Nosocomial Pneumonias In

Critical Illness
Edward M. Omron MD, MPH, FCCP
Pulmonary and Critical Care

History
44 year-old woman presents with 4 days
cough, chills, dyspnea and fever
Hemoptysis with right sided pleuritic chest
pain x 2 days
Unable to walk due to dyspnea
35 pack year tobacco use
Long term cocaine use
Tested HIV negative 3 months earlier

Physical Exam
Respiratory distress
Temp 101.8 F
Heart Rate 110
Blood pressure 80/55 mm Hg
Dullness to percussion on right side with
crackles

Initial Tests
ECG: Sinus Tachicardia with LVH
WBC: 18,600
Creatinine: 1.5, BUN 47
ABG
pH 7.32
PaCO2 = 47 mm Hg
PaO2 = 58 mm Hg on 4 L NC
PaO2/FIO2 = 175

ER Chest X-RAY
What is the most likely pathogen in this
patient?
S pneumoniae
H influenzae
S aureus
P aeroginosa
K pneumoniae
M tuberculosis
Other
Initial Treatment in the ER
Right IJ central venous access
Fluid bolus 1 Liter 0.9% LR
Oxygen converted to 40% venturi mask
Bipap on the way
Albuterol / Atrovent neb treatments
Transduced CVP < 8 mm Hg after fluid bolus
and second 1 L 0.9% LR given
Svo2 = 70%, appropriate oxygen extraction
GOAL DIRECTED THERAPY IS JUST AS IMPORTANT
AS CORRECT EMPIRIC ANTIBIOTICS!
SEPTIC SHOCK PRESENT
SBP 90 mmHg or MAP 65 mmHg
OR
Lactate 4 mmol/L
PLUS
Clinical Picture c/w Infection

Fluid bolus 20 ml/kg
(.9 NaCl or LR)
PLUS
Vasopressors if MAP is
judged to be critically low
SBP < 90 mmHg, or
MAP < 65 mmHg, or
Lactate > 4 mmol/L

CVP < 8 mmHg

Insert
CVP
Catheter
Boluses crystalloid
or colloid equivalent
until
CVP > 8 mmHg
Check
MAP
Asses
s
ScvO2

Achiev
e ALL
Goals?
< 70%
Dobutamine or
RBCs depending
on HCT
MAP 65

Resuscitation complete.
Establish re-evaluation
intervals.

YES


What antibiotic regimen would you
prescribe in the ER?
Beta Lactam
Respiratory quinolone
3
rd
Generation Cephalosporin+macrolide
3
rd
Generation Cephalosporin+ respiratory
quinolone
Carbapenem
Carbapenem+ aminoglycoside
Vancomycin+ respiratory quinolone
Linazolid + respiratory quinolone
Initial antibiotics given in the ER
Ceftriaxone 2 gram and levofloxacin 750 mg

Rationale:
Most likely diagnosis was thought to be CAP
(Streptococcus pneumo +/- H influ)
Atypical pathogen coverage for legionella
Pneumonia
Normal Lung
Pneumonia:
inflammatory cells
and debri in
alveolar spaces
Lobar Pneumonia
Deep Tracheal Aspirate?
Gram positive cocci in clusters?
Deep Tracheal Aspirate?
Spherical gram positive cocci arranged in chains or pairs?
Deep Tracheal Aspirate?
Gram negative bacillary organisms?
Deep Tracheal Aspirate?
Gram negative coccobacillary forms?
Gram-positive bacteria, the purple crystal violet stain is trapped by the
layer of peptidoglycan which forms the outer layer of the cell.
Gram-negative bacteria, the outer membrane prevents the stain from
reaching the peptidoglycan layer in the periplasm. The outer membrane is then
permeabilized by acetone treatment, pink safranin counterstain is trapped
by the peptidoglycan layer.
Follow Up
Urine legionella antigen negative
Deep tracheal aspirate:
PMNS 4+, gram + cocci in clusters 4+ which later
grew out MRSA
Blood Cultures: MRSA, PVL+ or CA-MRSA
Community Acquired MRSA

