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Abdullah Kharbosh, B.Sc.

Pharm
Definition
 HAP:
 Arises 48 hours or more after hospital admission
 Not incubated at the time of admission
 Ventilator-associated pneumonia (VAP):
 Arises 48-72 hours or more after endotracheal intubation
 Healthcare-associated pneumonia (HCAP):
 Arises within 90 d of having been admitted to an acute care facility
 Has resided in a nursing home or LTCF or
 Received I.V antimicrobial therapy, chemotherapy or wound care
within the 30 d prior to the current infection or
 Attends a hospital or hemodialysis clinic
Epidemiology
 Usually caused by bacteria, is currently the second most common
nosocomial infection in the US
 Has an associated crude mortality of 30-70%
 Occurs at a rate of approximately 5-10 cases per 1000 hospital
admissions
 Incidence increases by 6-20 fold in patients being ventilated
mechanically
 HAP accounts for up to 25% of all ICU infections and for more than
50% of the antibiotics prescribed
Incidence of Nosocomial Infections in Combined Medical-
Surgical ICU’s
Medical Patients Surgical Patients

Pneumonia 30% Pneumonia 33%


UTI 30% UTI 18%
Bloodstream infection 16% SSTI 14%
Lower resp. tract 6% Bloodstream infection 13%
(not pneumonia) Lower resp. tract 6%
(not pneumonia)

Richards et al. Infect Control Hosp Epidemiol 2000;21:510-515)


Risk Factors
Co-morbid
ICU Therapies Injuries Ventilation
Illnesses
 Cancer  CPR  Burns  Duration of
 COPD  Corticosteroid use  Coma mechanical
 Chronic cardiac  General surgery  Head injury ventilation
disease  Neurosurgery  Multiple organ  Intracuff pressure
Kidney failure system failure <20 cm H20
  Antacids
(MOSF)  Reintubation
 Paralytic agents
 Prior antibiotic therapy  Acute respiratory
distress syndrome
 Tracheostomy (ARDS)
 Use of a NGT
 Large-volume gastric
aspiration

Patel PJ, et al. Seminar Respir Crit Care Med 2002;23:415-25


Mehta RM. J Intensive Care Med 2003;18:175-88
American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416
Time of onset of pneumonia is an important epidemiologic variable and
risk factor for specific pathogens and outcomes in patients with HAP
and VAP
Time from Hospitalization (days)
0 1 2 3 4 5 6 7

Early-onset Late-onset
Early-onset HAP and VAP, usually carry a better prognosis, and are
more likely to be caused by antibiotic sensitive bacteria
Late-onset HAP and VAP are more likely to be caused by multidrug-
resistant(MDR) pathogens, and are associated with increased patient
mortality and morbidity
Early-onset HAP with risk factors for MDR pathogens are at greater
risk for colonization and infection with MDR pathogens and should be
treated similar to patients with late-onset HAP or VAP
Etiology
Causative Pathogens in Causative Pathogens in
patients with Early onset or patients with Late onset or
No Risk factors for MDR Risk factors for MDR
Pathogens Pathogens
Timing Within five days of admission or Five days or more after admission or
mechanical ventilation mechanical ventilation
Bacteriology Streptococcus pneumonia Same as before
Haemophilus influenzae Pseudomonas aeruginosa
Anaerobic bacteria Acinetobacter sp.
MSSA MRSA
Escherichia coli
Klebsiella pneumoniae Klebsiella pneumoniae-ESBL
Enterobacter species Legionella pneumophila
Proteus species
Serratia species
Prognosis Less severe, little impact on outcome Higher attributable mortality and
Mortality minimal morbidity
Diagnosis
 Not necessarily easy to accurately diagnose HAP
 Criteria frequently include:
 Clinical
 Fever ; cough with purulent sputum,
 Radiographic
 New or progressive infiltrates on CXR,
 Laboratorial
 Leukocytosis or leukopenia
 Microbiologic
 Suggestive gram stain and positive cultures of sputum, tracheal
aspirate, bronchial brushing, pleural fluid or blood

