1. Nosocomial Pneumonia Eliane Haron,M.D.

2. Nosocomial Pneumonia Epidemiology Common hospital-acquired infection Occurs at a rate of approximately 5-10 cases per 1000 hospital admissions Incidence increases by 6-20 fold in patients being ventilated mechanically. One study suggested that the risk for developing VAP increases 1% per day Another study suggested, highest risk occur in the first 5 days after intubation

3. Nosocomial Pneumonia

4. Epidemiology Nosocomial pneumonia is the leading cause of death due to hospital acquired infections Associated with substantial morbidity Has an associated crude mortality of 30-50% Hospital stay increases by 7-9 days per patient Estimated cost > 1 billion dollars/year

5. Hospital Mortality (%) 0 10 20 30 40 50 None Early Onset Late Onset Nosocomial Pneumonia P =.504P<.001 Mortality and Time of Presentation of HAP Ibrahim, et al. Chest. 2000;117:1434-1442. *Upper 95% confidence interval * * *

6. Nosocomial Pneumonia Hence, the importance of focusing on: Accurate diagnosis Appropriate treatment Preventive measures

7. Nosocomial Pneumonia Pathogenesis Risk factors Etiologic agents Differential diagnosis Treatment Prevention

8. Nosocomial Pneumonia Pathogenesis

9. Nosocomial Pneumonia Microaspiration may occur in up to 45% of healthy volunteers during sleep Oropharynx of hospitalized patients is colonized with GNR in 35-75% of patients depending on the severity and type of underlying illness Multiple factors are associated with higher risk of colonization with pathogenic bacteria and higher risk of aspiration

10. Nosocomial Pneumonia Pathogenesis Invasion of the lower respiratory tract by: Aspiration of oropharyngeal/GI organisms Inhalation of aerosols containing bacteria Hematogenous spread

12. Colonization Aspiration HAP MRSA*

13. Nosocomial Pneumonia Risk Factors

14. Nosocomial Pneumonia Risk Factors Host Factors Extremes of age, severe acute or chronic illnesses, immunosupression, coma, alcoholism, malnutrition, COPD, DM Factors that enhance colonization of the oropharynx and stomach by pathogenic microorganisms admission to an ICU, administration of antibiotics, chronic lung disease, endotracheal intubation, etc.

15. Nosocomial Pneumonia Risk Factors Conditions favoring aspiration or reflux Supine position, depressed consciousness, endotracheal intubation, insertion of nasogastric tube Mechanical ventilation Impaired mucociliary function, injury of mucosa favoring bacterial binding, pooling of secretions in the subglottic area, potential exposure to contaminated respiratory equipment and contact with contaminated or colonized hands of HCWs Factors that impede adequate pulmonary toilet Surgical procedures that involve the head and neck, being immobilized as a result of trauma or illness, sedation etc.

16. Nosocomial Pneumonia Etiologic Agents

17. Nosocomial Pneumonia Etiologic Agents S.aureus Enterobacteriaceae P.aeruginosa Acinetobacter sp. Polymicrobial Anaerobic bacteria Legionella sp. Aspergillus sp. Viral

18. Nosocomial Pneumonia (%) 0 5 10 15 20 25 30 35 40 PA OSSA ORSA 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 HAP Ibrahim, et al. Chest. 2000;117:1434-1442.

19. Nosocomial Pneumonia Diagnosis

20. Nosocomial Pneumonia Diagnosis Not necessarily easy to accurately diagnose HAP Criteria frequently include: Clinical fever ; cough with purulent sputum, Radiographic new or progressive infiltrates on CXR, Laboratorial leukocytosis or leukopenia Microbiologic Suggestive gram stain and positive cultures of sputum, tracheal aspirate, BAL, bronchial brushing, pleural fluid or blood Quantitative cultures

21. Nosocomial Pneumonia Problems All above criteria fairly sensitive, but very non- specific, particularly in mechanically ventilated patients Other criteria/problems include Positive cultures of blood and pleural fluid plus clinical findings (specific but poor sensitivity) Rapid cavitation of pulmonary infiltrate absent Tb or cancer (rare) Histopathologic examination of lung tissue (invasive)

