Diagnosis, Treatment and Prevention of Hospital Acquired Pneumonia

1. Diagnosis, Treatment and Prevention of Hospital Acquired Pneumonia Michael Zgoda, MD Asst. Professor, Division of Pulmonary, Critical Care and Sleep Medicine Director, Interventional Pulmonology University of Kentucky, Lexington, KY

2. A Case Study Day 1 • A 76-year-old white male is sent to the local hospital from a long-term care (LTC) facility for evaluation of a pneumonic process • Past medical history reveals multiple admissions, with a history of diabetes, hypertension, and foot ulcer • The patient was discharged 10 days ago following a cholecystectomy. • The patient is admitted for pneumonia. Necessary blood work, cultures, and labs are performed. Ceftriaxone and azithromycin IV are started.

3. Chest X-Ray

4. A Case Study Day 3 • The patient is still febrile and has developed a cough (mucoid). He is uncomfortable and very restless. Staff notes that he is somewhat disoriented to time and place. The patient has no history of dementia • Follow-up information sent from the LTC facility shows that the patient has been on oral dicloxacillin, for previous infections, with poor results • Current laboratory test values denote increased white blood cell count and Gram-positive cocci

5. A Case Study Days 5 to 7 • The patient’s therapy was reviewed by the attending physician: • Therapy was changed on day 3 by adding levofloxacin • At present the patient is worsening and requires intubation and mechanical ventilation • Several hours later he continues to spike temperatures at 102 degrees and becomes hypotensive despite 6 liters of lactated ringers IVF. • Pressors are started and the patient is then transferred to a tertiary care hospital

6. A Case Study Day 7 • Culture results from referring hospital reveal: • Species of bacteria; S aureus • Strain of bacteria; MRSA • The patient is treated with appropriate antibiotics upon arrival to tertiary care hospital and the pneumonia resolves. He has a prolonged ICU stay of 28 days at which point the family decides to withdraw care because profound malnutrition and subsequent ICU associated complications from his underlying diabetes including a NSTEMI, pseudomonas sinusitis, and Pseudomembranous colitis with associated diarrhea and a stage 3 sacral ulcer requiring debridement.

7. Nosocomial Infections and Resistance • 2 million nosocomial infections per year in US hospitals • 60% involve antibiotic-resistant bacteria • Staphylococcus aureus is the most common overall bacterial cause of infection involving bloodstream, respiratory tract, and skin/soft tissue, according to the SENTRY Antimicrobial Surveillance Program • Strains of S aureus that have acquired resistance to β-lactam antibiotics, most commonly through inheritance of the mecA resistance gene, are known as methicillin-resistant S aureus (MRSA) • MRSA accounts for 29% to 35% of all clinical isolates of S aureus in US and European hospitals • Estimated excess costs related to antibiotic resistance approach $30 billion per year in US hospitals Haddadin AS et al. Postgrad Med J. 2002;78:385-392. Diekema DJ et al. Clin Infect Dis. 2001;32(suppl 2):S114-S132. Deresinski S. Clin Infect Dis. 2005;40:562-573. Zetola N et al. Lancet Infect Dis. 2005;5:275-286.

8. The MRSA Story • Infections due to gram-positive cocci, eg, S aureus, particularly MRSA, are: • Rapidly emerging in the United States • More common in certain patient populations • Diabetes mellitus • Head trauma • Intensive-care unit (ICU) • 50% of ICU infections (US) caused by S aureus are MRSA ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.

9. Progression of Methicillin Resistance: S aureus Among Intensive Care Unit (ICU) Patients 63% CDC. Available at: http://www.cdc.gov/ncidod/hip/ARESIST/ICU_RESTrend1995-2004.pdf. Accessed August 30, 2005. Lowy FD. J Clin Invest. 2003;111:1265-1273.

10. Health care-associated pneumonia (HCAP) Includes HAP and VAP Pneumonia in patients Hospitalized for 2 days in an acute care facility within 90 days of infection Residing in a nursing home or long-term care (LTC) facility Attending a hospital or hemodialysis clinic Receiving immunosuppressive therapy or wound care within 30 days of infection Hospital-acquiredpneumonia (HAP) Pneumonia occurring 48 hours post-hospital admission Ventilator-associated pneumonia (VAP) Pneumonia occurring 48-72 hours post-intubation Definitions ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.

11. How Do Pathogens Find the Patient? • Routes of bacterial entry into the lower respiratory tract • Aspiration of oropharyngeal pathogens • Leakage around endotracheal tube cuff • Embolization of infected biofilm in the endotracheal tube to distal airways may play a role • Sources of infections • Healthcare devices • Environment (air, water, equipment, fomites) • Staff-patient/patient-patient transfer of microorganisms • Host- and treatment-related colonization factors • Severity of underlying disease • Prior surgery • Exposure to antibiotics • Other medications • Exposure to invasive respiratorydevices and equipment ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.