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


Diagnosis
 All above criteria fairly sensitive, but very non- specific, particularly in
mechanically ventilated patients
 In an effort to improve the specificity of clinical diagnosis, Pugin and
coworkers developed the clinical pulmonary infection score (CPIS),
which combines clinical, radiographic, physiological (PaO2/FiO2),
and microbiologic data into a single numerical result

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


CPIS Used for the Diagnosis of VAP*
1. Temperature C Points
  36.5 and  38.4 0
  38.5 and  38.9 1
  39.0 or  36.0 2
2. Blood leukocytes, mm-3
  4,000 and  11,000 0
 < 4,000 or > 11,000 1
 + band forms 500 1
3. Tracheal secretions
 Absence of tracheal secretions 0
 Presence of tracheal secretions 1
 Purulent secretions 1

*CPIS score > 6 Sensitivity: 93% Specificity: 100%


Pugin J et al. Am Rev Respir Dis 1991;143:1121-1129
CPIS Used for the Diagnosis of VAP* (cont.)

4. Oxygenation: PaO2/FiO2, mm Hg Points


 > 240 or ARDS 0
  240 and no evidence ARDS 2
5. Pulmonary radiography
 No infiltrate 0
 Diffuse or patchy infiltrate 1
 Localized infiltrate 2
6. Culture of tracheal aspirate (semiquantitative 0-1-2-3 +)
 Pathogenic bacteria cultured  1+ or no growth
0
 Pathogenic bacteria cultured > 1+ 1
 Same pathogenic bacteria on Gram Stain > 1+
*CPIS score > 6 Sensitivity: 93% Specificity: 1 100%

Pugin J, et al. Am Rev Respir Dis 1991; 143:1121-1129


Treatment Goals
A. The provision of appropriate antimicrobial therapy
B. The appropriate modification of therapy based on clinical response
as well as culture and susceptibility reports, serial monitoring of
clinical pulmonary infection score (CPIS)
C. Slowing the development of antimicrobial resistance
D. Minimization of superinfections

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


Initial Therapy
Inappropriate

Therapeutic Failure
or Inadequate
Antibiotic
Mortality

Therapy
Antibiotic
Resistance
Importance of Appropriate Initial 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 (CAP/HAP, 655 ICU Patients)
60
52* *P <.001
Hospital Mortality (%)

50
42*
40

30 24
18
20

10

0
All-Cause Mortality Infection-Related Mortality
Inadequate antimicrobial treatment (n=169) Adequate antimicrobial treatment (n=486)
ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.
Chest. 1999;115:462-474.
Antibiotic Selection
 General Approach (clinical decision  initiate therapy)

HAP or VAP Suspected


(All Disease Severity)

Late Onset or Risk Factors for


Multi-drug Resistant (MDR) Pathogens

No Yes

Limited Spectrum Broad Spectrum


Antibiotic Therapy Antibiotic Therapy
For MDR Pathogens
American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416
Risk Factors for MDR Pathogens
• Antimicrobial therapy in preceding 90 days
• Current hospitalization for 5 days or more
• High frequency of Abx resistance in community or specific hospital
units
•Immunosuppressive disease and/or therapy
•Risk factors for healthcare associated pneumonia
1. Hospitalization for 2 days or more in the preceding 90 days
2. Residence in nursing home or extended care facility
3. Home infusion therapy
4. Chronic dialysis within 30 days
5. House wound care
6. Family member with MDR pathogen

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


Initiation and Modification of Empiric Antibiotic Regimen
HAP, VAP, HACAP Suspected

Obtain Microbiologic Cultures


Begin Empiric Antimicrobial Therapy
Based On the Most Likely Pathogens & Local
Microbiologic Data

Days 2 & 3: Check Cultures & Assess Clinical Response:


(Temperature, WBC, Chest X-ray, Oxygenation,
Hemodynamic Changes & Organ Function)

Clinical Improvement at 48 -72 hours

Cultures - Cultures + Cultures - Cultures +


Initial empiric antibiotic for HAP in patients with No risk
factors for MDR, early onset & any disease severity
(Limited Spectrum Antibiotic Therapy)
Potential Pathogens Recommended Antibiotics

Strept.pneumoniae (if Pen R) Ceftriaxone


H.influenzae OR
MSSA Levo/Moxi/Ciproflox
Antibiotic sensitive enteric GNB: OR
-E.coli Ampi/Sulbactam
-K.pneumoniae
-Enterobacter sp OR
-Proteus.species Ertapenem
-Serratia.marcescens
American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416
Initial empiric antibiotic for HAP in patients with risk factors for MDR, or late
onset and any disease severity (Broad Spectrum Antibiotic Therapy)
Potential MDR Pathogens Combination Antibiotic Therapy

Pseudomonas aeruginosa Antipseudomonal cephal.


