HEALTHCARE-ASSOCIATED PNEUMONIA: EPIDEMIOLOGY, PATHOGENESIS

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HEALTHCARE-ASSOCIATED PNEUMONIA EPIDEMIOLOGY,
PATHOGENESIS PREVENTION 2014

• David Jay Weber, M.D., M.P.H.
• Professor of Medicine, Pediatrics, Epidemiology
• Associate Chief Medical Officer, UNC Health Care
• Medical Director, Hospital Epidemiology
• University of North Carolina at Chapel Hill

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HAZARDS IN THE ICU
Weinstein RA. Am J Med 199191(suppl 3B)180S
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TOPICS HCAP, HAP, VAP

• Epidemiology
• Impact of healthcare-associated infections
• Definitions
• NHSN surveillance definitions
• Incidence and prevalence of HCAP, HAP, VAP
• Pathogenesis
• Mechanisms of pneumonia
• Microbiology
• Risk factors
• Diagnosis
• Prevention

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GOALS OF LECTURE

• Understand the epidemiology of nosocomial
  pneumonia
• Impact
• Incidence
• Risk factors for acquisition and mortality
• Understand the pathophysiology of HAP VAP
• Microbiology
• Diagnosis
• Treatment
• Understand methods of prevention

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Marrow LE, Kollef MH. Crit Care Med
201038supplS352-S362
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Chroneou A, et al. Expert Opinion 200783117-31
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HEALTHCARE-ASSOCIATED PNEUMONIA

• HAI
• An infection is considered an HAI if ALL elements
  of a CDC/NHSN site-specific criterion were first
  present together on or after the 3rd hospital day
  (day of admission is Day 1). For an HAI, an
  element of the infection criterion must be
  present during the first 2 hospital days as long
  as it is also present on or after Day 3. All
  elements used to meet the infection criterion
  must occur within a timeframe that does not
  exceed a gap of 1 calendar day between elements
• Pneumonia (PNEU)
• Pneumonia is identified using a combination of
  radiologic, clinical and laboratory criteria. For
  VAP the date of the event is the date when the
  last element used to meet the pneumonia criteria
  are occurred.

http//www.cdc.gov/nhsn/acute-care-hospital/vae/in
dex.html
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VENTILATOR-ASSOCIATED EVENT(adult patients gt18
years of age
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VENTILATOR-ASSOCIATED EVENTS (VAE) SURVEILLANCE
ALGORITHM
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VENTILATOR-ASSOCIATEDCONDITION (VAC)
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INFECTION-RELATED VENTILATOR-ASSOCIATED
COMPLICATIONS (IVAC)
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POSSIBLE VENTILATOR-ASSOCIATED PNEUMONIA (VAP)
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PROBABLE VENTILATOR-ASSOCIATED PNEUMONIA (VAP)
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THRESHOLD VALUES FOR CULTURED SPECIMENS USED IN
THE PROBABLE VAP DEFINITION
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NHSN DEFINITIONS OF HAP AND VAP (children, lt18
years of age)

• Table 1. Specific site algorithms for clinically
  defined pneumonia (PNU1)
• Table 2. Specific site algorithms for pneumonia
  with common bacterial or filamentous fungal
  pathogens and specific laboratory findings (PNU2)
• Table 3. Specific site algorithms for viral,
  Legionella, and other bacterial pneumonias with
  definitive laboratory findings (PNU2)
• Table 4. Specific site algorithm for pneumonia
  in immunocompromised patients (PNU3)

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Marrow LE, Kollef MH. Crit Care Med
201038supplS352-S362
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PNU1
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PNU2
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PNU2
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PNU3
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HAP VAP IMPACT

• Potential complications of mechanical ventilation
• Pneumonia, acute respiratory distress syndrome
  (ARDS), pulmonary embolism, barotrauma, pulmonary
  edema, and death
• Complications result in longer ICU stays,
  increased costs, and increased risk of disability
  and death
• Mortalioty in patient with acute lung injury,
  estimated to range from 24 in patients 15-19
  years of age to 60 for patients gt85 years of age
• Prevalence 2010 NHSN 3,525 cases of VAP
• Incidence 2010 NHSN 0.0-5.8 per 1,000
  ventilator days

