1. 1 Understanding Healthcare –Associated Pneumonia Antonio Anzueto, MD Professor of Medicine University of Texas Health Science Center at San Antonio

2. Defining VAP, HAP, and HCAP HAP (hospital-acquired pneumonia) –Pneumonia that occurs ≥48 hours from time of admission VAP (ventilator-associated pneumonia) –Pneumonia 48 to 72 hours after endotracheal intubation HCAP (healthcare-associated pneumonia) –Prior hospitalization (within 90 days) –Resided in nursing home or long-term care facility –Received recent IV antibiotics (within 30 days) ATS. Am J Respir Crit Care Med. 2005;171:388-416. AJRCCM. 2005; 171:388-416

3. 3 Kollef M, et al. Chest. 2005;128:3854-3862. Epidemiology and Outcomes of HCAP: Results From a Large US Database of Culture-positive Pneumonia DESIGN –Retrospective cohort analysis (the Atlas database) –4,543 pneumonias identified via ICD-9 (2002-2003) PRIMARY OBJECTIVE –Characterize microbiology and outcome for culture-positive CAP, HCAP, HAP, and VAP

4. 4 OUTCOMES –49% CAP, 22% HCAP, 18% HAP, and 11% VAP –MRSA =most common cause of HCAP –MRSA as percentage of all S. aureas HCAP>HAP>CAP>VAP –Mortality for HCAP and HAP were similar; both were significantly higher than CAP and lower than VAP –HCAP differed from HAP and VAP to a lesser degree than CAP relative to: Pt characteristics Pathogen distribution patterns Outcomes Epidemiology and Outcomes of HCAP: Results From a Large US Database of Culture-positive Pneumonia Kollef M, et al. Chest. 2005;128:3854-3862.

5. 5 Epidemiology and Outcomes of HCAP: Results From a Large US Database of Culture-positive Pneumonia 0 10 20 30 MSSA MRSA Strep pneumo Pseudomonas Haemophilus Acinetobacter CAPHCAPHAPVAP Frequency of Bacterial Pathogens

6. Risk Factors for MDR Pathogens in HCAP Antimicrobial therapy in preceding 90 days Recent hospitalization of ≥5 days High frequency of antibiotic resistance in the community or in the specific hospital unit Presence of risk factors for HCAP Immunosuppressive disease and/or therapy ATS. Am J Respir Crit Care Med. 2005;171:388-416.

7. 7 Are HCAP Patients Bringing MDR Pathogens To The Hospital? Pop-Vicas AE, D’Agata EMC. Clin Infect Dis 2005; 40: 1792-8

8. 8 Are HCAP Patients Bringing MDR Pathogens To The Hospital? 1998-2003 with 464 MDR GNB (12%,35%, 53% resistant to 5,4,3 antibiotic groups) Case-control study of MDR (at least 3 antibiotic classes) GNB isolated w/I 24 hours admit from clinical infection (not pneumonia) Risk factors for MDR on admit: age > 65 (OR 2.8), prior antibiotics for > 14 d (OR 8.7), residence in LTCF (OR3.5). Univariate risks: > 2 hospitalizations in last yr., prior ICU stay. Pop-Vicas AE, D’Agata EMC. Clin Infect Dis 2005; 40: 1792-8

9. Factors associated with Resistant Pathogen 9 Shore et al Arch Inter Med 2008; 168:2205

10. 10 Shore et al Arch Inter Med 2008; 168:2205

11. Point Score and risk stratification for pneumonia due to resistant pathogens 11 Score: Recent hospitalization – 4 Nursing home – 3 Hemodyalysis – 2 ICU admission – 1 Total 10 Shore et al Arch Inter Med 2008; 168:2205

12. 12 What Do We Know About HCAP Therapy? ATS/IDSA guidelines (2005) recommend therapy be the same as HAP targeted at drug resistant gram-negatives and MRSA –Am J Respir Crit Care Med 2005; 171:388-416 Literature Search (PubMed 11/12/08) –Textword: healthcare associated pneumonia (399 articles), antibiotic therapy (201,780 articles) Combined with “AND” for a total of 19 articles –Textword: nursing home pneumonia (452 articles) Combined with “AND ANTIBIOTIC THERAPY” for a total of 47 articles

