Pneumonias HAP/HCAP/VAP

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 hours after intubation. 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 Added as a category of pneumonia in the 2005 ATS/IDSA guidelines as an increased risk for patients who may have been exposed to multidrug-resistant (MDR) pathogens from community settings. ATS/IDSA Am J Respir Crit Care Med. 2005;171:

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) Difficult because the clinical findings are nonspecific. 2005 ATS/IDSA guidelines on the management of adults with HAP, VAP and HCAP do not provide specific criteria.

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)

Study of 4543 pts. with Culture Positive Pneumonia: Incidence (%)
Epidemiology Study of 4543 pts. with Culture Positive Pneumonia: Incidence (%) 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 cases per 1,000 hospital admissions 0.88 per 1000 patients admission in Taif ( ) 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:

Crude mortality of HAP is 30-70% Attributable mortality is 20-50%
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 bacteremia, medical rather than surgical illness, ineffective and late antibiotic therapy. P>.05 P<.0001 Kollef MH, et al. Chest. 2005;128:

Mortality and Time of Presentation of HAP
50 P<.001 P = .504 * * 40 30 Hospital Mortality (%) 20 * 10 None Early Onset Late Onset *Upper 95% confidence interval Nosocomial Pneumonia Ibrahim, et al. Chest. 2000;117:

MRSA infection Crit Care 2006:10(3):R97.

HAP: Non-Vent vs. Vented Pts.
Pennsylvania study on nosocomial pneumonia, Davis J. The breath of hospital-acquired pneumonia: nonventilated versus ventilated patients in Pennsylvania. Focus on Infection Prevention. Pennsylvania Patient Safety Advisory. 2012;9:

Etiology Aerobic gram-negative bacteria: Gram-positive cocci
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:

Pathogens Associated With NAP
Early-onset NP 40 Late-onset NP 35 PA = P aeruginosa OSSA = Oxacillin-sensitive S aureus ORSA = Oxacillin-resistant S aureus ES = Enterobacter species SM = S marcescens 30 25 P = .408 P = .043 Nosocomial Pneumonia (%) 20 15 P = .985 P = .144 10 5 PA MSSA MRSA ES SM Pathogen Ibrahim, et al. Chest. 2000;117:

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.

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:

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 60 52* *P<.001 Importance of Initial, Appropriate Antibiotic Therapy Study objective: To evaluate the relationship between inadequate antimicrobial treatment of infections (both community-acquired and nosocomial infections) and hospital mortality for patients requiring ICU admission1 Study design: Prospective cohort study at a Missouri hospital, July 1997 through March 19981 The 169 patients who initially received inadequate antimicrobial therapy for infection represented 26% of the 655 patients assessed to have either community-acquired or nosocomial infections1 All-cause mortality was 52% in patients receiving inadequate antimicrobial therapy versus 24% in those receiving adequate therapy (P<.001)1 Infection-related mortality was 42% in patients receiving inadequate therapy versus 18% in those receiving adequate therapy1 Risk factors for mortality included prior antibiotic therapy (odds ratio [OR]=3.39) and bloodstream infection (OR=1.88) (data not shown on slide)1 Reference 1. Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115: 50 42* 40 Hospital Mortality (%) 30 24 18 20 10 All-Cause Mortality Infection-Related Mortality Inadequate antimicrobial treatment (n=169) Adequate antimicrobial treatment (n=486) ATS=American Thoracic Society; IDSA=Infectious Diseases Society of America. Adapted from Kollef MH et al. Chest. 1999;115: ATS/IDSA. Am J Respir Crit Care Med. 2005;171:

Effect of timing on survival
Fraction of total patients Time from hypotension onset (hours) Crit Care Med 2006;34:

Crit Care Resusc. 2007 Mar;9(1):8-18.
JAMA 2010 The outcome of patients with sepsis and septic shock presenting to emergency departments in Australia and New Zealand. Crit Care Resusc Mar;9(1):8-18.