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Magill SS, et al. New Engl J Med 20143701198
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HAP IMPACT

• Accounts for 15 of all healthcare-associated
  infections (3rd most common cause of HAIs after
  UTIs and SSIs)
• Accounts for 25 of all nococomial infections in
  the ICU (50 of antibiotics provided)
• Number of cases per year 275,000
• Prevalence
• VAP develops in 10 to 20 of mechanically
  ventilated patients
• VAP rate 1-4 cases/1,000 ventilator-days

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HAP IMPACT

• Cost
• Increases hospital stay by an average of 7-11
  days
• Cost per patient gt40,000
• Direct cost (estimated) of excess hospital stays
  1.5 billion/year
• Mortality
• Crude mortality 30-70 (average 40)
• Attributable mortality 33-50
• Deaths
• Deaths directly caused by infection 7,085
  (3.1)
• Deaths to which infection contributed 22,983
  (10.1)

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PREVALENCE ICU (EUROPE)

• Study design Point prevalence rate
• 17 countries, 1447 ICUs, 10,038 patients
• Frequency of infections 4,501 (44.8)
• Community-acquired 1,876 (13.7)
• Hospital-acquired 975 (9.7)
• ICU-acquired 2,064 (20.6)
• Pneumonia 967 (46.9)
• Other lower respiratory tract 368 (17.8)
• Urinary tract 363 (17.6)
• Bloodstream 247 (12.0)

Vincent J-L, et al. JAMA 1995274639
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PREVALENCE ICU (WORLDWIDE)

• Study design Point prevalence, 8 May 2007
• 75 countries, 1265 ICUs, 13,796 adult patients
• Frequency of infections 7,087 (51)
• Sites of infection
• Respiratory tract 4,503 (63.5)
• Abdominal 1,392 (19.6)
• Bloodstream 1,071 (15.1)
• Renal/urinary tract 1,011 (14.3)
• Antibiotic therapy 71
• Pathogens of infected patients 47 GPC, 62 GNR,
  19 fungi
• Infected patients had higher ICU (25.3 vs 10.7)
  and hospital mortality (33.1 vs 14.8)

Vincent J-L, et al. JAMA 20093022333-2329
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VENTILATOR-ASSOCIATED PNEU RATES, NHSN, 2012
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VENTILATOR-ASSOCIATED PNEU RATES, NHSN, 2012
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VAP TIME COURSE
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VAP TIME COURSE
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TOP 7 PATHOGENS ASSOCIATED WITH VAP NHSN, 200
Sievert DM. ICHE 2013 341-14
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ETIOLOGIC AGENTS ASSOCIATED WITH HAP NNIS vs
INVASIVE DX
Pathogen NNIS INVASIVE DX
S. aureus (ORSA 55.7) 19 20.4
S. Pneumoniae NA 4.1
Streptococcus spp. 3 8.0
Coagulase-negative staphylococcus 2 1.4
Enterobacteriaceae 26 14.15
Pseudomonas aeroginosa 17 24.4
Acinetobacter spp. 4 7.9
Stenotrophomonas maltophilia lt1 1.7
Hemophilus spp. 7.1 9.8
Neisseria spp. lt1 2.6
Anaerobes 2 0.9
Fungi 7 0.9
Other (lt1 each) 3.8
Chastre J, Fagon J-Y. Am J Respir Crit Care Med
2002165867-903
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MICROBIOLOGY

• Determinants of pathogens
• Setting
• Prior antibiotic use
• Duration of hospitalization
• Early (lt5 days) S. pneumoniae, H. influenzae,
  MSSA
• Late (gt5 days) P. aeruginosa, MRSA, Gram (-)
  bacilli
• ICU stay
• Colonization

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COMMON PATHOGENS BY PRESENCE OR ABSENCE OF RISK
FACTORS FOR MDROs
Vincent JL, et al. Drugs 2010701927-1944
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Weber DJ, et al. ICHE 200728825-831
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ICU (NNIS, 1989-99) Ventilator-Associated
Pneumonia
Open bars lt7 days hospitalization Closed bars gt7
days hospitalization
Fridkin SK. Crit Care Med 200129N67
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PATHOGENS AS A FUNCTION OF DURATION OF
HOSPITALIZATION
Weber DJ, et al. ICHE 200728825-831
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MICROBIOLOGY