Community Acquired MRSA Sensitivity in
this patient
Oxacillin Resistant
Fluoroquinolone Intermediate
Macrolide Resistant
Cephalosporin Resistant
Gentamycin Sensitive
Vancomycin Sensitive
Clindamycin Sensitive
Linezolid Sensitive
Bactrim Sensitive
What antibiotic would you have
prescribed now?
Vancomycin
Linazolid
Daptomycin
Tigecycline
Clindamycin
Bactrim
Respiratory quinolone
Other
CA-MRSA Pneumonia
MRSA is an increasing threat in all forms of
pneumonia
CA-MRSA is the newest threat to hospitalized
patients with pneumonia
Superbug
Enhanced antibiotic resistance
Higher mortality than MSSA strains
Expresses multiple virulence factors
CA-MRSA Virulence
Delays in the administration of an appropriate
antibiotic and clinician failure recognize risk
factors for MRSA pneumonia is a factor in
excess mortality
Panton-Valentine Leukocidin (PVL) Toxin
Potent mediator of inflammation and
activator of leukocytes
PVL destroys leukocytes by creating lytic
pores
Genes for PVL are found in CA-MRSA
isolates and is associated with CA-MRSA
mortality (SCC IV)
MRSA Virulence
CA-MRSA: 48 hours of destruction
Admission
48 hours later
MRSA as a CA and HA Pathogen
CA-MRSA HA-MRSA
Invasive
High percentage of soft tissue
infections
High rate of infection
Susceptible to non-beta-lactams
(so far)
Invading the hospital
SCC type IV

Less likely to cause soft tissue
infection
Growing cause of pneumonia
Multiresistant
May be becoming less prevalent in
hospital
SCC type I, II, III
MRSA = methicillin-resistant S aureus
CA = community-acquired
HA = hospital-acquired
SCC = Staphlococcal cassette cartridge

Healthcare Associated MRSA Infections
Prevalence
60% of ICU acquired S. aureus strains are MRSA
11% increase over the past 5 years
50% of non-ICU hospital acquired S. aureus
strains are MRSA
31% of S. aureus strains seen in hospital
outpatients are MRSA
Risk Factors for Healthcare
Associated MRSA
Extended care facilities patients
Diabetes Type I
Hemodialysis / peritoneal dialysis
Prolonged hospitalization
ICU admission
Indwelling vascular catheters
Recent or frequent antimicrobial usage
Healthcare Associated MRSA
Sensitivities
Oxacillin Resistant
Fluoroquinolone Resistant
Macrolide Resistant
Cephalosporin Resistant
Gentamycin Resistant
Clindamycin Resistant
Vancomycin Sensitive
Linezolid Sensitive
Bactrim Sensitive
Risk Factors for CA-MRSA Infection
Injecting drug users
Homeless persons
Competitive athletes, prisoners, soldiers
Ethnic populations (Native americans)
Men who have sex with men
Recent or frequent antimicrobial use
Sometimes no risk factors identified
Community Acquired MRSA
CA-MRSA is an emerging pathogen among
patients without established risk factors
No recent hospitalization
Immunocompetant
No injecting drug use
No residence in long-term facilities


Community Acquired MRSA
Almost 90% of cases are skin infections first
detected as clusters of abscesses
Sports, Jails, military recruits
Furuncles
Impetigo
Necrotizing soft tissue infections
Osteomyelitis
Pneumonia

CA-MRSA pneumonia


Associated with influenza outbreaks
Up to 25% of bacterial superinfections
after influenza