13. 13 What Do We Know About HCAP Therapy? –Textword: chronic hemodialysis (35,454 articles) Combined with “AND PNEUMONIA” for a total of 107 articles –Textword: prior hospitalization (5084 articles) Combined with “AND PNEUMONIA THERAPY” for a total of 205 articles

14. 14 Defining Empiric Therapy Issues: Should HCAP Be Treated The Same As HAP?? Site of care –All HAP, by definition, occurs in the hospital –HCAP can be inpatient or outpatient therapy Route of therapy –IV vs oral (many nursing home patients get only oral therapy) Bacteriology and Antibiotic choice : Direct at likely pathogens, including –CAP pathogens for some patients Pneumococcus and DRSP Atypicals/Legionella/Viruses: EPIDEMICS in nursing home –MDR gram negatives and MRSA for other patients

15. 15 Site of Care And Route of Therapy HAP, by definition, is ALWAYS treated in the hospital NOT ALL HCAP is treated in the hospital with IV therapy –Hemodialysis –Nursing home Out of hospital therapy of elderly and nursing home patients is common –Loeb M, et al. JAMA. 2006;295:2503-2510. Oral therapy in Nursing Home –Hospital at home for the elderly can include IV meds, oxygen. Leff B, et al. J Am Geriatr Soc. 2006;54:1355-1363. –Many nursing home pneumonia patients prefer therapy in the nursing home if possible. Carusone SC, et al. BMC Geriatr. 2006;6:2.

16. 16 Asp.=aspirations. *Expectorated sputum with >25 white blood cells per low-power field and <10 squamous epithelial cells per low-power field. Hutt E, Kramer AM. J Fam Pract. 2002;51:709-716. Bacteriology of NHAP: One form of HCAP Nursing home pneumonia etiology according to studies using verified sputum* or blood culture StudyNYear S. Pneumoniae (%) S. Aurus (%) Gram- negative rods (%) H. Influenzae (%) Anerobes (%)Multiple Organisms (%) Alvarez414198832—29——22 Peterson1231988103219—— Marrie13119891613 —4— Hirata-Davis5019911241510—— Drinka171994306—25—(Atypicals=0) Marrie and Blanchard 7119972/5— ——— Pick257 (98 asp.) 199633863—Group B streptococci 43%

17. 17 Bacteriology of NHAP: Can Include Virus and Atypical Pathogens Legionella and viruses are important causes of pneumonia in nursing homes and are NOT covered by empiric therapies for HAP –Epidemics of Legionella have occurred in nursing homes, often related to colonization of drinking water. Each facility may need to test annually. Seenivasan MH, et al. J Am Geriatr Soc. 2005;53:875- 880. –Rhinovirus outbreaks reported in 2 nursing homes in Pennsylvania, with up to 40% of hospitalized pneumonia patients infected by this organism. Hicks LA, et al. J Am Geriatr Soc. 2006;54:284-289.

18. 18 El Solh AA, et al. Clin Infect Dis. 2004;39:474-480. Suggest therapy for NHAP: Avoid broad-spectrum rx and use 1 drug if functionally active, no recent antibiotics, even if severely ill. Triple therapy (incl. MRSA) if poor ADL or prior antibiotics, with severe illness. MDR= Multi- Drug resistant pathogen BAL Confirmed Bacteriology of Severe NHAP: Not all at risk for MDR Pathogens N=88 DRP=17 19% N=71 DRP=5 7% N=17 DRP=12 71% N=42 MDR=0 0% N=29 MDR=5 17% N=7 MDR=3 42% N=10 MDR=9 90% No prior antibiotics Prior antibiotics (at least 3 days in last 6 months) ADL <12.5 ADL ≥12.5 ADL <12.5 ADL ≥12.5

19. 19 Need for anaerobic coverage Aspiration pleuro-pulmonary syndrome: –History of loss of consciousness due to alcohol/and or drug overdose –s/p seizures –Gingival disease –Esophageal motility disorder

20. Role of Anaerobes in Patients With VAP and Aspiration Pneumonia (AP) 185 episodes of suspected VAP and 25 AP patients requiring mechanical ventilation support Bacterial pneumonia diagnosed in 63 of 185 episodes (34%) of suspected VAP and 12 of 25 cases (48%) of suspected AP More than 1 organism was found in 11 VAP and 4 AP patients Only 1 anaerobic organism (Veillonella paravula) was isolated from entire group of patients. It was not considered to be a true pathogen Marik and Careau. Chest. 1999;115:178-183.