• 135 consecutive cases of VAP, French ICUs
• Potentially resistant bacteria P. aerugninosa,
  Acinetobacter baumannii, Stenotrophomonas
  maltophilia, MRSA higher mortality
• Risk factors for resistant bacteria
• Duration mechanical ventilation gt7d, OR6.0
• Prior antibiotic use, OR13.5
• Broad spectrum antibiotic, OR4.1
• Source Troullet, AJRCCM 1998157531

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Antibiotic-Resistant VAP
OddsRatio
Variable
P Value

• Prior MVgt7 days 6 0.009
• Prior ABs 13 lt0.001
• Broad ABs 4 0.025

MV Mechanical ventilation. MRSA
Methicillin-resistant S aureus.
Trouillet JL, et al. Am J Respir Crit Care Med.
1998157531-539.
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PATHOGENESIS

• Colonization, aspiration, pneumonia in the
  setting of impaired host defenses
• Inhalation
• Instillation
• Bacteremic spread
• Contiguous spread

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Kollef MH, et al. Chest 2004321396
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VAP RISK FACTORS

• Intrinsic Risk Factors
• Chronic lung disease/COPD
• Severity of illness
• ARDS
• Witnessed aspiration
• Age gt60 years
• Coma
• Head trauma/ICP monitoring
• Upper abdominal surgery
• Thoracic surgery
• Fall-winter season

• Extrinsic Risk Factors
• Duration of intubation
• Emergent intubation
• Reintubation
• Elevated gastric pH
• Prior antibiotic therapy
• Nasogastric tube
• Enteral nutrition
• Supine head position
• Patient transport out of ICU

Kollef M. Crit Care Med 2004321396 (adapted)
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Hospital Mortality by Classification
P lt 0.001
P lt 0.0001
P gt 0.05
10.0
29.3
18.8
19.8
Kollef MH, et al. Chest 20051283854
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RISK FACTORS FOR MORTALITY (VAP)

• High risk pathogens P.aeruginosa, Acinetobacter,
  S. maltophilia - 65 (Kollef, Chest 1995108165)
• Severity of underlying illness shock
• Age
• Inappropriate antibiotic therapy
• Bilateral infiltrates
• Duration of prior hospitalization
• Prior antibiotic therapy
• Supine head position in ventilated patients

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METHODS OF DIAGNOSIS

• Clinical findings (symptoms, signs)
• Blood, pleural fluid analysis cultures, tissue
  diagnosis
• Non-bronchoscopic
• Endotracheal aspiration
• Percutaneous needle aspiration
• Blind bronchial sampling (Blind BAL)
• Bronchoscopic techniques
• Protected specimen brush (PSB)
• Bronchoalveolar lavage (BAL)

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CLINICAL DIAGNOSIS

• Symptoms and signs Fever, respiratory distress
• Chest radiography Infiltrate, consolidation,
  cavity
• Laboratory Leukocytosis, leukopenia
• Sputum Purulence (WBC), culture
• Clinical diagnosis (ATS/IDSA)
• New or progressive infiltrate
• gt2 of the following Temperature gt38 oC,
  leukocytosis or leukopenia, purulent secretions

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DIFFERENTIAL DIAGNOSISFEVER AND PULMONARY
INFILTRATES

• Pulmonary infection
• Pulmonary embolism
• Pulmonary drug reaction
• Pulmonary hemorrhage
• Chemical aspiration
• Sepsis with acute respiratory distress syndrome
• Drug reaction

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DIAGNOSING VAP PNEUMONIA
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INDICATIONS FOR INVASIVE DIAGNOSIS

• Routine for all patients with possible nosocomial
  pneumonia?
• Targeted use of invasive diagnosis
• Critically ill
• Immunocompromised patient (esp. T-cell defect)
• Deterioration on empiric therapy
• Failure to respond to empiric therapy
• Other therapeutic consideration (e.g.,
  foreign-body)

