Pneumonia: Epidemiology: Pneumonia PHMPR-732 John A. Bosso, Pharm.D

PNEUMONIA
PHMPR-732
John A. Bosso, Pharm.D.
Pneumonia: Epidemiology
PNEUMONIA • Most common infectious cause of death

Therapeutics/PHMPR-732 in USA
• ~ 4 million cases per year
• Occurs throughout the year
– Prevalence from various etiologies varies
John A. Bosso, Pharm.D. from season to season
• Affects all age groups
– Most severe in infants, elderly, chronically ill
Host Defenses of the Respiratory Tract Pneumonia: Pathogenesis

• Microorganisms gain access to the lungs
• Anatomical • Immune Function
– Aspiration of oropharyngeal contents
– Gag reflex – Alveolar macrophages
– Inhalation
– Cough reflex – Chemotactic response of
phagocytic cells – Blood-borne
– Aerodynamic turbu-
lence/filtration – Secretory IgA • Factors promoting aspiration
– Humidification – Secretory IgG – Altered sensorium, neuromuscular disease,
– Mucus blanket – Complement viral pulmonary infections, alcohol,
– Ciliary movement narcotics
– Alveolar surfactant • Organisms normally cleared with intact
immune system/defenses
PHMPR732.pneumo.rev 9.07 1
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Pneumonia: Pathogenesis Pneumonia: Etiology

• Varies with age group and comorbidities
Impairment of Colonization of • Bacterial
host defense upper respiratory
tract – Community-, Nursing Home-, vs Hospital-
acquired
• Viral
Pulmonary Aspiration of oropharyn- – Account for most pneumonias in pediatric
infection geal secretions age group
• N.B.: causative pathogen identified in
only 40-60% of cases
Pathogens Associated with CAP

S. pneumoniae is the primary bacterial cause of respiratory
infections
Etiology: “Typical” Pathogens
16%
40% • S. pneumoniae: accounts for as many as
S. pneumoniae
6% M. catarrhalis
60-70% of all cases of CAP in which a
Atypical H. influenzae pathogen is identified
Pathogens: 10% Legionella spp. – Particulary common in elderly, those with
23% M. pneumoniae
chronic comorbid conditions,
C. pneumoniae
7% Others immunocompromise
20%
1% • S. aureus: seen in either CAP or HAP
Reimer and Carroll. Clin Infect Dis. 1998;26:742-748.
• Group B streptococci
Marrie. Infect Dis Clin North Am. 1998;12:723-740.
Bartlett et al. Clin Infect Dis. 1998;26:811-838.
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Etiology: “Typical” Pathogens Etiology: “Atypical” Pathogens

• H. influenzae: esp. with chronic cardio- • Mycoplasma pneumoniae:
pulmonary diseases – accounts for ~20% of all CAP
• M. catarrhalis: esp. with immuno- – Esp. in outpatients with milder infections
compromise and hospitalization – Peak incidence in adolescents & young adults
• Gram-negative bacilli • Chlamydophila pneumoniae:
– K. pneumoniae – 5-15% of all CAP
– E. coli • Legionella pneumophila
– Proteus spp – ≤ 15% of all CAP
– Enterobacter spp
Etiology: Anaerobic Pathogens Etiology: Viruses

• Most likely seen in those predisposed to
• Account for most cases in children and
aspiration or with bronchogenic carcinoma
many cases in adults
• Gram-positive anaerobes – Influenza and adenovirus especially common
– Peptostreptococcus spp. & Peptococcus spp. in adults
• Gram-negative anaerobes – RSV, parainfluenza, and adenovirus predom-
– Bacteroides spp. & Fusobacterium inate in infants and young children
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Patient Characteristics Related

to Specific Pathogens Signs & Symptoms of Pneumonia
Condition Pathogen
• Generally similar regardless of etiology
Alcoholism S. pneumoniae, anaerobes, gram- • Onset is abrupt or sometimes subacute
negative bacilli
S. pneumoniae, H. influenzae,
• Fever, chills, dyspnea, productive cough
COPD/smoker M. catarrhalis, Legionella spp. most common
Nursing home residency S. pneumoniae, gram-negative
bacilli, H. influenzae, S. aureus,
• Sputum production (sometimes
anaerobes, C. pneumoniae hemoptysis)
S. pneumoniae, H. influenzae,
HIV infection M. tuberculosis, P. carinii
• Tachypnea, tachycardia, retractions,
P. aeruginosa, Pseudomonas spp., S. grunting respirations, decreased or
Structural lung disease aureus abnormal breath sounds
Adapted from Bartlett et al, 1998.
Signs & Symptoms of