Clinical Presentation CA-MRSA
High Fever
Severe necrotizing pneumonia
Leukopenia
Respiratory Failure
Shock
Majority require ICU admission with severe
protracted illness and morbidity
Panton-Valentine Leukocidin gene (specialized
centers)
Treatment of CA-MRSA Pneumonia
FDA Approved
Vancomycin
Linazolid
Other Treatments
Clindamycin
Trimethoprim/Sulfamethazole (Bactrim)
Doxycycline/Minocycline
Rifampin (with vancomycin)
Vancomycin
Prevents peptidoglycan formation
Remains 1
st
line empiric treatment option at some
institutions
Dosing needs to be optimized to achieve trough
levels of 15-20 mcg/mL
Treatment successful in 35-57% of patients
Potential problems
Poor tissue concentrations in the lung
No effect on toxin production at ribosomal level
Increasing trough does not appear to improve outcome
Dosing and Frequency: 15 mg/kg IV q12 hours.
Linazolid
New class of synthetic antimicrobial angents
Oxazolidones
Enhanced pulmonary penetration relative to
vancomycin: ELF 100% vs 18%
Equal efficacy, possibly better, more expensive
Thrombocytopenia (uncommon)
Reversible non-selective MAO inhibitor
Serotonin syndrome
Affects toxin production
No adjustment necessary for renal dysfunction
Dosing and frequency: 600 mg IV/po q12
Other Treatments
CA-MRSA isolates retain susceptibility to
several non B-lactam antibiotics
Clindamycin
Trimethoprim/Sulfamethazole (Bactrim)
Doxycycline/Minocycline

Efficacy not established clinically
Not appropriate as first line therapy


ICU patient develops fever
56 yo male with COPD and CAP on
mechanical ventilation treated with
solumedrol, ceftriaxone, levofloxacin for CAP
Develops fever to 102 F and new, copius
purulent sputum with increased FIO2
requirement on day 5
An ICU Fever workup is initiated?
Fever in the ICU
Noninfectious Causes
Inflammatory
Medications
(antibiotics, anticonvulsants)
Blood products
Vasculitis
Pancreatitis
Interstitial and eosinophillic pneumonias
Aspiration pneumonitis
ARDS
Fever Workup
Noninfectious causes
Vascular
DVT or PE, Mesenteric Ischemia
Hemorrhage into brain, lung, or adrenal glands
Metabolic
Hyperthyroidism
ETOH withdrawal, DTs
Neuroleptic malignant syndrome, malignant
hyperthermia
Neoplasia
Fever in the ICU
Infectious Sources
UTI
Vascular Devices (central line)
Respiratory (pneumonia, abscess, sinusitis, empyema)
Wound Infection
Skin / Soft Tissue (decubitus or cellulitis)
Gastro (C. difficile, typhlitis, hepatitis, cholecystitis)
Prosthetic valves or devices (endocarditis)
Meningitis (unusual except in head trauma or ICP
monitor in place)
ICU Fever Workup
Initial Workup
Blood and Urine Cultures
CXR
Amylase, Lipase, Liver associated
enzymes
Dopplers Lower Extremities (upper too if
central line)
Lukenss trap if on ventilator for deep
tracheal aspirate
Deep Tracheal Aspiration Technique
Change in-line suction system to reduce URT
contamination
Attach in-line suction to lukens trap
100% FIO
2
on ventilator
Infuse 5 cc normal saline bullets
Advance in-line suction to left/right mainstem
bronchi and aspirate back into lukens trap
Gram stain, respiratory, fungal, and AFB culture
Equivalent to bronchoalveolar lavage with
quantitative culture of lavage fluid
NEJM 2006; 355: 2619-2630
Deep Tracheal Aspiration Technique
Closed suction in-line
catheter system
Lukens Traps
ICU Fever Workup
Subsequent studies
Bronchoscopy, echocardiogram, RUQ Ultrasound
CT of Brain, Chest, Abdomen, Pelvis
Eye exam
Thoracentesis, paracentesis, and / or lumbar
puncture
Random cortisol and ACTH stimulation test
Connective tissue markers: ANA, ANCA, CRP

This patient is diagnosed with
ventilator associated pneumonia
What initial therapy would you give?
Why is it important to get it right from
the start?
Therapy and Response
The patient is started on Linezolid 600 mg
IV q12, Zosyn 4.5 gm IV PTD, and
Tobramycin 7 mg/kg PTD based on the
local hospital epidemiology for infection
A deep tracheal aspirate is performed and
sent for gram stain, resp. culture, acid-fast
bacilli smear and fungal smear and culture

What if a deep tracheal aspirate
or bronchoscopic lavage revealed
the following?
Gram-negative bacillary organisms?
Aerobic rod shaped organism
(+) Catalase test, (+) oxidase test
Virulence: Exotoxin A and S, endotoxin
Gram-negative bacillary rods?
Encapsulated, non-motile
Facultative anaerobe and Lactose fermentating
Extended spectrum beta-lactamase producers (ESBL)


Gram-negative organism that is rod shaped during rapid
growth and coccobacillary in the stationary phase?
Nonmotile, encapsulated, negative oxidase test
No cytotoxins are produced (limited virulence)
Can retain crystal violet and be incorrectly identified
as gram positive.