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PROTECTED SPECIMEN BRUSH
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BRONCHOALVEOLAR LAVAGE
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Meta-analysis of Invasive Strategies for the
Diagnosis of Ventilator-Associated Pneumonia
their Impact on Mortality
Weight
Odds Ratio
Study
Favors Invasive Approach
Favors Non-Invasive Approach
(95 CI)
13.0
Sanchez-Nieto, et al.
2.42 (0.75,7.84)
19.5
0.71 (0.28,1.77)
Ruiz, et al.
50.9
0.71 (0.47,1.06)
Fagon, et al.
16.5
1.08 (0.39,2.98)
Violan, et al.
0.89 (0.56,1.41)
Overall (95 CI)
0.13
1
7.84
Odds Ratio for Mortality
Random effects model Test of heterogeneity
p0.247, for Odds ratio p0.620
Shorr A, Kollef. MH Crit Care Med 20053346.
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Morrow LE, Kollef MH. Crit Care Med
201038supplS352-352
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EMPIRIC THERAPY GENERAL RULES

• Know the flora and susceptibilities of the
  pathogens causing nosocomial pneumonia at your
  own institution
• Obtain history of antibiotic-allergies from all
  patients (adjust regimen appropriately)
• Choose empiric therapy to minimize drug
  interactions
• Dose adjust (when appropriate) in patients with
  renal and/or hepatic failure
• Consider specific contraindications or
  precautions (e.g., pregnancy, neuromuscular
  disease)
• All other things being equal use the least
  expensive therapy
• Provide appropriate non-antibiotic care

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IMPACT OF ANTIMICROBIALS
Kollef Chest 115462, 1999
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HAP The Importance of Initial Empiric Antibiotic
Selection
Alvarez-Lerma F. Intensive Care Med 1996
May22(5)387-394. Rello J, Gallego M, Mariscal
D, et al. Am J Respir Crit Care Med 1997
Jul156(1)196-200. Luna CM, Vujacich P,
Niederman MS, et al. Chest 1997111(3)676-685. Ko
llef MH and Ward S. Chest 1998 Feb113(2)412-20.
Sanchez-Nieto JM, Torres A, Garcia-Cordoba F, et
al. Am J Respir Crit Care Med. 1998157371-376. R
uiz M, Torres A, Eqig, S, et al. Am J Respir Crit
Care Med. 2000162119-125. Dupont H, Mentec H,
Sollet, JP, et al. Intensive Care Med.
200127(2)355-362
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ATS/IDSA. Am J Respir Crit Care Med
2005171388-416
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ATS/IDSA. Am J Respir Crit Care Med
2005171388-416
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Vincent J-L, et al. Drugs 2010701927-1944
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INITIAL EMPIRIC THERAPY FOR HAP/VAPEARLY ONSET
NO KNOWN RISK FACTORS FOR MDR PATHOGENS
Common Pathogen Initial Empiric Therapy
Streptococcus pneumoniae Haemophilus influenzae OSSA Antibiotic-sensitive GNR E. coli, K. pneumoniae, Enterbacter spp., Proteus spp., S. marcescens Ceftriaxone (3o cephalosporin) OR Levo, Moxi, Cipro (FQ) OR Ampicillin/sulbactam (?-lactam/inhibitor) OR Ertapenem (carbapenem)
ATS/IDSA. Am J Respir Crit Care Med
2005171388-416
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INITIAL EMPIRIC THERAPY FOR HAP/VAP/HCAPLATE
ONSET OR RISK FACTORS FOR MDR PATHOGENS
Common Pathogen Initial Empiric Therapy
MDR-GNR P. aeruginosa K. pneumoniae (ESBL) Acinetobacter spp. Non-MDR GNR L. pneumophila MDR-Gram-Positive Cocci MRSA Antipseudomonal cephalosporin (Cefepime, Ceftazidime) OR Antipseudomonal carbapenem (Imipenem, Meropenem) OR ?-lactam/inhibitor (Piperacillin-tazobactam) PLUS Antipseudomonal FQ (Cipro or Levo) OR Aminoglycoside (Gent, Tobra, Amikacin) PLUS Linezolid or vancomycin (MRSA suspected)
ATS/IDSA. Am J Respir Crit Care Med
2005171388-416
67
RISK FACTORS FOR MDR-PATHOGENS CAUSING HAP