Klebsiella pneumoniae (ESLB) (cefepime,ceftazidime)
OR
Acinetobacter species
Antipseudomonal carbapenem
(Imipenem/Meropenem)
OR
B-lactam,B-lactamase inhibitor
(Piperacilin/tazobactam)
PLUS
Antipseudomonal FQ. (Cipro/Levof)
PLUS
MRSA Linezolid or Vancom (if risk factors present)
PLUS
Legionella pneumophila Macolide (e.g., azithromycin) or FQ
(e.g., cipro or levof) not aminoglycoside

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


Initial IV, adult doses of antibiotics for empiric therapy of HAP,
including VAP, & HCAP in patients with late-onset disease or
risk factors for MDR pathogens

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


Recommendations for initial antibiotic therapy
 Selection of appropriate antibiotics for the initial management of HAP
should be based on:
 Time of onset of disease
 The presence/absence of risk for MDR pathogens
 Choice of specific agents should be dictated by local microbiology,
cost, availability and formulary restrictions
 Use optimal dosages
 Initial therapy should be administered IV with a switch to oral/enteral
therapy in selected patients
 Aerosolized antibiotics have not been proven to be of value in the
therapy of VAP but may be considered as adjunctive therapy in MDR
infections
 Combination therapy should be used in patients likely infected with
MDR pathogens
Recommendations for initial antibiotic therapy
 If patients receive combination therapy , the aminoglycoside can be
stopped after 5-7 days in responding patients
 Monotherapy with selected agents can be used in patients with
severe VAP and HAP in the absence of MDR pathogens
 If patients receive initially appropiate therapy efforts should be made
to shorten therapy to 7 days

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


If P. aeruginosa pneumonia is documented, combination therapy is recommended

Linezolid is an alternative to vancomycin for the treatment of MRSA VAP and may be
preferred on the basis of a subset analysis of two prospective randomized trials
(BUT? VANCO trough & Patients Comorbidities)
This agent may also be preferred if:
Patients have renal insufficiency or
Receiving other nephrotoxic agents, but more data are needed

If ESBL Enterobacteriaceae are isolated, then monotherapy with a third-generation


cephalosporin should be avoided
The most active agents are the carbapenems

If Acinetobacter species are documented to be present, the most active agents are the
carbapenems, sulbactam, colistin, & polymyxin
There are no data documenting an improved outcome if these organisms are treated with
combination regimen
Combination vs. Monotherapy
 Combination therapy is common practice in the therapy of suspected and
proven gram-negative HAP (B- lactam–aminoglycoside)
 Synergism
 Clearly documented to be valuable only in vitro and in patients with
neutropenia or bacteremic infection
 Prevention of resistance (P. aeruginosa, Enterobacter)
 Not well documented

 Nephrotoxicity

 Provide a broad-spectrum empiric regimen

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


Combination vs. Monotherapy
 Monotherapy should be used when possible (expensive/drug exposure)
 Patients with nosocomial pneumonia with no risk factors for MDR
organisms are likely to respond to monotherapy
 Monotherapy is also the standard when gram-positive HAP, including
MRSA, is documented
 Monotherapy in patients with mild HAP (defined as a CPIS of 6 or less):
ciprofloxacin, but is less effective in severe HAP
 Monotherapy in patients with moderately severe HAP not due to MDR
pathogens include: ciprofloxacin, levofloxacin, imipenem, meropenem,
cefepime, and piperacillin–tazobactam