Gram positive cocci in clusters?
Golden yellow colonies on agar
Catalase and coagulase positive
Hemolysis on blood-agar
Multiple virulence factors
VAP Pathogens
PA: Pseudomonas aeruginosa
SA: Staphylococcus aureus
AS: Acinetobacter species
Clinical Infectious Disease 2000; 321(suppl 4): s131-138
Definitions: The ATS/IDSA Guidelines
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 LTC facility
Attending a hospital or
hemodialysis clinic
Receiving
immunosuppressive therapy
or wound care within 30 days
of infection
HAP
Pneumonia occurring
48 hours posthospital
admission

VAP
Pneumonia occurring
48-72 hours
postintubation
Am J Respir Crit Care Med. 2005;171:388-416.
HAP=hospital-acquired pneumonia
HCAP=healthcare-associated pneumonia
LTC=long-term care; VAP=ventilator-associated pneumonia
Kollef et al. Chest 2005; 128:3854-3862
Regarding therapy, the new guidelines emphasize:
use of early and appropriate therapy, in correct doses
avoiding excess use of antibiotics and de-escalating the
initial therapy based on culture results and the patients
clinical response
limiting the duration of therapy to the minimal effective
period of time

Guidelines for the management of adults with hospital-
acquired, ventilator-associated, and healthcare-
associated pneumonia
Am J Respir Crit Care Med 2005;171:388416
Antibiotic therapy
In patients with pneumonia, a lack of appropriate
antimicrobial therapy is associated with increased
mortality
There is clear evidence that antibiotic therapy
should be given early to improve survival
A strong association between the administration of
inappropriate antibiotic therapy and mortality has
also been described in VAP
Archives Internal Med 2004:164:637-644
Chest 2002; 122:262-268
AJRCCM 1997; 156:196-200
Relationship between the delay of antibiotic
administration after the onset of shock and
mortality of patients in septic shock
Curr Opin Crit Care, Volume 13(5).October
2007.586591
Early Antibiotic Therapy in Shock
Management strategies summary
HAP, VAP or HCAP suspected
Obtain lower respiratory tract (LRT) sample for culture (quantitative, semi-
quantitative, deep tracheal aspirate) and gram stain
Unless there is both a low clinical suspicion for pneumonia and negative microscopy of
LRT sample, begin empiric antimicrobial therapy using an algorithm and local
microbiological data
ATS/IDSA Guidelines. Am J Respir Crit Care Med 2005;171:388416
Days 2 and 3: check cultures and assess clinical response: (temperature, WBC, chest X-ray,
oxygenation,
Purulent sputum, haemodynamic changes and organ function)
Management strategies summary
Clinical improvement at 4872 hours
No Yes
Cultures + Cultures Cultures Cultures +
Adjust antibiotic therapy,
search for other pathogens,
complications, other diagnosis
or other sites of infection
Search for other pathogens,
complications, other
diagnoses
or other sites of infection
Consider stopping
antibiotics
De-escalate antibiotics,
if possible, treat
selected patients for
78 days and re-assess
ATS/IDSA Guidelines. Am J Respir Crit Care Med 2005;171:388416
Risk factors for MDR pathogens in
HCAP, HAP, and VAP
Prior antimicrobial therapy in preceding 90 days
Current hospitalisation of >5 days
High frequency of antibiotic resistance in the
community or in the specific hospital unit
Presence of risk factors for HCAP:
hospitalisation for >2 days 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
Initial empiric therapy, no known risk factors for
MDR pathogens, early onset (< 5days) and any
disease severity
Streptococcus pneumoniae
Haemophilus influenzae
Methicillin-susceptible
Staphyloccus aureus (MSSA)
Antibiotic-sensitive enteric
Gram-negative bacilli (EGNB)
Escherichia coli
Klebsiella pneumoniae
Enterobacter spp.
Proteus spp.
Serratia marcescens
Ceftriaxone
OR
Levofloxacin, moxifloxacin
or ciprofloxacin
OR
Ampicillin/sulbactam
OR
Ertapenem