22. Nosocomial pneumonia Bronchoscopically Directed Techniques for diagnosis of VAP and Quantitative cultures Bronchoscopy with BAL/bronchial brushings (10,000 to 100,000 CFU/ml and less than 1% of squamous cells) Protected specimen brush method (>10³ CFU/ml) Protected BAL with a balloon tipped catheter (>5% of neutrophils or macrophages with intracellular organisms on a Wright-Giemsa stain)

23. Nosocomial pneumonia Multiple studies looked into the accuracy of quantitative culture and microscopic examination of LRT secretions as compared to histopathologic examination and tissue cultures (either lung biopsy or immediate post mortem obtained samples) Several trials conclude that use of FOB techniques and quantitative cultures are more accurate At least 4 studies concluded that bronchoscopically directed techniques were not more accurate for diagnosis of VAP than clinical and X-ray criteria, combined with cultures of tracheal aspirate Therefore no gold standard criteria exist CDC- Emerging Infectious Diseases, March-April 2001

24. Nosocomial Pneumonia Differential diagnosis ARDS Pulmonary edema Pulmonary embolism Atelectasis Alveolar hemorrhage Lung contusion

25. Nosocomial Pneumonia Treatment

26. Nosocomial Pneumonia Antimicrobial Treatment Broad spectrum penicillins 3 rd and 4 th generation cephalosporins Carbapenems Quinolones Aminoglycosides Vancomycin Linezolid

27. Inadequate Antibiotic Therapy Antibiotic Resistance

28. Clinical Pulmonary Infection Score (CPIS) Randomize Antibiotics 10-21 days Ciprofloxacin 3 days Antibiotics 10-21 days >6: treat as pneumonia  6: discontinue Ciprofloxacin Reevaluate CPIS at 3 days Singh, et al. Am J Respir Crit Care Med. 2000;162:505-511. >6 66

29. Outcomes Death* 13%31%.06 ABs>3d 28%97%.0001 Mean AB costs † $259$640.0001 *At 30 days † For patients with CPIS  6 at day 3 VariableCiprofloxacinControlP Value (n = 39)(n = 42) Singh, et al. Am J Respir Crit Care Med. 2000;162:505-511.

30. Antimicrobial Superinfections and Resistance (S&R) S&R15%35%.017 MRSA5%14% Candida species8%14% P aeruginosa8%16% VariableCiprofloxacinControlP Value Singh, et al. Am J Respir Crit Care Med. 2000;162:505-511.

31. Nosocomial Pneumonia- Treatment Micek et al.Chest,May 2004 Randomized, controlled trial of antibiotic discontinuation for patients with suspected VAP Discontinuation group vs. conventional group (clinical judgment of treating ICU physician) Discontinuation policy(clinical criteria) Non-infectious etiology identified or Signs and symptoms suggestive of infection had resolved (fever, leukocytosis, purulent sputum, PaO2/FiO2 ratio > 250, improvement of CXR) Only statistically different outcome was duration of antibiotic therapy Mortality, length of ICU stay and 2 nd episode of VAP were similar in both groups

32. Torres, A. et al. N Engl J Med 2004;350:433-435 Proposed Strategy for Management of Suspected Ventilator-Associated Pneumonia

33. Treatment of Nosocomial Pneumonia Vancomycin versus Linezolid for MRSA pneumonia Rubinstein et al. CID2001;32:402-12 Randomized, double blinded, multi-center study 203 patients received Linezolid /193 patients received Vancomycin Clinical success equivalent( 66.4% linezolid vs.68.1% Vancomycin) Microbiological success equivalent (67.9% Linezolid and 71.8%Vanc) VRE in stools (0% linezolid vs. 4% Vancomycin)

34. Treatment of Nosocomial Pneumonia Vancomycin versus Linezolid for MRSA infections/pneumonia Stevens et al. CID 2002; 34:1481-90 Randomized, open label study 460 patients Clinical success equivalent( 73.2% linezolid vs.73.1% Vancomycin) Microbiological success equivalent (58.9% Linezolid and 63.2%Vanc) GI side effects higher in the Linezolid arm