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


Combination vs. Monotherapy
 For gram-negatives, use two drugs (B-lactam, plus FQ, or AG)
 FQ can penetrate into the lung better than aminoglycosides
 FQ have less potential for nephrotoxicity
 Improved survival has been seen with aminoglycoside-
containing, but not with FQ-containing, combinations
 To use monotherapy in patients with severe VAP, patients should
initially receive combination therapy, but therapy could be focused to a
single agent if lower respiratory tract cultures did not demonstrate a
MDR pathogen

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


Local Instillation and Aerosolized Antibiotics
 To enhance antibiotic penetration to the lower respiratory tract
 The aminoglycosides (tobramycin) and polymyxin B
 Did not improve clinical outcome compared with placebo
 Significantly greater microbiologic eradication
 May be useful to treat microorganisms resistant to systemic therapy
 When used as prophylaxis (not as therapy) increase risk of MDR
pneumonia
 Side effects: bronchospasm induced by the antibiotic or the diluents
 More data are needed before determining its value

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


Duration of Therapy
 Prolonged therapy simply leads to colonization with antibiotic resistant
bacteria, which may precede a recurrent episode of VAP
 Most patients with VAP, who receive appropriate antimicrobial therapy,
have a good clinical response within the first 6 days
 Eradication from tracheal aspirates:
 Rapid: VAP caused by H. influenzae and S. pneumoniae, the organisms
 Slow: Enterobacteriaceae, S. aureus, and P. aeruginosa could (despite in
vitro susceptibility to the antibiotics administered)
 Relapse:
 A trend to greater rates of relapse for short duration therapy was seen if the
etiologic agent was P. aeruginosa or an Acinetobacter species

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


Duration of Therapy
 Negative lower respiratory tract cultures can be used to stop antibiotic
therapy in a patient who has had cultures obtained in the absence of
an antibiotic change in the past 72 hours
 A shorter duration of antibiotic therapy (7 to 8 days) is recommended
for patients with uncomplicated HAP, VAP, or HCAP who have received
initially appropriate therapy and have had a good clinical response,
with no evidence of infection with non-fermenting gram-negative bacilli

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


Assessment of Non-responders

Wrong Diagnosis Wrong Organism


Pulmonary Embolus
Drug-resistant Pathogen:
ARDS
(bacteria, mycobacteria, virus, fungus)
Pulmonary Hemorrhage
Inadequate Antimicrobial Therapy
Underlying Disease
Neoplasm

Complication
Empyema or Lung Abscess
Clostridium difficile Colitis
Occult Infection
Drug Fever

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


Bacterial variables associated with failure
 Pathogen can be resistant to the chosen antibiotic or acquire resistance
during therapy (P. aeruginosa treated with a single agent)
 Some organisms are inherently difficult to eradicate, even with effective
therapy
 Certain types of infection are associated with a poor outcome, especially
those with gram-negative bacilli, polymicrobial flora, or bacteria that have
acquired antibiotic resistance
 In patients who are M.ventilated, superinfection with P. aeruginosa or
Acinetobacter species has a particularly high mortality, approaching 90%
 Pneumonia due to other pathogens (i.e., M.tuberculosis, fungi, or
respiratory viruses) or an unusual bacterial pathogen not included in the
initial empiric regimen
 Unrecognized immunosuppression (e.g., AIDS), & Pneumocystis carinii
pneumonia
American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416
Host factors associated with failure
 The presence of any condition that is known to increase mortality such as:
 Prolonged mechanical ventilation
 Respiratory failure
 An underlying fatal condition
 Age > 60 years
 Bilateral radiographic infiltrates
 Prior antibiotic therapy
 Prior pneumonia (i.e., the current episode represents superinfection), and/or
 Chronic lung disease (e.g., COPD)

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


Recommendations for Assessing
Response to Therapy
 Use serial assessment of clinical parameters plus microbiology to define
the response and to modify initial empiric therapy
 Clinical improvement usually takes 48–72 hours, and thus therapy should
not be changed during this time unless there is rapid clinical decline
 Non-response to therapy is usually evident by day 3 using clinical
parameters
 The responding patient should have de-escalation of antibiotics, narrowing
therapy to the most focused regimen possible on the basis of culture data
 The non-responding patient should be evaluated for noninfectious mimics
of pneumonia, unsuspected or drug-resistant organisms, extrapulmonary
sites of infection, and complications of pneumonia and its therapy

American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416


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