12. Pneumonia (%) Most Common Isolates: All ICU HAP vs VAP 20 18 18 18 18 17 16 All HAP * 14 VAP † 12 12 11 10 8 7 7 6 5 5 4 4 4 4 4 2 0 S aureus Pseudomonas Enterobacter spp Klebsiella Candida albicans Escherichia coli Haemophilus aeruginosa pneumoniae influenzae *January 1992-May 1999. †1990-1995. NNIS. Am J Infect Control. 1999;27:520-532. Fridkin SK et al. Infect Dis Clin North Am. 1997;11:479-496.

13. Risk Factors for Multidrug-Resistant (MDR)Pathogens Causing HAP, HCAP, and VAP • Antimicrobial therapy in preceding 90 days • Current hospitalization of 5 days • High frequency of community or hospital-unit antibiotic resistance • Presence of risk factors for HCAP • Hospitalization for 2 days in preceding 90 days • Residence in a nursing home or LTC facility • Home infusion therapy (including antibiotics) • Chronic dialysis within 30 days • Home wound care • Family member with MDR pathogen • Immunosuppressive disease and/or therapy ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.

14. HAP, VAP, and HCAP Mortality • Crude mortality rate for HAP may be as high as 30% to 70% • However, many critically ill patients with HAP do not die of pneumonia, but rather of their underlying disease • Mortality attributable to HAP estimated at 33% to 50% • Increased mortality rates were associated with • Bacteremia • P aeruginosa or Acinetobacter spp • Medical, not surgical, illness • Ineffective antibiotic therapy ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416. Heyland DK et al. Am J Respir Crit Care Med. 1999;159:1249-1256.

15. Improving Outcomes • Prevention • Decreasing resistance • Improving our antibiotic selections

16. Benefits of Early, Appropriate Therapy Cumulative evidence from multiple studies has demonstrated that early, appropriate therapy is associated with: • Shorter duration of antibiotic therapy • Short-course therapy is only an option when the right antibiotic is used from the start • Decreased length of ICU or hospital stay • Lower total cost • Decreased mortality • Appropriate antimicrobial therapy reduces infection-related and all-cause mortality Craven DE et al. Infect Dis Clin North Am. 2004;18:939-962. Singh N et al. Am J Respir Crit Care Med. 2000;162:505-511. Lodise TP et al. Cin Infect Dis. 2003;36:1418-1423.Kollef MH et al. Chest. 1999;115:462-474.

17. Importance of Initial, Appropriate Antibiotic Therapy “…selection of initial appropriate antibiotic therapy (ie, getting the antibiotic treatment right the first time) is an important aspect of care for hospitalized patients with serious infections.” – ATS/IDSA Guidelines A Study by Kollef and Colleagues Evaluating the Impact of Inadequate Antimicrobial Therapy on Mortality 60 52* *P<.001 50 42* 40 Hospital Mortality (%) 30 24 18 20 10 0 All-Cause Mortality Infection-Related Mortality Adequate antimicrobial treatment (n=486) 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.

18. Initial Empiric Therapy in Patients Without Risk Factors for MDR Pathogens ESBL=extended-spectrum β-lactamase producer. *The frequency of penicillin-resistant S pneumoniae and MDRSpneumoniae is increasing. †Levofloxacin or moxifloxacinare preferred to ciprofloxacin and the role of other new quinolones, such as gatifloxacin, has not been established. Adapted from ATS/IDSA. Am J Respir Crit Care Med. 2005;171:401. Table 3.

19. Initial, Broad-Spectrum, Potential Pathogens Combination Antibiotic Therapy Initial Empiric Therapy for Late-Onset Disease, Risk Factors, or MDR Pathogens Antipseudomonal cephalosporin or Antipseudomonal carbepenem or -Lactam/-lactamase inhibitor plus Antipseudomonal fluoroquinolone‡ or Aminoglycoside‡ MDR pathogens* P aeruginosa K pneumoniae (ESBL+)† Acinetobacter spp† Non-MDR, gram-negative bacilli Legionella pneumophila† MDR, gram-positive cocci MRSA plus¶ Linezolid 600 mg q12h or Vancomycin 15 mg/kg q12h§ *Including pathogens from slide 19, (S pneumoniae, H influenzae, MSSA, E coli, K pneumoniae (ESBL-), Enterobacter spp, Proteus spp, S marcescens. †If an ESBL+ strain K pneumoniae or MDR Acinetobacter spp is suspected, a carbepenem is suggested as initial therapy. ‡If L pneumophila is suspected, the combination antibiotic regimen should include a macrolide or a fluoroquinolone rather than an aminoglycoside. ¶If MRSA is suspected or there is a high incidence locally. §Trough levels for vancomycin should be 15 µg/mL to 20 µg/mL. Adapted from ATS/IDSA. Am J Respir Crit Care Med. 2005;171:402. Tables 4 and 5.

