (1999-2003)
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%

Attributable mortality is 20-50%

Worse outcomes in patients with

P>.05

P<.0001

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

PATHOGENS AMONG PNEUMONIA

TYPES

Kollef MH,et al. Chest .2005;128:3854-62.

PATHOGENS ASSOCIATED WITH NAP

Nosocomial Pneumonia (%)

40

P = .003

Early-onset NP
Late-onset NP

35
30
P = .408

25
P = .043

20
15

MSSA

MRSA

OSSA =

Oxacillin-sensitive
S aureus

ORSA =

Oxacillin-resistant
S aureus

ES =

Enterobacter species

SM =

S marcescens

P = .144

ES

SM

5
PA

P aeruginosa

P = .985

10

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
frequency of antibiotic resistance in the community or hospital
High
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.

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, Parkinsons 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

20

18

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.

Antipseudomonalcephalosporin
OR
Antipseudomonalcarbepenem
OR
Lactam/lactamaseinhibitor
Plus
Antipseudomonalfluoroquinolone
OR
Aminoglycoside
Plus
Sever pneumonia, necrotizing or cavitary
AntiMRSA
infiltrates, empyema
AntiLegionellapneumophilaandanti
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;17891797.)
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 postoperative 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

199219982

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

Concentration (g/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 S aureus
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)

17.74

2.41.2

ELF (mg/L)

14.45.6

2.61.7

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

Intent-to-treat (ITT)

S aureus NP

Linezolid 600 mg q12h IV

10/20

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 multicenter, multinational, comparator-controlled
A randomized, double-blind,
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
0

221/417 202/387

70/136 59/136

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).

36/61

22/62

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.

Clinical Cure (%)

62
49

45
37

35
21

103/227

76/207

43/88

32/91

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).

23/37

7/33

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

Sakoulas G, et al. J Clin Microbiol 2004;42:2398 402

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; 33:19837.

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
Microbiological Survival
response (ITT)

eradication

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 investigators 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) , per-protocol
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

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)