Antipseudomonal cephalosporin OR Antipseudomonal carbepenem
β-Lactam/β-lactamase inhibitor Plus Antipseudomonal fluoroquinolone Aminoglycoside 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 Pathogens Recommended Antibiotic Streptococcus pneumoniae H influenzae Methicillin-sensitive S aureus (MSSA) Antibiotic-sensitive, enteric, gram-negative bacilli E coli K pneumoniae (ESBL-) Enterobacter spp Proteus spp Serratia marcescens Ceftriaxone/Azithromycin or Levofloxacin, moxifloxacin, or ciprofloxacin† Ampicillin/sulbactam/Azithromycin 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; ) 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

Preventive Measures sulcrafate; antacids; H2 receptor antagonists
Incentive spirometry Promote early ambulation Avoid CNS depressants Decrease duration of immunosupression Infection control measures Educate and train personnel Semi-recumbent position( 30-45°head elevation) Subglottic secretions drainage Preventive Measures Remove NGT when no longer needed Avoid gastric overdistention Stress ulcer prophylaxis: sulcrafate; antacids; H2 receptor antagonists Acidification of enteral feedings Oral care program Vaccines ( Influenza; Strep.pneumoniae) Davis J. The breath of hospital-acquired pneumonia: nonventilated versus ventilated patients in Pennsylvania. Focus on Infection Prevention. Pennsylvania Patient Safety Advisory. 2012;9:

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, 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 Drug-resistant Pathogens: (Bacteria, Mycobacteria, Virus, Fungus) Inadequate Antimicrobial Therapy Wrong Diagnosis 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
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 5 10 15 20 25 30 19751 1992–19982 20031 S aureus P aeruginosa Enterobacter spp. E coli K pneumoniae Serratia marcescens Acinetobacter spp 1. Gaynes R, et al. Clin Infect Dis .2005; 41: NNIS system report. Am J Infect Control. 2000; 28(6): 2. Richards MJ, et al. Infect Control Hosp Epidemiol. 2000; 21:510-5.

Time After Last Dose (h)
Lung Penetration Concentration vs MIC90 of Linezolid Against Gram-Positive Organisms Epithelial lining fluid Plasma MIC90 S aureus MIC90 Enterococcus spp MIC90 S pneumoniae 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 Lung Penetration Concentration vs MIC90 of Linezolid Against Gram-Positive Organisms1 Drug concentrations were either measured or calculated for pulmonary epithelial lining fluid (ELF), plasma, and pulmonary alveolar cells The MIC90 of linezolid is ≤4 µg/mL for S aureus, enterococci, and S pneumoniae ELF concentrations of linezolid in healthy volunteers exceeded MIC90 values for S aureus, enterococci, and S pneumoniae throughout the dosing interval Plasma concentrations were above the MIC90 for S pneumoniae throughout the dosing interval and for S aureus and enterococci at all time points except the last Pharmacokinetics in healthy adult volunteers and in vitro activity do not necessarily imply a correlation with clinical effectiveness Reference 1. Conte JE Jr, Golden JA, Kipps J, Zurlinden E. Intrapulmonary pharmacokinetics of linezolid. Antimicrob Agents Chemother. 2002;46: Concentration (µg/L) Time After Last Dose (h) MIC90=minimum concentration needed to inhibit 90% of organisms. Adapted from Conte JE Jr et al. Antimicrob Agents Chemother. 2002;46:

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 Pharmacokinetic Characteristics of Linezolid in Adults Linezolid is rapidly absorbed, with 100% bioavailability IV and oral formulations can be interchanged without dose adjustment Linezolid may be administered with or without food. Dosing of linezolid is unaffected by timing of food intake, advanced age, gender, race, renal function, or mild-to-moderate impairment of hepatic function The volume of distribution of linezolid at steady state averaged 40 L to 50 L in healthy volunteers Linezolid is available in injection, tablet, and oral suspension (PO) formulations The plasma protein binding is 31% and is 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 Linezolid Pharmacokinetics in VAP1 The linezolid pharmacokinetic profile for 16 patients with late-onset VAP was evaluated 2 days after starting therapy (600 mg q12h IV). Samples for linezolid determination from ELF were collected with a mini-BAL brush. All MRSA VAP patients improved after 10 days of linezolid therapy. Baseline characteristics for the study population1: Age, 59±15 years Gender (m/f), 10/6 Weight, 73±15 kg Simplified acute physiology score (SAPS II), 40±13 Creatinine clearance, 81±45 mL/min PaO2/FIO2 ratio, 231±117 Main diagnosis1: Pneumonia, 7 Abdominal surgery, 5 Pancreatitis, 2 Encephalitis, 2 Steady State Pharmacokinetics1: Plasma/BAL Urea concentration ratio, 8.2±4.6 Volume of distribution, 57±18 L AUC0-12, 77.3±23.7 mg·h/L Elimination half-life, 4.4±0.9 Reference 1. Boselli E, Breilh D, Rimmelé T, et al. Pharmacokinetics and intrapulmonary concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia. Crit Care Med. 2005;33: 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:

Intent-to-treat (ITT)
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 70 58 55 60 53 52 50 46 50 First Prospective Comparison of Linezolid vs Vancomycin for Empiric Treatment of Nosocomial Pneumonia (NP)1 There were no significant differences in baseline characteristics between the 2 groups.1 Clinical cure was defined as resolution of baseline signs and symptoms of pneumonia. Data from patients with indeterminate or missing clinical cure outcomes were excluded.1 There were no significant differences between linezolid and vancomycin for clinical cure rate in any of the 3 patient populations evaluated. Not shown, the clinical cure rates were also similar for the clinically evaluable (66.4% versus 68.1%) and microbiologically evaluable (69.8% versus 68.4%) groups (linezolid versus vancomycin respectively).1 Reference 1. Rubinstein E, Cammarata SK, Oliphant TH, Wunderink RG, and the Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU ) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind multicenter study. Clin Infect Dis. 2001;32: 40 Clinical Cure (%) 30 20 10 86/161 74/142 31/56 19/41 18/31 10/20 Intent-to-treat (ITT) S aureus NP MRSA 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: 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. 10 20 30 40 50 60 70 ITT S aureus NP MRSA NP 60 53 52 49 Second Prospective Comparison of Linezolid vs Vancomycin for Empiric Treatment of NP This study was designed to extend the experience with linezolid as originally reported by Rubinstein et al,1 to satisfy international regulatory requirements. The study protocol in this report2 is identical to that described by Rubinstein et al.1 Baseline characteristics in this study population were similar between groups, except for a higher rate of multilobar pneumonia in the linezolid-treated groups (56.1% versus 44.3% for linezolid versus vancomycin respectively, P=.004).2 Clinical cure was defined as resolution of baseline signs and symptoms of pneumonia, with improvement or lack of progression of radiologic findings. Data from patients with indeterminate or missing clinical cure outcomes were excluded. Clinical cure rates for clinically evaluable patients, excluding patients with missing or indeterminate outcomes, were equivalent between the linezolid and vancomycin groups (114/168 [67.9%] and 111/171 [64.9%], respectively.2 References 1. Rubinstein E, Cammarata SK, Oliphant TH, Wunderink RG, and the Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU ) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind multicenter study. Clin Infect Dis. 2001;32: 2. Wunderink RG, Cammarata SK, Oliphant TH, Kollef MH, for the Linezolid Nosocomial Pneumonia Study Group. Continuation of a randomized, double-blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia. Clin Ther. 2003;25: 42 Clinical Cure (%) 29 135/256 128/245 40/81 40/95 18/30 12/41 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: 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) 70 59 60 53 52 52 50 43 Linezolid Demonstrates Excellent Efficacy in a Retrospective Analysis of Two Prospective Clinical Trials From the original cohort of 1019 patients with suspected Gram-positive pneumonia enrolled in 2 individual registration trials1,2 who received at least 1 dose of study medication, 339 were documented to have S aureus pneumonia, and 160 patients were documented to have MRSA pneumonia.3 All results were locked into the database before the retrospective analysis was started.3 MIC testing of S aureus isolates revealed that 90% had MIC ≤1 μg/mL and only 1 isolate had an MIC greater than 2 μg/mL.3 Clinical cure was defined as resolution of baseline signs and symptoms of pneumonia. References 1. Rubinstein E, Cammarata SK, Oliphant TH, Wunderink RG, and the Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU ) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind multicenter study. Clin Infect Dis. 2001;32: 2. Wunderink RG, Cammarata SK, Oliphant TH, Kollef MH, for the Linezolid Nosocomial Pneumonia Study Group. Continuation of a randomized, double-blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia. Clin Ther. 2003;25: 3. Wunderink RG, Rello J, Cammarata SK, Croos-Dabrera RV, Kollef MH. Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest. 2003;124: 36 40 Clinical Cure (%) 30 20 10 221/417 202/387 70/136 59/136 36/61 22/62 ITT S aureus NP MRSA NP 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). Wunderink RG et al. Chest. 2003;124: 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. 62 49 45 Linezolid Demonstrates Excellent Efficacy in a Retrospective Analysis of Two Prospective Clinical Trials Data from 2 prospective, randomized, double-blind registration studies1,2 comparing linezolid to vancomycin were combined and retrospectively analyzed to identify variables that affected outcome as measured by survival and clinical cure rate in patients with Gram-positive VAP.3 Of the 1019 patients from the combined data set 544 (53%) met the clinical description for VAP and received at least one dose of study medication. Of this group, 264 had Gram-positive pathogens, with 221 patients with S aureus and 91 patients with MRSA.3 There was no difference in survival between linezolid- and vancomycin–treated groups (data not shown).3 References 1. Rubinstein E, Cammarata SK, Oliphant TH, Wunderink, and the Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU ) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: A randomized, double-blind multicenter study. Clin Inf Dis. 2001;32: 2. Wunderink RG, Cammarata SK, Oliphant TH, Kollef MH, for the Linezolid Nosocomial Pneumonia Study Group. Continuation of a randomized, double-blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia. Clin Ther. 2003;25: 3. Kollef MH, Rello J, Cammarata SK, Croos-Dabrera RV, Wunderink RG. Clinical cure and survival in Gram-positive ventilator-associated pneumonia: retrospective analysis of two double-blind studies comparing linezolid with vancomycin. Intens Care Med. 2004;30: 37 35 Clinical Cure (%) 21 103/ /207 43/ /91 23/ /33 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). Kollef MH et al. Intens Care Med. 2004;30: Wunderink RG et al. Chest. 2003;124: Data on file. Pfizer Inc.