• Antimicrobial therapy in preceding 90 days
• Current hospitalization of 5 days or more
• High frequency of antibiotic resistance in the
  community or in the specific hospital unit
• Presence of risk factors of HCAP
• Hospitalization for 2 days or more in the
  preceding 90 days
• Residence in a nursing home or extended care
  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
2005171388-416
68
INITIAL EMPIRIC THERAPY (DOSES)

• Antipseudomonal cephalosporin
• Cefepime 1-2 g Q8-12h
• Ceftazidime 2g Q8h
• Carbapenem
• Imipenem 500 mg Q6h or 1g Q8h
• Meropenem 1g Q8h
• Doripenem 500 mg Q8h
• ?-lactam/inhibitor
• Pip/tazo 4.5g Q6h

• Antipseudomonal FQ
• Levofloxacin 750 mg Q24h
• Ciprofloxacin 400 mg Q8h
• Aminoglycoside
• Gentamicin 7 mg/kg Q24h
• Tobramycin 7 mg/kg Q24h
• Amikacin 20mg/kg Q24h
• MRSA Coverage
• Vancomycin 15mg/kg Q24h
• Linezolid 600 mg Q12h

ATS/IDSA. Am J Respir Crit Care Med
2005171388-416
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ATS/IDSA. Am J Respir Crit Care Med
2005171388-416
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DURATION OF THERAPY STUDY DESIGN

• Authors Chastre J, et al. JAMA 20032902988
• Study goal Compare 8 vs 15 days of therapy for
  VAP
• Design Prospective, randomized, double-blind
  (until day 8), clinical trial
• VAP diagnosed by quantitative cultures obtained
  by bronchoscopy
• Location 51 French ICUs (N401 patients)
• Outcomes Assessed 28 days after VAP onset (ITT
  analysis)
• Primary measures death from any cause
• Microbiologically documented pulmonry infection
  recurrence
• Antibiotic free days

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DURATION OF THERAPY RESULTS

• Primary outcomes (8 vs 15 days)
• Similar mortality, 18.8 vs 17.2
• Similar rate of recurrent infection, 28.9 vs
  26.0
• MRSA, 33.3 vs 42.9
• Nonfermenting GNR, 40.6 vs 25.4 (plt0.05)
• More antibiotic free days, 13.1 vs 8.7
  (plt0.001)
• Secondary outcomes (8 vs 15 days)
• Similar mechanical ventilation-free days, 8.7 vs
  9.1
• Similar number of organ failure-free days, 7.5 vs
  8.0
• Similar length of ICU stay, 30.0 vs 27.5
• Similar frequency death at day 60, 25.4 vs 27.9
• Multi-resistant pathogen (recurrent infection),
  42 v 62 (p0.04)

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THERAPY SUMMARY I

• Negative lower respiratory tract cultures can be
  used to stop antibiotic therapy if obtained in
  the absence of an antibiotic change in past 72
  hours
• Early, appropriate, broad spectrum therapy,
  antibiotic therapy should be prescribed with
  adequate doses to optimize antimicrobial efficacy
• An empiric therapy regimen should include agents
  that are from a different antibiotic class than
  the patient is currently receiving
• De-escalation of antibiotic should be considered
  once data are available on the results of the
  patients cultures and clinical response
• A shorter duration of therapy (7-8 days) is
  recommended for patients with uncomplicated HAP,
  VAP, or HCAP who have had a good clinical response

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THERAPY SUMMARY II

• Low risk patients
• Single-drug, broad spectrum therapy adequate
• Ceftriaxone (3rd generation cephalosporin)
• Ertapenem (carbapenem)
• Ampicillin/sulbactam (?-lactam/? -lactamase
  inhibitor combination)
• Ciprofloraxin, Levofloxacin, Moxifloxacin
  (fluoroquinolone)
• Therapy directed by local epidemiology and costs

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THERAPY SUMMARY III

• High risk patients
• Multiple-drug regimens required
• Combine beta-lactam with aminoglycoside
  (preferred) or quinolone (levo or cipro)
• Consider need for coverage of oxacillin-resistant
  S. aureus, Legionella