21. Absence of Anaerobes in HAP VAP IsolatesAP Isolates (n = 74)(n = 17) P aeruginosa16- Methicillin-sensitive S aureus 152 Enterobacter spp83 S pneumoniae52 Methicillin-resistant S aureus 4- S agalactiae4- S maltophilia3- H influenzae32 A baumannii3- K pneumoniae32 E coli12 Flavobacterium spp-2 Serratia sp11 V paravula-1 Other8- Marik and Careau. Chest. 1999;115:178–183. Marik and Careau. Chest. 1999;115:178-183.

22. Aspiration Pneumonia 22 NEJM 2008

23. 23 Slinin Y, et al. Kidney Int. 2006;70:1135-1141. Pneumonia in Hemodialysis Patients DESIGN –Retrospective analysis of Medicare data set on 10,635 dialysis patients PRIMARY OBJECTIVE –Define incidence, mortality risk, and bacteriology of pneumonia OUTCOMES –Cumulative probability of pneumonia 0.09 at 1 year, 0.36 at 5 years. –One-year mortality 45%, 83% at 5 years

24. 24 Pneumonia in Hemodialysis Patients Slinin Y, et al. Kidney Int. 2006;70:1135-1141. Organism% No organism identified81.8 Gram-positive bacteria 4.8 Streptococcus pneumoniae 3.4 Other Streptococcus species 1.0 Staphylococcus species 0.4 Gram-negative bacteria11.1 Pseudomonas aeruginosa 2.8 Hemophilus influenzae 1.5 Klebsiella pneumoniae 1.6 Escherichia coli 0.7 Other gram-neg organisms 4.5 Anaerobic bacteria 0.03 Atypical bacterium: Mycoplasma pneumoniae 0.3 Viral 1.0 Fungal 1.0 Microbiologic spectrum among index pneumonia hospitalizations (n=3101) Adjusted mortality hazards ratios (with 95% CIs) from Poisson regression analysis, in 6-month intervals 65432106543210 Adjusted Post-pneumonia Hazards Ratio for Death 62442607896 Follow up Intervals (Months)

25. 25 Data On Therapy of HCAP Proven Efficacy of Therapies That May Not Be Expected To Be Effective

26. 26 Peterson PK, et al. Am J Med. 1988;85:164-171. Prospective Study of LRTI in an Extended-care Nursing Home: Oral Cipro vs IM Cefamandole DESIGN –40 patients with pneumonia, 20 with acute bronchitis –Prospective, randomized study in nursing home PRIMARY OBJECTIVE –Compare efficacy of oral quinolone vs IM cephalosporin OUTCOMES –Both therapies effective, with low in-hospital mortality (6.5%) –Pneumococcus most common but 81% with gram negatives in sputum

27. 27 Trenholme GM, et al. Am J Med. 1989;87:116S-118S. Prospective Study of Hospital or Nursing Home-acquired Pneumonia: IV Ciprofloxacin vs IV Ceftazidime DESIGN –45 patients –Prospective, randomized study in hospitalized adults with nursing home or hospital-acquired pneumonia PRIMARY OBJECTIVES –Compare efficacy of IV quinolone vs IV cephalosporin –Switch to oral therapy when able OUTCOMES –More favorable response with cipro (100% vs 70%, P=0.025) –More severely ill with ceftazidime by APACHE II score –One relapse on oral therapy after ceftazidime

28. 28 Oral Quinolone Therapy of Nursing Home-acquired Pneumonia Loeb M, et al. JAMA. 2006;295:2503-2510. DESIGN –Cluster-randomized trial of 680 patients age >65 at 20 nursing homes in Canada with radiographic pneumonia –10 with usual care, 10 with clinical pathway PRIMARY OBJECTIVE –To determine the efficacy of a clinical pathway for oral therapy of pneumonia in the nursing home OUTCOMES –Clinical pathway: oral rx with levofloxacin 500 mg qD, oxygen saturuation monitor, rehydration, close nursing observation –Fewer hospitalizations (10% vs 22%, P=0.001), fewer hospital days (0.79 vs 1.74, P=0.004), similar mortality and functional status. NO BACTERIOLOGY. Cost saving of $1,016 per resident