Vancomycin Failure despite Adequate MIC in MRSA Bacteremia
Sakoulas G, et al. J Clin Microbiol 2004;42:2398 – 402

Higher vancomycin MICs associated with higher mortality rates
Influence of Vancomycin Minimum Inhibitory Concentration on the Treatment of Methicillin‐Resistant Staphylococcus aureus Bacteremia Alex Soriano, Francesc Marco, José A. Martínez, Elena Pisos, Manel Almela, Veselka P. Dimova, Dolores Alamo, Mar Ortega, Josefina Lopez, and Josep Mensa Clin Infect Dis 2008; 46:

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 mg/L) than traditional dosage (5-15 mg/L) ATS/IDSA. Am J Respir Crit Care Med. 2005;171: Craven DE et al. Infect Dis Clin N Am. 2004;18: Rello J, et al. Crit Care Med 2005; 33:1983–7.

Vancomycin Therapeutic Guidelines 2009, IDSA, ASAHP, SIDP
Recommend Loading : mg/kg Achieve rapid target concentration Maintain : mg/kg, q8~12h, if MIC < 1 mg/L Trough : mg/L Achieve AUC/MIC >400, if MIC < 1 mg/L Infusion period : 1.5 ~ 2h, or continuous infusion Alternative therapy considered if MIC ≧ 2 mg/L 現行CLSI規定 MIC > 2 mg/L: I, =2: S Clinical Infectious Diseases 2009; 49:325-7.