Diagnosis of Pneumonia
“Atypical” Pneumonia
• Physical exam and history
• Begins with nonspecific constitutional • Chest x-ray
symptoms which increase over 2-4 days
• Gram’s stain of sputum
• Non-productive cough is prominent
• Other laboratory tests
• Non-pulmonary symptoms
– Blood cultures
– Nausea, vomiting, diarrhea, myalgias
– CBC with WBC differential
– Blood gases
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Diagnosis: Chest Radiograph

Diagnosis: Gram’s Stain of Sputum
Other Diagnostic Testing

Use of a Sputum Gram’s Stain
for Pneumonia
• Variable specificity and sensitivity Outpatients Inpatients
• Assess illness severity • Sputum Gram’s
• May allow pathogen-directed therapy stain/culture?
• Sputum Gram’s stain?
• CBC with differential
• Validates adequacy of specimen for • Consider sputum
• Serum chemistries
culture
culture • Renal and liver
function
• Adequate specimens difficult to obtain • Blood gases or
oximetry
• Blood cultures
Adapted from Bartlett et al, 1998.
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Community-Acquired Pneumonia Factors Predisposing to CAP &

(CAP) Epidemiology Increased Risk of Morbidity & Mortality
• Sixth leading cause of death • Advanced age • Neoplastic diseases
• Leading cause of death due • Chronic pulmonary • Diabetes mellitus
to infectious disease
disease • Immunosuppression
• More than 3 million cases of
CAP per year • Neurologic disorders • Neutropenia
• 500-600,000 hospitalizations • Congestive heart • Cigarette smoking
per year failure
• 45-90,000 deaths per year
• Alcoholism
• Chronic liver disease
• Cost: $21 billion (2000)
• Chronic renal disease
Bartlett JG, et al. Clin Infect Dis. 2000;31:347-382.
Marrie TJ, et al. JAMA. 2000;283:749-755.
Fine MJ, et al. N Engl J Med. 1997;336:243-250.
Bacterial Etiology of CAP: In General Bacterial Etiology of CAP:

Organism % of Cases by Age & Co-morbidity
• Bacteria
S. pneumoniae 15–60 •No Comorbidity •Comorbidity and/or
H. influenzae 3–10 ≤60 Years Old >60 Years Old
M. catarrhalis 1–2
Staphylococcus aureus 3–5 – Streptococcus pneumoniae – S. pneumoniae
Gram-negative bacilli 3–10
• “Atypical agents” – Mycoplasma pneumoniae – H. influenzae
Mycoplasma 1–30
Chlamydia 5–30 – Chlamydia pneumoniae – K. pneumoniae
Legionella 2–8 (and other
• Viruses 2–15
– Haemophilus influenzae gram-negative bacilli)
• Aspiration pneumonia 6–10 – Others: Legionella – S. aureus
• Other considerations pneumophila, Streptococcus
(TB, PCP, Q Fever, Fungi...) aureus, Klebsiella pneumoniae – Others:
• No diagnosis 30–60 (and other gram-negative L. pneumophila
Modified from Bartlett JG, et al. N Engl J Med. 1995;333:1618-1624.
bacilli), Moraxella catarrhalis
File TM. Infect Dis Clin Pract. 1996;5(Suppl 4):S127-135. Niederman MS et al. Am Rev Respir Dis. 1993;148:1418-1426.
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Ohio Pneumonia Study Bacterial Etiology of CAP:

by Patient Type/Location1
Cases per 100,000 Population
Age-specific rates of hospital