29. 29 Oral Quinolone Therapy of Nursing Home-acquired Pneumonia Loeb M, et al. JAMA. 2006;295:2503-2510. Resident of nursing home with ≥2 of the following Symptoms or signs of lower respiratory tract infection: – New or increased cough – – New or increased sputum production – – Temperature >38° C – – Pleuritic chest pain – – New or increased abnormal findings on chest examination – Obtain mobile chest radiograph Does the resident meet the following criteria? – Ability to eat and drink – – Pulse ≤100/min – – Respiratory rate <30/min – – Systolic BP ≥90 mm Hg – – Oxygen saturation ≥92% – Treatment on-site in the nursing home Quinolone orally for 10 days Hypodermodysis to treat dehydration if needed Transfer to hospital if no longer meets criteria for nursing home treatment Transfer to hospital Quinilone orally or IV for 10 days Transfer back to nursing home when criteria for nursing home treatment met Yes No

30. 30 Yakovlev SV, et al. Eur J Clin Microbiol Infect Dis. 2006;10:633-641. TOC Response by Bacteriology Prospective Randomized Trial of Ertapenem vs Cefepime for HCAP and Nonintubated HAP DESIGN –Prospective, double-blind, randomized trial –303 enrolled, 195 clin eval –HCAP: 23 ertapenem, 28 cefepime. Minimum 3 days IV –Exclude if Pseudomonal risks or severe illness PRIMARY OBJECTIVES: –Comparative efficacy, bacteriology OUTCOMES –At TOC, both equivalent, with 86%- 87% efficacy –Favorable response NHAP: 75% ertapenem vs 90% cefepime –Of 103 with bacteriology: 81 gram negatives, 41 gram positives. Equivalent responses in all groups

31. 31 Wenisch C, et al. Infection. 2006;34:190-195. Pneumonia After Prior Antibiotic Therapy and Failure in CAP DESIGN –Prospective randomized trial of 63 patients hospitalized after failing outpatient antibiotics for CAP –Moxifloxacin vs standard therapy PRIMARY OBJECTIVE –Clinical failure rates with therapy OUTCOMES –Clinical failure during therapy in 30% standard vs 6% moxifloxacin (P=0.009) –28-day failure in 21% standard vs 6% moxifloxacin (P=0.003)

32. 32 Pneumonia After Prior Antibiotic Therapy and Failure in CAP Wenisch C, et al. Infection. 2006;34:190-195. Severity at the time of admission, laboratory data, outcome of treatment. Parameter Standard Therapy (n=33) Moxifloxacin Therapy (n=30)P Value Leukocytes (g/L)15.2 ± 121.513.2 ± 6.70.39 CRP (g/L)127 ± 111142 ± 920.34 PSI118 ± 55127 ± 360.23 Risk class at admission I-III11 (33%)10 (30%)0.58 IV-V22 (67%)20 (70%) Admission to the ICU within 72 h 6 (18%) 8 (26%)0.33 Failure of initial intra-hospital therapy during treatment 10 (30%) 2 (6%)0.009

33. 33 Pneumonia After Prior Antibiotic Therapy and Failure in CAP Wenisch C, et al. Infection. 2006;34:190-195. Severity at the time of admission, laboratory data, outcome of treatment. Parameter Standard Therapy (n=33) Moxifloxacin Therapy (n=30)P Value Microbiology Staphylococcus aureus 2 3 Steptococcus pneumoniae 1 2 Pseudomonas aeruginosa 1 0 Klebsiella pneumoniae 1 1 Haemphilus influenzae 1 2 Negative 8 7 Not available1915

34. 34 Pneumonia After Prior Antibiotic Therapy and Failure in CAP Wenisch C, et al. Infection. 2006;34:190-195. Severity at the time of admission, laboratory data, outcome of treatment. Parameter Standard Therapy (n=33) Moxifloxacin Therapy (n=30)P Value Preclinical therapy microbiologically inadequate/adequate/not available 3/1/304/3/23 Clinical therapy failure (day 28) 7 (21%) 2 (6%)0.003 Cure26 (78%)27 (90%)0.56 Death due to any cause 5 (15%) 3 (10%)0.20 Discharge To go home22250.42 To the nursing home 7 50.29 Duration of hospitalization11.7 ± 8.39.1 ± 4.00.11