20. Inpatient Antibiogram of SOMC Special thanks to Timothy R. Cassity, Ph. D.

21. Outpatient Antibiogram SOMC (2004-2005) Special thanks to Timothy R. Cassity, Ph. D.

22. Nursing Home Patients Antibiogram SOMC Special thanks to Timothy R. Cassity, Ph. D.

23. Oxazolidinone: Birth of a New Antimicrobial Agent Class • 1987: First report of oxazolidinone family of molecules at the 27th ICAAC meeting. Early studies illustrated: • Potent activity against Gram-positive organisms, including S aureus (MSSA and MRSA), Staphylococcus epidermidis, Streptococcus pneumoniae, and enterococci; modest activity against a few fastidious Gram-negative bacteria was noted • Equally effective when administered orally • Novel inhibition of protein synthesis • 1995: 25 presentations at the 35th ICAAC meeting, including the first phase I study results • 2000: FDA approval based on 9 trials in more than 4000 patients Ford CW et al. Curr Drug Targets Infect Disord. 2001;1:181-199.

24. Available in oral and intravenous formulations Oral formulation has 100% bioavailability Has activity against most clinically important Gram-positive pathogens Resistance remains uncommon Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of the other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely O O O N N O C N C H 3 H F H Linezolid Characteristics A Small Molecule With Good Penetration Into Lung and Skin Tissue Pharmacokinetics in healthy volunteers and in vitro activity do not necessarily imply a correlation with clinical effectiveness. Conte JE Jr et al. Antimicrob Agents Chemother. 2002;46:1475-1480. Adapted from French G. Int J Clin Pract. 2001;55:59-63. Meka VG et al. Clin Infect Dis. 2004;39:1010-1015.

25. Lung Penetration Concentration vs MIC90 of Linezolid Against Gram-Positive Organisms Epithelial lining fluid Plasma MIC90S aureus MIC90Enterococcus spp MIC90S 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 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;46:1475-1480.

26. Pharmacokinetic Characteristics of Linezolid in Adults

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

28. 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 40 Clinical Cure (%) 30 20 10 31/56 19/41 18/31 10/20 86/161 74/142 0 MRSA NP Intent-to-treat (ITT) S aureus NP Vancomycin 1 g q12h IV Linezolid 600 mg 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.

29. 70 60 50 40 30 20 10 0 ITT MRSA NP S aureus NP Vancomycin 1 g q12h IV Linezolid 600 mg q12h IV 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. 60 53 52 49 42 Clinical Cure (%) 29 18/30 12/41 135/256 128/245 40/81 40/95 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.

30. 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 53 60 52 52 43 50 36 40 Clinical Cure (%) 30 20 10 22/62 221/417 202/387 36/61 70/136 59/136 0 S aureus NP MRSA NP ITT Vancomycin 1 g q12h IV 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). Wunderink RG et al. Chest. 2003;124:1789-1797. Data on file. Pfizer Inc.

31. Vancomycin 1 g q12h IV Linezolid 600 mg q12h IV 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 37 35 Clinical Cure (%) 21 103/227 76/207 23/37 7/33 43/88 32/91 Linezolid was equally effective in the ITT and S aureus NP populations (P=NS). The outcome difference in the MRSA NP subgroup is provided as a descriptive measure only. No further inference should be drawn due to the retrospective nature of the analysis (P<.01). Kollef MH et al. Intens Care Med. 2004;30:388-394. Wunderink RG et al. Chest. 2003;124:1789-1797. Data on file. Pfizer Inc.

32. Key Points About Vancomycin Recommendations • The new ATS/IDSA guidelines recommend dosing vancomycin by body weight (mg/kg) and adjusted for renal impairment • Monitor and adjust trough levels to maintain 15 μg/mL to 20 μg/mL • Clinical trials report 40% or greater failure rate for MRSA pneumonia with vancomycin at standard dosing (1 g q12h) • No prospective clinical trials have shown the value of dosing vancomycin to achieve a trough level at 15 μg/mL or more • Combination therapy with vancomycin + rifampin, or vancomycin + aminoglycosides has not been proven effective in randomized controlled trials ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416. Craven DE, et al. Infect Dis Clin North Am. 2004;18:939-962.

33. Key Points About Linezolid in Treating MRSA HAP • linezolid is now recommended as empiric therapy, on a par with vancomycin, for late-onset HAP or for patients with risk factors for MRSA • Clinical setting where linezolid may be preferred: • Patients at risk for, or already with, renal insufficiency • In these patients, physicians may have a stronger tendency to prescribe less adequate doses of vancomycin • Patients at increased risk of nephrotoxicity or on concomitant nephrotoxic drugs ATS/IDSA. Am J Crit Care Med. 2005;171:388-416. Craven DE et al. Infect Dis Clin North Am. 2004;18:939-962.