admission for community-acquired
pneumonia due to Ambulatory Hospitalized Severe
S. pneumoniae, Legionella, Patients (Non-ICU)2 (ICU)2
M. pneumoniae or
C. pneumoniae. Rates for infection
with each organism are calculated • S. pneumoniae S. pneumoniae S. pneumoniae
based on criteria for definite • M. pneumoniae M. pneumoniae H. influenzae
diagnosis. Rates of infection with
Legionella, • H. influenzae C. pneumoniae Legionella species
M. pneumoniae, and • C. pneumoniae H. influenzae GNB
C. pneumoniae are adjusted for
incomplete testing. • Viruses Legionella species S. aureus
Aspiration
18-34 35-49 50-64 65-79 ≥80
Age Group, y ICU=Intensive care unit
1Based on collective data from recent studies
Streptococcus Mycoplasma 2Excluding Pneumocystis species

pneumoniae pneumoniae
Legionella species Chlamydia
pneumoniae
Marston BJ et al. Arch Intern Med. 1997;157:1709-1718. File TM, et al. Curr Opin Pulm Med. 1997;3:89-97.
Bacterial Etiology of CAP: Effect on Mortality

CAP: Pathogens of Increasing Importance Meta-Analysis of 33,148 Cases of CAP from 1966 to 1996: Mortality in
Cases With Identified Bacterial Pathogen (n = 6866)
Immunocompetent Adults
– C. pneumoniae
– Legionella (non pneumophilia serogroup 1) spp. Agent Number of Cases Mortality Rate*
• Legionella-like amoebal pathogens 4432 12.3%
S. pneumoniae
– Viruses 272 14.7%
• Hantavirus Legionella spp.
• Adenovirus M. pneumoniae 507 1.4%
• Respiratory Syncytial Virus 41 9.8%
C. pneumoniae
• Parainfluenzae
H. influenzae 833 7.4%
– Other
• Burkholderia 781 0–61.1%*
Other
• Coxiella 6866
Total
• Anthrax
*Mortality rates depend on pathogen: mortality for P. aeruginosa was 61.1%, but that organism was
• Plague isolated in only 18 cases; mortality for C. psittaci was 0, and that organism was isolated in 32 cases.
• Tularemia Fine et al, JAMA 275:134-141 1996.
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Prognostic Factors Associated With CAP Management Issues

Mortality in Patients With CAP
• Diagnosis of community-acquired pneumonia
• Age and male gender • Hypotension (Need chest x-ray?).Other diagnostic testing.
• Alcoholism • Hypothermia
• Site of care: inpatient vs outpatient
• Diabetes mellitus • Leukopenia
9 • Therapy: empiric vs pathogen-directed
• Renal failure ≤10 × 10 /L
—Causative pathogen frequently not found
• Neurologic and • Multilobar pulmonary
neoplastic disease infiltrate —Treatment predominantly empiric
• Bacteremia • Tachypnea —Pneumococcal and atypical coverage important

—Increasing antibiotic resistance
Fine et al, JAMA 275:134-141, 1996.
Differences in Intrapulmonary
Antimicrobial Disposition CAP Management Issues
Single-dose Studies
40 (continued)
35 ELF Clarithromycin
30 Serum • Importance of initial therapy (timing

Concentration (µg/ml)
25
Moxifloxacin & selection)
20
15
• Switch therapy
Trovafloxacin Levofloxacin
Gatifloxacin
10
Cefuroxime • Evaluation of nonresponding patient
5 Amoxicillin Ciprofloxacin
Azithromycin
0 • Quality indicators
1-2 3 3 4 4-6 6 6 6 6
Time of Sampling Post-dose (hr)
Honeybourne, et al. J Antimicrob Chemother. 2001;48:63-66.
Morrisey, et al. Int J Antimicrob Agents. 2001;17:33-37 Bartlett JG. Clin Infect Dis 2000;31:347-383.
Various sources
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Pneumonia: Considerations for Admission

Hospitalization or Outpatient Care? to the ICU
• Degree of hypoxemia • Respiratory distress/high work of breathing
• Underlying medical conditions • PaO2/FiO2 ratio <250 mmHg
• Ability to take oral medications • Need for mechanical ventilation
• Reliability of patient adherence
• Shock
• Availability of home care
• Need for vasopressors
• Availability of outpatient follow-up
• Urine output <20 mL/h or acute renal failure
Talan DA, Moran GJ. Can Respir J 6(Suppl A):10A-14A, 1999.
ATS, Am Rev Respir Dis 148:1418-1426, 1993.
Pneumonia Severity of Illness Scoring

