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