35. Treatment of Nosocomial Pneumonia Vancomycin versus Linezolid for MRSA pneumonia Wunderink RG et al.Chest Nov.2003 Retrospective analysis of 2 prospective double blind multinational studies 160 patients with MRSA VAP received Linezolid or Vancomycin Outcome assessed 12-28 days post treatment Logistic regression analysis used to determine the effect of treatment, and other baseline variables on outcome Cure rates showed linezolid to be superior ( 59% Linezolid vs.35.5% Vancomycin, p=0.009)) Survival rates favored Linezolid (80% Linezolid vs. 63.5% Vancomycin, p=0.03)

36. Linezolid vs. Vancomycin for VAP

37. Nosocomial Pneumonia Duration of antimicrobial treatment Optimal duration of treatment has not been established Most experts recommend 14-21 days of treatment Recent data support shorter treatment regimens (8 days)

38. Treatment of Nosocomial Pneumonia Comparison of 8 vs.15 days of antibiotics for VAP Prospective, randomized, double blind clinical trial 51 French ICUs 401 patients with VAP (quantitative culture results) Clinical effectiveness comparable, with the possible exception of VAP caused by non fermenting GNR JAMA 290 No 19, November 2003

39. Treatment of Nosocomial Pneumonia

40. Nosocomial Pneumonia Prevention

41. Nosocomial pneumonia- Surveillance *Ventilator associated pneumonia benchmarks include only data from January 2002-June 2003. The number of pneumonias and ventilator days is a relatively small sampling and the data should be considered provisional. Quarter/Year# Infections#Ventilator Days# Vent pneumonia/1000 vent days 3qtr 2003 3400.0 4qtr 2003 2 3945.1 1qtr 2004 0 3470.0 2qtr 2004 0 2980.0 Last 4 qtrs 2 13791.5

42. Nosocomial Pneumonia Preventive Measures Incentive spirometry Promote early ambulation Avoid CNS depressants Decrease duration of immunosupression Infection control measures Educate and train personnel

43. Nosocomial Pneumonia Preventive Measures Avoid prolonged nasal intubation Suction secretions Semi-recumbent position( 30-45°head elevation) Do not change ventilator circuits routinely more often than every 48 hours Drain and discard tubing condensate Use sterile water for respiratory humidifying devices Subglottic secretions drainage

44. Craven, et al. Chest. 1995;108:s1-s16.

45. Nosocomial Pneumonia Preventive Measures Remove NGT when no longer needed Avoid gastric overdistention Stress ulcer prophylaxis: sulcrafate; antacids; H2 receptor antagonists Acidification of enteral feedings Prophylactic antibiotics Inhaled antibiotics Selective digestive decontamination Chlorexidine oral rinses Vaccines ( Influenza; Strep.pneumoniae)

46. Bibliography MMWR, January 3,1997/vol.46/No.RR-1 Infectious Disease Clinics of North America- December 2003 American J. Resp. Crit Care Medicine Vol. 165, 2002: 867- 903 NEJM Volume 340: 627-634, 1999 Am J Resp Crit Care Med 1995:153:1711. ATC Guidelines : Hospital-acquired pneumonia in adults Annals Int. Med.Vol.129,No 6:433-440, 1998 NEJM Volume 344:665-671, 2001 Chest/120/3/September 2001

47. Bibliography Thorax; 57:366-371, 2002 NEJM Vol. 350: 433-35, 2004 Emerging Infectious Diseases Vol. 7,No 2, 2001 Up To Date: Diagnosis of ventilator-associated pneumonia, March 2004 Chest /125/5/Pages 1791-1799 and 1600-1601, May 2004 JAMA vol.290, No 19, November 19, 2003 Chest 124(5):1789-97,November 2003 AntimicrobAgentsChemother 47(11):3442-7, 2003

48. Bibliography Intensive Care Medicine2004Mar;30(3):343-6 Am J Resp Crit Care Med 162(2):505-511, 2000 CID 32:402-412, February 2001 Crit. Care Med.vol.32(1):137-143, January 2004 Am J Resp Crit Care Med vol.168:173-179, 2003 Chest/117:1434-42/September 2000