CAP and HCAP Gary Skankey, MD, FACP, FIDSA University of Nevada School of Medicine
Community-Acquired Pneumonia (CAP)Epidemiology • Sixth leading cause of death • Leading cause of death due to infectious disease • More than 3 million cases of CAP per year • 500,000 hospitalizations per year • 45,000 deaths per year • Cost: $21 billion Bartlett et al: Clin Inf Dis 26:811-838, 1998; File and Tan: Curr Opin Pul Med 3:89-97, 1997; Marston et al: Arch Int Med 157:1709-1718, 1997.
Key Bacterial Pathogens in CAP S. pneumoniae is the primary recognized bacterial cause of respiratory infections 16% AtypicalPathogens:23% 40% S. pneumoniae 6% M. catarrhalis H. influenzae Legionella spp. 10% M. pneumoniae C. pneumoniae Others 7% 1% 20% Reimer and Carroll: Clin Infect Dis 26:742-748, 1998. Marrie: Infect Dis Clin North Am 12:723-740,1998. Bartlett et al: Clin Infect Dis 26:811-838, 1998
S. pneumoniae resistance trend 50 40 30 20 10 0 Intermediate resistance High-level resistance 43.8% 36.0% 27.8% 33.5% 22.0% % Resistant 19.9% 23.6% 14.1% 17.8% 15.2% 16.0% 14.0% 13.6% 9.5% 4.0% 3.8% 2.6% 0.2% 1988–89 1992–93 1994–95 1996–97 TRUST I 1997–98 TRUST II Jan.–June 1997 SENTRY Doern et al: Clin Infect Dis 27:764-70, 1998 Thornsberry et al: Diagn Microbiol Infect Dis 29:249-257, 1997.
Diagnosis of Pneumonia • MYTH: • Diagnosis of pneumonia is made by sputum culture • Diagnosis of pneumonia is made by CXR
Diagnosis of Pneumonia • Clinical data points • Cough • Pleuritic chest pain • Purulent sputum, WBCs on gram stain • Fever • Leukocytosis • Abnormal CXR • Abnormal ABG • Sputum cultures identify the pathogen
Diagnosis of CAP • Clinical presentation is not diagnostic of an etiology • Yield of pathogens from Gram stain of adequate expectorated sputum, blood culture, sputum culture from patients with CAP 30%–40% • Immunologic/serologic tests
IDSA Guidelines for Empiric Treatment of Outpatient CAP • Previously healthy, no use of abx in past 3 months • A macrolide (Biaxin, Azithromycin) • Doxycycline • Comorbidities, immune suppression, abx in last 3 months • Respiratory FQ (Avelox, Tequin, Levaquin [750 mg]) • Beta-lactam (cefuroxime, amox/clav) plus macrolide (clarithromycin, azithromycin) • If high incidence of macrolide-resistant pneumococcus, substitute FQ for macrolide
IDSA Guidelines for empiric treatment of Inpatient CAP • Non-ICU • Respiratory FQ • Beta-lactam (ceftriaxone, amp/sulb) or ertapenem plus macrolide • ICU • Beta-lactam or ertapenem plus macrolide or resp FQ • (I add vancomycin to cover cephalosporin-resistant pneumococcus or CA-MRSA)
Timing and duration of therapy for CAP • First dose must be given in ER • Outcome dependent on early institution of appropriate antibiotics • Switch from IV to PO abx when pt hemodynamically stable and improving clinically, is able to ingest medications, and has a normally functioning gastrointestinal tract
Timing and duration of therapy for CAP • Rx for a minimum of 5 days, should be afebrile for 48–72 h, and should have no more than 1 CAP-associated sign of clinical instability before discontinuation of therapy • Criteria for clinical stability • 1) Temperature 37.8°C, 2) Heart rate 100 beats/min, 3) Respiratory rate 24 breaths/min, 4) Systolic blood pressure 90 mm Hg, 5) Arterial oxygen saturation 90% or pO2 60 mm Hg on room air, 6) Ability to maintain oral intake, 7) Normal mental status
HCAP • Healthcare associated pneumonia (HCAP) • Any hospitalization in the past 90 days • Any IV antibiotics in the past 30 days • Resident of or transferred from a long term acute care facility or skilled nursing facility • Likely to be due to MDR hospital-acquired organisms • Pseudomonas, MDR acinetobacter, ESBL Klebsiella, MDR enterobacter, etc • MRSA • These patients are too frequently started on standard CAP empiric antibiotics
VAP and HAP • VAP – ventilator associated pneumonia • Pneumonia developing >72 hrs after intubation • HAP – Hospital acquired pneumonia • Pneumonia developing > 72 hrs after hospitalization
Impact of Hospital-Acquired Infections • Incidence • >2 million persons per year1 • 5% to 35% admitted to ICU1 • Most common causes • Pneumonia 47% • Other lower respiratory tract infections 18% • Urinary tract infection 18% • Laboratory-confirmed bloodstream infection 12% • Hospital-acquired pneumonia • A new pulmonary infiltrate after 1 week of hospitalization that resembles a bacterial pneumonia on the chest x-ray2 VAP is a leading cause of death from hospital-acquired infections in the ICU setting.3 1. Eggimann and Pittet. Chest. 2001;120:2059-2093. 2. Cunha. eMedicine. 8/31/04. 3. Kollef. Chest.1999;115:8-11.