Initial empiric therapy with late onset (>5 days) or
risk factors for MDR pathogens, and any disease
severity
MDR pathogens
P. aeruginosa
K. pneumoniae ESBL
Acinetobacter spp.
MRSA

Anti-pseudomonal cephalosporin (cefepime,
ceftazidime) OR
anti-pseudomonal carbapenem
(imipenem or meropenem)
OR -lactam/-lactamase inhibitor
(piperacillin/tazobactam)
PLUS
Anti-pseudomonal fluoroquinolone
(ciprofloxacin or levofloxacin)
OR aminoglycoside
(amikacin, gentamicin or
tobramycin)
PLUS
Linezolid or vancomycin
(if MRSA risk factors are present or
there is a high incidence locally)

ATS-IDSA recommendations and
principles
All patients need a lower respiratory tract culture
(bronchoscopically or deep tracheal aspirate- quantitative
or qualitative) before antibiotic therapy
Should not delay the initiation of appropriate, broad-
spectrum therapy in critically ill patients based on local
hospital epidemiology
Negative LRT cultures can be used to stop antibiotic
therapy in a patient who has had cultures obtained in the
absence of a change in antibiotic in the past 72 hours
ATS-IDSA recommendations and principles
Empiric therapy should include antibiotics from a different
class than those the patient has recently received
Use short duration (5 days) of aminoglycoside when
treating pseudomonas
De-escalation should be considered once data are
available on the results of LRT cultures and the patients
clinically responds.
Shorter duration of antibiotic therapy (78 days) is
recommended for some patients with uncomplicated HAP
MRSA HCAP mortality by BAL semi-quantitative cultures
Retrospective single-center cohort study of 102 patients Dr Kollef
Optimization of Vancomycin PK indices did not correlate with
mortality
Chest 2006; 130: 947-955
Pharmacokinetics/Pharmacodynamics
Pharmacokinetic parameters
Route, dose, and frequency
Absorption,distribution, metabolism, and
elimination
Pharmacodynamic parameters
Drug concentration at tissue site
Toxicology
Pharmacokinetics and Pharmacodynamics
C (mg/dL)
AUC/MIC
Vancomycin
Linezolid
MIC
Cmax
T (hours)
T > MIC (B-lactams/Carbapenems)
Cmax / MIC (aminoglycosides)
C: Antimicrobial concentration
AUC: Area Under Curve drug concentration against time
MIC: Minimal inhibitory concentration
Cmax: Maximum drug concentration
Antibiotic
MIC Breakpoint
(ug/mL) PK/PD
Dose/
Frequency
Lung
Penetration
Pseudomonas a. MRSA
Ceftazidime 8 T> MIC 2 gm IV q8 ELF = 21%
Pip/Tazo 64/4 T> MIC 4.5 gm IV q6 ELF = 57%/91%
Imipenem 4 T> MIC 1 gm IV q8 LT = 60%
Tobramycin 4 Cmax/MIC 7 mg/kg day IV ELF 42-153%
Vancomycin 2 AUC/MIC 15 mg/kg q12 ELF = 18%
Linezolid 4 AUC/MIC 600 mg IV q12 ELF = 100%
Prevention of Nosocomial
Pneumonia
Handwashing/disinfection(1)
NIV(1)
Orotracheal intubation(1)
Suctioning subglottic secretions (1)
Semi-erect position(1)
Weaning/Sedation protocols (2)
Adequate nursing/resp. therapist staffing (2)
Chlorhexidine oral decontamination (?)
Post-pyloric feeding to reduce aspiration (2)
References
Mayo Clin Proc 2005;80(9): 1201-1208
J AMA 2007; 297:1583-1593
Chest 2005; 128: 3854-3862
Am J Respir Crit Care Med 2005; 171: 388-416
N Eng J Med 2006; 355: 2619-2630