Is Toxicity Limiting the Ability to Optimize Vancomycin Area Under the Curve (AUC)/Minimum Inhibitory Concentration (MIC)? The relationship between achieving target vancomycin trough levels and nephrotoxicity was evaluated for 95 elderly patients with nosocomial MRSA infections. Nephrotoxicity was defined as a 0.5-mg/dL (44.2 µmol/L) or a 50% or more increase from baseline in serum creatinine levels in 2 consecutive laboratory tests.1 In a chart review between January 2004 and January 2006, the relationship between vancomycin trough levels and nephrotoxicity was evaluated in a group of 59 patients (>18 years of age with calculated creatinine clearance >30 mL/min) receiving vancomycin therapy for 14 days. Nephrotoxicity was defined as an increase in serum creatinine levels of ≥0.5 mg/dL above baseline values.2 In a retrospective chart review, 94 patients with MRSA healthcare-associated pneumonia confirmed by bronchoalveolar lavage, the relationship between trough vancomycin concentration and nephrotoxicity was evaluated. Nephrotoxicity was defined as a 25% decrease in the estimated creatinine clearance during vancomycin therapy.3 In a retrospective cohort review of randomly selected patients from a single hospital receiving vancomycin or linezolid for suspected or proven Gram-positive infections between 2005 and Nephrotoxicity was defined as a 0.5-mg/dL (44.2 µmol/L) or a 50% or more increase from baseline in serum creatinine levels. Patients who met entry criteria were divided into 3 groups: standard vancomycin dose (<4 g/day), high-dose vancomycin (≥4 g/day); or linezolid. The selection pool included 1412 unique patients who received vancomycin for more than 48 hours and 115 unique patients who received linezolid for more than 48 hours between January 1, 2005, and December 31, Overall nephrotoxicity rates were 34.6% in the high-dose vancomycin group, 10.6% in the standard nephrotoxicity group, and 6.7% in the linezolid group.4 References 1. Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections. Arch Intern Med. 2006;166: 2. Lee-Such SC, Overholser BR, Munoz-Price LS. Nephrotoxicity associated with aggressive vancomycin therapy. Presented at: 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract L-1298. 3. Jeffres MN, Micek ST, Isakow W, Doherty JA, Kollef MH. Increased incidence of nephrotoxicity with higher vancomycin serum trough concentrations. Presented at: 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract K-789. 4. Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother. 2008;52: 66

Heteroresistance Etest Macromethod: using a higher inoculum to detect the presence of a less susceptible subpopulation J Clin Microbiol 2007;45: The annals of pharmacotherapy 2010;44:

Potential benefit of linezolid

69 Linezolid: Unique Mechanism of Action on Protein Synthesis
Linezolid is a fully synthetic inhibitor of protein synthesis with a unique site of action1 Initiation requires formation of a ternary complex consisting of N-formylmethionyl-tRNA, mRNA, and the ribosome. Linezolid binds to the 50S subunit of the ribosome on a site that has not been shown to interact with other classes of antibiotics. As a result, linezolid prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process1,2 To date, no clinical studies have been done to confirm a lack of cross-resistance; however, the unique mechanism of action supports the contention that cross-resistance between linezolid and other antibiotic classes is unlikely1 As a protein synthesis inhibitor, linezolid also inhibits production of virulence factors and toxins. Of note, the latter effects are observed at lower concentrations than are required to achieve minimum inhibitory concentration results1 References 1. Ford CW, Zurenko GE, Barbachyn MR. The discovery of linezolid, the first oxazolidinone antibacterial agent. Curr Drug Targets Infect Disord. 2001;1: 2. Swaney SM, Aoki H, Ganoza MC, Shinabarger DL. The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria. Antimicrob Agents Chemother. 1998;42: 69