34. Indication Linezolid formulations are indicated for the treatment of infections caused by susceptible strains of the designated microorganisms: Pneumonia • Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), or Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP*]). Combination therapy may be clinically indicated if the documented or presumptive pathogens include gram-negative organisms • Community-acquired pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible strains only), including cases with concurrent bacteremia or S aureus (methicillin-susceptible strains only) *MDRSP refers to isolates resistant to 2 or more of the following antibiotics: penicillin, second-generation cephalosporins, macrolides, tetracycline, and trimethoprim/sulfamethoxazole.

35. Indication • Skin infection • Complicated skin and skin structure infections, including diabetic foot infections without concomitant osteomyelitis, caused by S aureus (methicillin-susceptible and -resistant strains), S pyogenes, or S agalactiae. linezolid has not been studied in the treatment of decubitus ulcers. Combination therapy may be clinically indicated if the documented or presumptive pathogens include gram-negative organisms • Uncomplicated skin and skin structure infections caused by S aureus (methicillin-susceptible only) or S pyogenes Vancomycin-resistant Enterococcus • Vancomycin-resistant E faecium infections including cases with concurrent bacteremia

36. Important Safety ConsiderationsContraindications • Linezolid is contraindicated in patients who have known hypersensitivity to linezolid or any of the other product components Warnings Pseudomembranous colitis • Pseudomembranous colitis has been reported with nearly all antibacterial agents, including linezolid, and may range in severity from mild to life-threatening. It is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of any antibacterial agent

37. Important Safety ConsiderationsWarnings Myelosuppression • Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid • In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels • Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than 2 weeks, those with preexisting myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy • Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression

38. Important Safety ConsiderationsPrecautions Lactic acidosis • Lactic acidosis has been reported with the use of linezolid. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving linezolid should receive immediate medical evaluation Serotonin syndrome (linezolid + serotonergic agent) • Spontaneous reports of serotonin syndrome associated with co-administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported • Patients who are treated with linezolid and concomitant serotonergic agents should be closely observed for signs and symptoms of serotonin syndrome (eg, cognitive dysfunction, hyperpyrexia, hyperreflexia, incoordination) • If any signs or symptoms occur, physicians should consider discontinuation of either one or both agents (linezolid or concomitant serotonergic agents)

39. Important Safety ConsiderationsPrecautions Peripheral/optic neuropathy • Peripheral and optic neuropathy have been reported in patients treated with linezolid, primarily those patients treated for longer than the maximum recommended duration of 28 days • In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration • Visual blurring has been reported in some patients treated with linezolid for less than 28 days • If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended • Visual function should be monitored in all patients taking linezolid for extended periods (≥3 months) and in all patients reporting new visual symptoms regardless of length of therapy with linezolid • If peripheral or optic neuropathy occurs, the continued use of linezolid in these patients should be weighed against the potential risks

40. Important Safety ConsiderationsPrecautions Drug interactions • Linezolid is a reversible nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents • A reversible enhancement of the pressor response with either pseudoephedrine HCl or phenylpropanolamine HCl was observed when linezolid was administered to healthy normotensive subjects. Patients should inform their physician if they are taking medications containing pseudoephedrine HCl or phenylpropanolamine HCl, such as cold remedies and decongestants • A significant pressor response has been seen in normal adult subjects receiving linezolid and tyramine doses of more than 100 mg. Advise patients to avoid large quantities of foods or beverages with high tyramine content while taking linezolid

41. Important Safety ConsiderationsAdverse Events The most common adverse events include:

42. DosingSpecial Populations Renal insufficiency • The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any degree of renal insufficiency • Both linezolid and its metabolites are eliminated by dialysis. Approximately 30% of dose was eliminated during a 3-hour dialysis; therefore, linezolid should be administered after hemodialysis • Two primary metabolites may accumulate in patients with renal insufficiency; in the absence of information on the clinical significance of metabolite accumulation, use of linezolid in patients with renal insufficiency should be weighed against the risks of metabolite accumulation • Because similar plasma concentrations of linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal insufficiency Hepatic Insufficiency • No adjustment recommended for mild-to-moderate hepatic insufficiency • Pharmacokinetics in severe hepatic insufficiency have not been evaluated

43. Questions? Opening Day April 7th

44. Summary • The progressive emergence of gram-positive organisms as dominant isolates in nosocomial infections has become a primary health care concern • As demonstrated, a multitude of risk factors exist for the development of MRSA, including previous hospitalization, longer length of stay before infection, previous surgery, enteral feedings, and previous use of antibiotics • Linezolid is an effective treatment for NP due to MRSA Jones RN. Clin Infect Dis. 1999;29:495-502. Graffunder EM et al. J Antimicrob Chemother. 2002;49:999-1005.