Epidemiology of HAP, VAP, and HCAP • Incidence • HAP: 5 to 10 cases per 1000 hospital admissions • VAP: 6- to 20-fold greater • Increased risk for MDR pathogens • Late-onset HAP and VAP • More likely caused by MDR pathogens • Higher crude mortality vs early-onset disease ATS. Am J Respir Crit Care Med. 2005;171:388-416.
Risk Factors for MDR Pathogens in HAP, VAP, HCAP • Antimicrobial therapy in preceding 90 days • Current 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.
Microbiology of HAP, VAP, and HCAP • Gram-negative pathogens • P aeruginosa • E coli • K pneumoniae • Acinetobacter species • Stenotrophomonas • Gram-positive cocci • S aureus, much of which is MRSA • Anaerobes are an uncommon cause of VAP ATS. Am J Respir Crit Care Med. 2005;171:388-416.
Prevalence of Bacterial Pathogens in Hospitalized Patients With Pneumonia – North America Other 6.4% 18 species Gm-positive Gm-negative Other Other Gm- Each <4% n=2712 S aureus 28% H influenzae 7.3% Klebsiella spp 7.5% S pneumoniae 9.1% P aeruginosa 20% Enterobacter spp 5.8% Adapted from Hoban, et al. Diagn Microbiol Infect Dis.2003 Apr;45(4):279-285.
Clinical Diagnosis of HAP • Chest radiographic abnormality • New, progressive, or persistent for > 24 hours • More likely if… • Progressive cavitation • Air space process abutting a fissure • Air bronchograms • Infiltrate next to an empyema • Evidence of infection (> 2 of the following) • Purulent sputum • Temperature < 36 C° or > 38 C° • Leukocyte count < 5000 or > 10000 • Blood culture • Specific, but not sensitive Higgins. Curr Treat Options Infect Dis.1999;1:159-175.
Nosocomial PneumoniaDiagnostic Studies • Sputum culture • Beware of colonization • Sputum gram stain - WBCs • Bronchoscopy • controversial • problems with accuracy • questionable contribution to outcome
Nosocomial PneumoniaInterpreting Sputum Cultures • Low numbers of epithelial cells suggests a reliable specimen • High numbers of WBCs should be seen in lower respiratory tract infection. If not: • poor quality specimen (saliva) • no pulmonary infection • If one morphologic type predominates it suggests etiologic agent
What to do with a positive sputum culture – Must decide if it is a colonizer or pathogen Does the patient have pneumonia? • Is the WBC elevated? • Is the patient febrile? • Is there an infiltrate on CXR? • Are the respiratory secretions purulent? • Is pulmonary function impaired? • DO NOT TREAT COLONIZATION! • Don’t be a “knee-jerk” doctor
Antimicrobial Therapy Definitions • Appropriate Therapy • Matches antibiotic sensitivities of the organism to the antibiotic used • Adequate Therapy • Choosing an appropriate initial antibiotic therapy • Optimal dosing • Correct route of administration to ensure antibiotic penetration at site of infection • Use of combination therapy if necessary ATS. Am J Respir Crit Care Med. 2005;171:388-416
Inappropriate Antibiotic Therapy Increases Mortality Appropriate therapy Inappropriate therapy 100 90 80 70 60 Mortality (%) 50 40 30 20 10 0 Ibrahim Leibovici Luna Alvarez-Lerma Rello Nosocomial Pneumonia/VAP Bloodstream Infections Ibrahim, et al. Chest. 2000;118:146–155. Leibovici, et al. J Intern Med. 1998;244:379–386. Luna, et al. Chest. 1997;111:676–685. Alvarez-Lerma, et al. Intensive Care Med.1996;22:387–394. Rello, et al. AJRCCM.1997;156:196–200.
Hospital Mortality Rate of Infected Patients • 2000 consecutive patients admitted to an MICU or SICU • Pneumonia in 411 cases • 305 with adequate therapy • 106 with inadequate therapy N = 312 P<.001 Mortality % Inadequate Adequate Antibiotic Treatment Kollef, et al. Chest. 1999;115:462–474.
Management Strategies Days 2 and 3:Check Cultures and Assess Clinical Response (Temperature, WBC, Chest X-ray, Oxygenation, Purulent Sputum, Hemodynamic Changes, and Organ Function) Clinical Improvement at 48 to 72 Hours NO YES Cultures - Cultures + Cultures - Cultures + Search for Complications, or Other Pathogens, Dx, or Sites of Infection Adjust Antibiotic Tx, Search for complications, Other Pathogens, Dx, or Sites of infection Consider Stopping Antibiotics De-escalate Antibiotics, if Possible. Treat Selected Patients 7 to 8 days and Reassess ATS. Am J Respir Crit Care Med. 2005;171:388-416.