Site of Care: IDSA (2000) System (PSI) Prediction Rule
(also referred to as Fine or PORT rule)
– Significant impact on Patients with Community-Acquired Pneumonia
• Extent of laboratory evaluation Over age 50
• Antimicrobial therapy No
If Yes, then assign patient to
• Cost History of Risk Class II-V,
cancer, CHF,
– Prediction rule by Fine et al.1 endorsed CVA, renal or based on Step 2
liver disease
(CTS, IDSA) No
• Based on derivation and validation studies Altered mental status; pulse ≥ 125;
respiratory rate ≥ 30; systolic BP < 90 mm Hg;
• Two-step process based on mortality risks temperature < 35° C or ≥ 40°C
• Validated by controlled studies2,3 No
Assign patient to Risk Class I
1Fine MJ et al. N Engl J Med. 1997;336:243-250.
2Atlas SJ et al. Arch Intern Med. 1998;158:1350-1356.
Fine MJ et al. N Engl J Med. 1997;336:243-250.
3Marrie TJ. JAMA. 2000;283:749-755.
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Step 2 Prediction Rule

Step 2 (continued)
•Demographic factors Points
– Age: Male Age in years
Female Age (years) –10 Physical-examination findings Points
– Nursing home resident +10 – Altered mental status +20
– Respiration rate ≥ 30/minute +20
•Comorbid medical conditions
– Systolic blood pressure
– Neoplastic disease
(active < 1 year) +30 < 90 mm Hg +20
– Liver disease +20 – 35°C < temperature ≥ 40°C +15
– Congestive heart failure +10 – Pulse ≥ 125/minute +10
– Cerebrovascular disease +10
– Renal disease +10
Risk Class, PSI Score, Mortality

Step 2 (continued) and Site for Care
Laboratory and radiographic findings Risk Class PSI points % Mortality Recommend-
Points ed care site
– Arterial pH < 7.35 +30 I. Low - 0.1 outpatient

– BUN ≥ 30, sodium < 130 mmol/L +20 II. Low ≤ 70 0.6 outpatient
– Glucose ≥ 250 +10 III. Low 71 - 90 2.8 outpatient or
brief inpatient
– Hematocrit < 30% +10
IV. Moderate 91 - 130 8.2 inpatient
– Partial pressure of arterial
oxygen < 60 +10 V. High > 130 27.0 inpatient
– Pleural effusion +10
Fine et al. NEJM 1997;336:243-50.
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Limitations of the Prediction Rule Rules and Policies

Well, them are really
more like…
guidelines. But, what about the
• Overemphasis on age pirates’ code?
• Does not account for continuing patient

evaluation and improvement
• Not prospectively studied or compared with
physician judgment
• Thresholds but not continuous variables are
used for abnormal findings (e.g., respiratory
rate ≥30/min)
Pneumonia Outcome Based on

Treatment of Initial Antibiotics
Community-acquired Pneumonia – Retrospective review of 13,000 elderly
hospitalized Medicare patients with CAP
– Adjusted for baseline differences in illness
Importance of Initial Therapy severity and processes of care by Cox
proportional hazards models
– Comparison to third-generation
nonpseudomonal cephalosporin alone
as reference
Gleason PP et al. Arch Intern Med. 1999;159:2562-2572.
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Overall Outcomes
(Hazards ratios)
– Lowest 30-day mortality when analyzed by Treatment of
initial antibiotic regimen (8 hours)
• Third-generation cephalosporin alone (ref. gp.; Community-acquired Pneumonia
1.0)
• Second-generation cephalosporin + macrolide
(0.71)
• Non-Pseudomonas third-generation cephalosporin Guidelines
+ macrolide (0.74)
• Fluoroquinolone alone (0.64)
– Highest mortality with
• β-Lactam/β-lactamase inhibitor + macrolide (1.77)
• Aminoglycoside + any other (1.21)
Gleason PP et al. Arch Intern Med. 1999;159:2562-2572.
Community-Acquired Pneumonia: 2003 IDSA Treatment Guidelines for