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THERAPY SUMMARY IV

• Bronchoscopy directed therapy
• May improve outcome
• Demonstrated by a randomized study
• Several cohort studies have failed to
  demonstrated benefit
• Mortality reduced by initial use of appropriate
  antibiotics
• Duration of therapy, in general, should be 7-8
  days

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Kollef M. Chest 2004321396
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Morrow LE, Kollef MH. Crit Care Med
201038supplS352-352
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Morrow LE, Kollef MH. Crit Care Med
201038supplS352-352
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STRENGTH OF RECOMMENDATIONSAND QUALITY OF
EVIDENCE
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STRATEGIES TO PREVENT VAPIN ACUTE CARE HOSPITALS

• Surveillance
• Definition of VAP most subjective of all device
  associated HAIs
• Significant intra-observer variability exists
• Use active surveillance (not administrative data
  alone)
• Ideally perform semiquantitative culture of
  endotracheal secretions or quantitative culture
  of BAL fluid
• Prevention
• Follow CDC guidelines to prevent VAP
• Interrupt most common mechanisms by which VAP
  develops
• Aspiration of secretions
• Colonization of the aerodigestive tract
• Use of contaminated equipment

Coffin SE, et al. ICHE 200829 (suppl 1)S31-S40
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STRATEGIES TO PREVENT VAPIN ACUTE CARE HOSPITALS

• Prevention General strategies
• Conduct active surveillance
• Adhere to hand hygiene recommendations
• Use non-invasive ventilation whenever possible
• Minimize the duration of ventilation
• Perform daily assessments of readiness to wean
• Educate personnel regarding prevention
• Prevention Strategies to prevent aspiration
• Maintain patients in a semirecumbent position
  (30o-45o elevation)
• Use a cuffed ET tube with in-line or subglottic
  suctioning

Coffin SE, et al. ICHE 200829 (suppl 1)S31-S40
82
STRATEGIES TO PREVENT VAPIN ACUTE CARE HOSPITALS

• Prevention Strategies to reduce colonization
• Orotracheal intubation preferred to nasotracheal
  intubation
• Avoid acid suppressive therapy
• Perform oral care with an antiseptic solution
• Prevention Strategies to minimize contamination
• Use sterile water to rinse reusable respiratory
  equipment
• Remove condensate from the ventilatory circuit
• Change the ventilatory circuit only when visibly
  soiled or malfunctioning
• Store and disinfect respiratory equipment properly

Coffin SE, et al. ICHE 200829 (suppl 1)S31-S40
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STRATEGIES TO PREVENT VAPIN ACUTE CARE HOSPITALS

• Special approached for the prevention of VAP
• Use an ET tube with in-line and subglottic
  suctioning
• Approaches that should not be routinely used
• Do not routinely administer IVIG, GM-CSF, or
  chest physiotherapy
• Do not routinely use rotational therapy with
  kinetic or continuous lateral rotational therapy
  beds
• Do not routinely administer prophylactic
  aerosolized or systemic antimicrobials
• Unresolved issues
• Selective digestive tract decontamination
• Avoidance of H2 antagonists or proton pump
  inhibitors
• Use of antiseptic-impregnated ET tubes

Coffin SE, et al. ICHE 200829 (suppl 1)S31-S40
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IHI GUIDELINE VAP BUNDLE

• Elevation of the head of the bed to between 30
  and 45 degrees
• Daily sedation vacation and daily assessment of
  readiness to extubate
• Peptic ulcer disease (PUD) prophylaxis
• Deep venous thrombosis (DVT) prophylaxis (unless
  contraindicated)

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CONCLUSIONS I

• Nosocomial pneumonia remains an important cause
  of patient morbidity and mortality in the US
• Nosocomial pneumonia results in a more prolonged
  hospital stay and increased cost
• Local epidemiology of pathogens and antibiograms
  are critical to empiric and directed chemotherapy
• Determining the etiologic agent(s) of nosocomial
  pneumonia is problematic even with new invasive
  diagnostic techniques

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CONCLUSIONS II

• Use of empiric, broad-spectrum regimens remain
  critical to favorable patient outcomes
• Single-drug regimens may be appropriate for some
  low-risk patients, but two-drug regimens with
  broad spectrum (including P. aeruginosa) are
  necessary for high-risk patients
• Prevention is superior to treatment