Empiric Therapy for HAP, VAP and HCAP in Patients With Late-onset Disease or Risk Factors for MDR Pathogens and all Disease Severity Combination Therapy Antipseudomonal cephalosporin (cefepime, ceftazidime) or Antipseudomonal carbepenem (imipenem or meropenem) or Beta-lactam/beta-lactamase inhibitor (piperacillin-tazobactam) plus Antipseudomonal fluoroquinolone* (ciprofloxacin or levofloxacin) or Aminoglycoside (amikacin, gent, tobra) plus Linezolid or vancomycin† Potential Pathogens MDR pathogens • P aeruginosa • K pneumoniae (ESBL+) • Enterobacter • Acinetobacter sp • MRSA *If an ESBL+ strain (eg, K pneumoniae or an Acinetobacter sp) is suspected, a carbepenem is a reliable choice. If L pneumophila is suspected, the combination regimen should include a macrolide (eg, azithromycin) or a fluoroquinolone (eg, ciprofloxacin or levofloxacin) rather than an aminoglycoside. † If MRSA risk factors are present, or there is a high incidence locally. ATS. Am J Respir Crit Care Med. 2005;171:388-416.
Wrong Diagnosis Atelectasis, Pulmonary Embolus, ARDS,* Pulmonary Hemorrhage, Underlying Disease, Neoplasm Wrong Organism Drug-resistant pathogen (bacteria, mycobacteria, virus, fungus) Inadequate Antimicrobial Therapy Complication Empyema or Lung Abscess Clostridium difficile Colitis Occult Infection, Drug Fever Assessment of Nonresponders *ARDS = adult respiratory distress syndrome ATS. Am J Respir Crit Care Med. 2005;171:388-416.
Concentration Versus MIC90 of Linezolid Against Gram-Positive Organisms Pharmacokinetics in healthy adult volunteers and in vitro activity do not necessarily imply a correlation with clinical effectiveness. MIC90 = minimum concentration needed to inhibit 90% of organisms. Adapted from Conte JE Jr et al. Antimicrob Agents Chemother. 2002;46:1477. Please see full prescribing information available in this kit.
100 80 60 Linezolid 600 mg q12h Vancomycin 1 g q12h 40 20 0 MRSA NP Linezolid Versus Vancomycin in the Treatment of Nosocomial Pneumonia Clinical cure rates in NP patients with MRSA 59% Clinical Cure (%) 36% P<.01 22/62 36/61 A post hoc analysis of 2 identical, randomized, double-blind, multicenter, multinational, comparator-controlled trials that compared the safety and efficacy of linezolid IV and vancomycin IV for 7 to 21 days in 1019 patients with nosocomial pneumonia, including ventilator-associated pneumonia. Patients were treated for 7 to 21 days with optional aztreonam 1 g to 2 g q12h. Excludes missing and indeterminate. MRSA = methicillin-resistant Staphylococcus aureus. Adapted from Wunderink RG et al. Chest. 2003;124:1789-1797. Please see full prescribing information available in this kit.
100 90 80 70 Linezolid 600 mg q12h 60 50 Vancomycin 1 g q12h 40 30 20 10 0 MRSA VAP Linezolid Versus Vancomycin in the Treatment of VAP Clinical cure rates in VAP patients with MRSA 62% Clinical Cure (%) 21% P=.001 23/37 7/33 A post hoc analysis of 2 identical, randomized, double-blind, multicenter, multinational, comparator-controlled trials that compared the safety and efficacy of linezolid IV and vancomycin IV for 7 to 21 days in 1019 patients with nosocomial pneumonia, including VAP. Patients were treated for 7 to 21 days with optional aztreonam 1 g to 2 g q12h. VAP = ventilator-associated pneumonia; MRSA = methicillin-resistant Staphylococcus aureus. Adapted from Kollef MH et al. Intensive Care Med. 2004;30:388-394. Please see full prescribing information available in this kit.
Empiric therapy for Hospital-Acquired Pneumonia - notes • MRSA coverage • Vancomycin, Zyvox recommended • Lean towards Zyvox • Lung penetration: Zyvox > Vancomycin • Don’t use Daptomycin for pneumonia – inactivated by surfactant • Synercid not mentioned – possible last ditch drug • Gram Negative coverage • Don’t use ceftriaxone or ertapenem for patient in hospital longer than 3 days – no pseudomonas coverage • Anaerobic coverage – don’t need
Tygecycline – New Antibiotic Class • New class of antibiotic – glycacycline • Similar to tetracyclines • Broad spectrum coverage: MRSA, VRE, MDR gram negatives, ESBL gram negatives, Anaerobes • Low side effect profile • 50 mg IV Q12 • Current indications for intraabdominal infections and skin and soft tissue infections • Soon may have indication for hosp-acquired pneumonia – highly concentrated in lung tissue
Tygecycline - Disadvantages • Recommended dose had to be reduced to 50 mg Q12 because of nausea • May not result in serum concentrations high enough to overcome some infections • Not exceeding MPC • Bacterostatic • Does not cover pseudomonas