35. 35 Bacteriology and Therapy of Severe NHAP Requiring Mechanical Ventilation El Solh AA, et al. Am J Respir Crit Care Med. 2001;163:645-651. DESIGN –Case series of 104 patients with severe pneumonia, including 47 from nursing homes PRIMARY OBJECTIVE –Define natural history, bacteriology (usually bronchoscopic) and therapies OUTCOMES –57% mortality for NHAP vs 55% for CAP –Higher mortality with inadequate therapy (OR 2.6, P=0.034) –Common therapy: 2nd and 3rd gen cephs, BL/BLI, macrolide, quinolone; 47% monotherapy and mortality the same as combination therapy

36. 36 Bacteriology and Therapy of Severe NHAP Requiring Mechanical Ventilation El Solh AA, et al. Am J Respir Crit Care Med. 2001;163:645-651. MicroorganismsHome, n (%)Nursing Home, n (%) Streptococcus pneumoniae8 (14) 4 (9) Staphylococcus aureus4 (7)14 (29) Methicillin-sensitive4 (7)11 (23) Methicillin-resistant0 3 (6) Morexalla catarrhalis2 (4) 1 (2) Chlamydia pneumonaie1 (2) 0 Enterococcus sp.0 1 (2) Hemophilus influenzae4 (7) 1 (2) Kebsiella pneumonia2 (4) 3 (6) The distribution of respiratory pathogens isolated from patients with severe pneumonia

37. 37 Bacteriology and Therapy of Severe NHAP Requiring Mechanical Ventilation El Solh AA, et al. Am J Respir Crit Care Med. 2001;163:645-651. MicroorganismsHome, n (%)Nursing Home, n (%) Esherichia coli4 (7) 1 (2) Proteus sp.1 (2) 0 Serratia sp.1 (2) Providencia sp.0 1 (2) Enterobacter sp.0 1 (2) Pseudomonas aeruginosa1 (2) 2 (4) Legionella pneumophila5 (9) 0 Mycobacterium tuberculosis0 1 (2) Influenza virus1 (2) 0 The distribution of respiratory pathogens isolated from patients with severe pneumonia

38. 38 Conclusions: Initial Empiric Therapy For HCAP Is Not Always The Same As For HAP –HAP therapy is always in hospital and almost always IV HCAP can be treated out of hospital Oral therapy (quinolone ) effective –HCAP therapy may need to cover pathogens not covered in HAP Legionella –Not all patients with HCAP are at risk for MDR Gram negatives and MRSA (LEVEL II B) Nursing Home without severe illness Hemodialysis Prior antibiotics alone not enough of a risk: may require other factors such as impaired functional status or severe illness in nursing home patients

39. 39 Conclusions: Initial Empiric Therapy For HCAP Is Not Always The Same As For HAP (CONTINUED) –In clinical trials, therapies that would NOT be recommended for HAP are effective (LEVEL I B) Quinolone for NHAP Moxifloxacin for failure of outpatient antibiotic in CAP Monotherapies (cefepime, ertapenem, ciprofloxacin) in NHAP –Therapies are effective even if the spectrum of pathogens appears not to be covered –For more severely ill HCAP patients with more comorbidity, poor functional status, prior antibiotics, need therapy of MDR gram-negatives and MRSA

40. 40 Zilberberg et al Chest 2008; 134:963

41. 41 Zilberberg et al Chest 2008; 134:963

42. HCAP mortality according to treatment 42 Zilberberg et al Chest 2008; 134:963

43. 43 Zilberberg et al Chest 2008; 134:963

44. 44 Are at least 2 present? Local Epidemics? Severe: Treat for MDR pathogens With HAP recommendations Need 3 drugs Non-Severe: Treat for common CAP Pathogens (consider oral rx) Quinolone,Beta-lactam/ Macrolide Assess: Severity of Illness (ICU or Mechanical Ventilation), Recent Antibiotic Therapy, Presence of Poor Functional Status YES NO HCAP Is Present: From a nursing home, Home infusion Therapy, Home wound care, Dialysis center, Hospitalized in past 90 days Non-Severe: Treat for MDR pathogens With HAP recommendations Severe: Treat IV, consider hospital Beta-lactam with Macrolide Or Quinolone Proposed Algorithm For HCAP Therapy

45. Obrigado, Muchas Gracias, Thank you 45