Pneumonias HAP/HCAP/VAP

Salim A Baharoon MDInfectious 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

• 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

Study of 4543 pts. with Culture Positive Pneumonia: Incidence (%)

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

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

P<.0001

P>.05

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 bacteremia, medical rather than surgical illness, ineffective and late antibiotic therapy.

Ho

sp

ita

l Mo

rta

lity

(%

)

0

10

20

30

40

50

None Early Onset Late Onset

Nosocomial Pneumonia

P = .504P<.001

P<.001

MORTALITY AND TIME OF PRESENTATION OF HAP

Ibrahim, et al. Chest. 2000;117:1434-1442.

*Upper 95% confidence interval

*

**

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 PATHOGENS AMONG PNEUMONIA TYPESTYPES

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

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PA MSSA MRSA ES SM

P = .003

P = .043

P = .408

P = .985 P = .144

Pathogen

Early-onset NP

Late-onset NP

PA = P aeruginosa

OSSA = Oxacillin-sensitive S aureus

ORSA = Oxacillin-resistant S aureus

ES = Enterobacter species

SM = S marcescens

PATHOGENS ASSOCIATED WITH NAP

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

• 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

HOSPITAL ADMISSION

PSI SCORE

Adapted from Kollef MH et al. Chest. 1999;115:462-474.ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.

A Study by Kollef and Colleagues Evaluating the Impact of Inadequate Antimicrobial Therapy on Mortality

Inadequate antimicrobial treatment(n=169)

Adequate antimicrobial treatment(n=486)

0

10

20

30

40

50

60

All-Cause Mortality Infection-Related Mortality

24

42*

18

Ho

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(%

) 52* *P<.001

INITIAL APPROPRIATE ANTIBIOTIC THERAPY

ATS=American Thoracic Society; IDSA=Infectious Diseases Society of America.

EFFECT OF TIMING ON SURVIVAL

Crit Care Med 2006;34:1589-96

Time from hypotension onset (hours)

Frac

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atie

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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.

JAMA 2010

Antipseudomonal cephalosporinOR

Antipseudomonal carbepenem OR

β-Lactam/β-lactamase inhibitor Plus

Antipseudomonal fluoroquinolone OR

Aminoglycoside Plus

Anti MRSA Anti Legionella pneumophila and anti

Viral

Sever pneumonia, necrotizing or cavitary infiltrates, empyema

INITIAL EMPIRIC THERAPY IN PATIENTS WITHOUT RISK FACTORS FOR MDR PATHOGENS

Potential PathogensPotential Pathogens Recommended Antibiotic Streptococcus pneumoniaeH influenzaeMethicillin-sensitive S aureus (MSSA)

Antibiotic-sensitive, enteric, gram-negative bacilli E coli K pneumoniae (ESBL-) Enterobacter spp Proteus spp Serratia marcescens

Ceftriaxone/Azithromycin

orLevofloxacin, moxifloxacin, or ciprofloxacin†

orAmpicillin/sulbactam/Azithromycin

orErtapenem/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 ofnursing, 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 PATIENTSINCIDENCE OF PNEUMONIA: 0.37%

Assessment of Non-Responders

Wrong Organism

Drug-resistant Pathogens:(Bacteria, Mycobacteria, Virus, Fungus)

Inadequate Antimicrobial Therapy

Wrong Diagnosis

AtelectasisPulmonary EmbolismARDSPulmonary HemorrhageUnderlying Decease Neoplasm

ComplicationsEmpyema or Lung AbscessClostridium Difficile Colitis

Occult InfectionDrug 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

Staph areus

Pseudomonas

Other

PATHOGENS CAUSING NOSOCOMIAL PNEUMONIA (TRENDS OVER TIME)NATIONAL NOSOCOMIAL INFECTIONS SURVEILLANCE SYSTEM

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.

0

5

10

15

20

25

30

19751 1992–19982 20031

S aureus

P aeruginosa

Enterobacter spp.

E coli

K pneumoniae

Serratia marcescens

Acinetobacter spp

Adapted from Conte JE Jr et al. Antimicrob Agents Chemother. 2002;46:1475-1480.

Time After Last Dose (h)

Co

nce

ntr

atio

n (

µg

/L)

Epithelial lining fluid

Plasma

MIC90 S aureus

MIC90 Enterococcus spp

MIC90 S pneumoniae

Lung Penetration Concentration vs MIC90 of Linezolid Against Gram-Positive Organisms

• 5 doses of linezolid 600 mg q12h were administered orally to 25 healthy volunteers

• Plasma and pulmonary epithelial lining fluid (ELF) linezolid concentrations exceeded MIC90 for staphylococci and streptococci through the dosing interval

MIC90=minimum concentration needed to inhibit 90% of organisms.