70 Linezolid Characteristics1
In 2000, linezolid was the first in the class of oxazolidinone antibiotics to be approved by the FDA. Clinical and microbiologic findings demonstrate that linezolid has clinical utility and is effective and safe for the treatment of certain infections caused by indicated aerobic Gram-positive organisms. It is available in oral and intravenous formulations; the oral formulation has 100% bioavailability Resistance is uncommon; cross-resistance between linezolid and other classes of antibiotics is unlikely Linezolid readily distributes to well-perfused tissues Plasma protein binding is ≈31% and is concentration-independent Metabolism is not dependent on any single organ system Both active drug and metabolites are excreted by multiple routes Linezolid is not detectably metabolized by the cytochrome P450 enzyme system, so interactions between linezolid and other medications metabolized by this system are unlikely References 1. French G. Linezolid. Int J Clin Pract. 2001;55:59-63. 2. Conte JE Jr, Golden JA, Kipps J, Zurlinden E. Intrapulmonary pharmacokinetics of linezolid. Antimicrob Agents Chemother. 2002;46: 3. Gee T, Ellis R, Marshall G, Andrews J, Ashby J, Wise R. Pharmacokinetics and tissue penetration of linezolid following multiple oral doses. Antimicrob Agents Chemother. 2001;45: 70

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, Clin Ther 2003 RCT, N=623 52% vs 52% (p = NS) 61% vs 53% Chest 2003 Retrospective N=1019 MRSA 59% vs 35% (p < 0.01) 80% vs 63% (p = 0.03) Kollef, ICM 2004 N=544 62% vs 21% (p = 0.001) 60% vs 22% MRSA: 84% vs 61% (p = 0.02) One arm: zyvox+ aztreonam Another: vancomycin+aztronam

Linezolid vs Vancomycin in Nosocomial Pneumonia (empirical)
Rubinstein, et al. Clin Infect Dis 2001: 32; Wunderink et al. Clin Ther 2003; 25: Linezolid vs Vancomycin Chest 2003;124;

Linezolid vs Vancomycin. Chest 2003;124:

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:

Inhibition of toxin synthesis
Linezolid can inhibition of protein synthesis and bacterial toxin Panton-Valentine leukocidin (PVL) toxin Wunderink RG, et al. Chest 2008:134(6): Oxacillin increase PVL Vancomycin has no effect on PVL

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 (4):

Limitation of the retrospective study
Post hoc analysis Subgroup analysis is not randomized. Chest 2004:126(1): Chest 2004:125(6): Chest 2005:127(6):

Limitation of the pharmacokinetics study
Vancomycin level study: study in patients without pneumonia. Cruciani M. J antimicrob chemother 1996:38(5): Other study in pneumonia patients did not show sub-therapeutic lung concentration. Lamer C. Antimicrob agents chemother (2):

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 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
Randomized controlled trial, linezolid Walkey AJ, et al. Chest. E-publish Sep 23, 2010

Walkey AJ, et al. Chest. E-publish Sep 23, 2010

Risk of thrombocytopenia: no significantly 2.97 times higher in linezolid group (95% CI: P=0.10) Risk of renal impairment: no significantly difference (RR: 1.09, 95% CI: , 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);

Clinical cure: RR 1.01 ( ), P=0.83 Kalil AC, et al. Crit care Med 2010;38(9);

For MRSA pneumonia: RR: 1.10 ( ), P=0.44 Kalil AC, et al. Crit care Med 2010;38(9);

GI events Thrombocytopenia Renal failure Kalil AC, et al. Crit care Med 2010;38(9);

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. International journal of antimicrobial agents. 2010;35: 3-12.

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 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 For other GNB can use maxipime or other antibiotics according to PI’s adjustment

156 centers worldwide in 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)

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 4.3 rash 2.7 nausea 1.9 constipation 1.0 1.7 anemia 1.4 Acute renal failure

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; ) 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)

Pneumonias HAP/HCAP/VAP

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