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)

DistributionReadily 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

Boselli E et al. Crit Care Med. 2005;33:1520-1533.

Peak Trough

Plasma (mg/L) 17.7±4 2.4±1.2

ELF (mg/L) 14.4±5.6 2.6±1.7

Steady State Concentrations in 16 VAP Patients

FIRST PROSPECTIVE COMPARISON OF LINEZOLID VS VANCOMYCIN FOR EMPIRIC TREATMENT OF NOSOCOMIAL

PNEUMONIA (NP)

Clin

ica

l Cu

re (

%)

86/161 19/41 18/31

A randomized, double-blind, multicenter, multinational, comparator-controlled trial to compare the safety and efficacy of linezolid versus vancomycin for NP

Linezolid 600 mg q12h IV 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.

53 52 55

46

5850

74/142 31/56 10/200

10

20

30

40

50

60

70

Intent-to-treat (ITT) S aureus NP MRSA NP

0

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50

60

70

ITT S aureus NP MRSA NP

SECOND PROSPECTIVE COMPARISON OF LINEZOLID VS VANCOMYCIN FOR EMPIRIC TREATMENT OF NP

Clin

ica

l Cu

re (

%)

128/245 40/95 12/41

A randomized, double-blind, multicenter, multinational, comparator-controlled trial to compare the safety and efficacy of linezolid versus vancomycin for NP.

Linezolid 600 mg q12h IV 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.

53 52 4942

60

29

18/3040/81135/256

LINEZOLID DEMONSTRATES EXCELLENT EFFICACY IN A RETROSPECTIVE ANALYSIS OF TWO PROSPECTIVE CLINICAL TRIALS

Clin

ica

l Cu

re (

%)

221/417 70/136 36/61

A retrospective analysis of the combined results from the 2 prospective, identical design trials in 1019 patients with NP including ventilator-associated

pneumonia (VAP)

Linezolid 600 mg q12h IV Vancomycin 1 g 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).

53 52 52

43

59

0

10

20

30

40

50

60

70

ITT S aureus NP MRSA NP

36

Wunderink RG et al. Chest. 2003;124:1789-1797.Data on file. Pfizer Inc.

202/387 59/136 22/62

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.

0

10

20

30

40

50

60

70

80

ITT S aureus NP MRSA NP

Clin

ical

Cur

e (%

)

Linezolid 600 mg q12h IV Vancomycin 1 g q12h IV

103/227 76/207 43/88 32/91 23/37 7/33

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).

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.

4537

49

35

62

21

VANCOMYCIN FAILURE DESPITE ADEQUATE MIC IN MRSA BACTEREMIA

56

10

9

21

0%

20%

40%

60%

80%

100%

MIC ≤ 0.5 MIC 1-2

Failure

Success

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

* P = .01* P = .01

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.

• 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)

Rello J, et al. Crit Care Med 2005; 33:1983–7.

Inadequate Antimicrobial Therapy Vancomycin for MRSA

NP/VAP

Craven DE et al. Infect Dis Clin N Am. 2004;18:939-962.

ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.

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 SUMMARY OF CLINICAL TRIALS FOR NOSOCOMIAL PNEUMONIA DUE TO MRSAPNEUMONIA DUE TO MRSALINEZOLID 600 MG IV Q12H VS VANCOMYCIN 1 G IV Q12HLINEZOLID 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, Clin Ther 2003

Prospective RCT, N=623

52% vs 52% (p = NS)

61% vs 53% (p = NS)

-

Wunderink, Chest 2003

RetrospectiveN=1019

MRSA59% vs 35%(p < 0.01)

- MRSA 80% vs 63% (p = 0.03)

Kollef, ICM 2004

RetrospectiveN=544

MRSA62% vs 21%(p = 0.001)

MRSA60% 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

Beibei L, et al. International journal of antimicrobial agents 2010

Gram-positive bacterial infections

Linezolid vs Vancomycin

Treatment success

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 Renal failure

Kalil AC, et al. Crit care Med 2010;38(9); 1802-1808.

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

Beibei L, et al. 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.

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

Beibei L, et al. International journal of antimicrobial agents 2010

Gram-positive bacterial infections

Linezolid vs Vancomycin

Treatment success

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) , 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

• No statistical significance in the risk of thrombocytopenia

Linezolid % vancomycin

%

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

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)