Community-Acquired Pneumonia: Outpatient
Guidelines
•Year •Guidelines
• 19931 British Thoracic Society (BTS) – Previously healthy
Canadian Thoracic Society (CTS) • No recent abx tx: macrolide or doxycycline
American Thoracic Society (ATS)
• 1998 Infectious Diseases Society of America2 (IDSA) • Recent abx tx: FQ† or macrolide* + amox or amox/clav
European Respiratory Society3 (ERS) – Comorbidities (COPD, diabetes, CHF etc)
• 2000 IDSA, CTS
Drug Resistant Streptococcus pneumoniae • No recent abx tx: macrolide* or FQ†
Therapeutic Working Group (DRSPTWG)4 • Recent abx tx: FQ† or macrolide* + ß-lactam
Japanese Respiratory Society (JRS)5
• 2001 ATS6
– Suspected aspiration with infection
• 2003 IDSA7 • Amox/clav or clindamycin
• 2007 IDSA/ATS8 – Influenza with bacterial superinfection
1Niederman
MS, et al. Amer Rev Resp Dis. 1993;148:1418-1426, 2Bartlett JG, et al. Clin Infect Dis. 1998;26:811-838,
3European
Respiratory Society. European Respiratory Review, 4Heffelfinger JD, et al. Arch Intern Med. • ß-lactam or FQ†
2000;160:1399-1408, 5 Japanese Respiratory Society. 2000, 6 Am J Resp Crit Care Med. 2001, 7 Mandell LA et al. Clin *Azithromycin or clarithromycin.
Infect Dis 2003;37:1405-33, 8 Mandell LA et al. Clin Infect Dis 2007;44:S27-72. †Levofloxacin, moxifloxacin, gatifloxacin, or another fluoroquinolone with enhanced activity vs S. pneumoniae.
Mandell, et al. Clin Infect Dis. 2003. IDSA=Infectious Diseases Society of America.
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2007 IDSA/ATS Treatment Guidelines for 2007 IDSA/ATS Treatment Guidelines for
Community-Acquired Pneumonia: Outpatient Community-Acquired Pneumonia: Inpatient
– Previously healthy
• And, no risk factors for DRSP infection – Medical ward
• macrolide or doxycycline • FQ‡ or β-lactam* with a macrolide or
doxycycline
– Comorbidities (COPD, diabetes, CHF etc)
• FQ† or ß-lactam (amox/clav) plus a macrolide
• Recent abx tx: FQ‡ or macrolide + ß-lactam
– Regions with >25% of infections with high-
level macrolide resistance (MIC≥15 µg.ml)
• FQ†, ß-lactam
*Cefotaxime, ceftriaxone, ampicillin-sulbactam, or ertapenem. ‡ Levofloxacin, gemifloxacin, or
moxifloxacin.
†moxifloxacin, levofloxacin or gemifloxacin
Mandell et al. Clin Infect Dis 2007;44:S27-72. Mandell et al. Clin Infect Dis 2007;44:S27-72.
Risks for Drug-Resistant

2007 IDSA/ATS Treatment Guidelines for
Community-Acquired Pneumonia: ICU S. pneumoniae (DRSP)
• Pseudomonas not an issue – Recent antimicrobial use
– ß-lactam + azithromycin or FQ
– With ß-lactam allergy: FQ + aztreonam – Recent hospitalization
• Pseudomonas infection an issue
– Anti-pseudomonal ß-lactam + cipro or levo OR anti- – Association with daycare
pseudomonal ß-lactam + aminoglycoside + azi-
thromycin OR anti- pseudomonal ß-lactam + – HIV
aminoglycoside + levo or moxi
– With ß-lactam allergy: substitute aztreonam for ß- – Age, immunosuppression
lactam in above regimens
Mandell et al. Clin Infect Dis 2007;44:S27-72.
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Trend for Penicillin-Resistant (MIC ≥ 2 µg/ml) *

S. pneumoniae in the US (1990-2004) Antimicrobial Resistance Rates Among
Streptococcus pneumoniae in the US
Eryth Clinda Tetra Chloro TMP/SMX
% of Isolates Resistant
35
to Penicillin
30
Percent resistant
25
20
15
10
5
0
Year 1987-88 1994-95 1997-98 1999-00 2001-02
(n = 487) (n = 1527) (n = 1601) (n = 1531) (n=1925)
Breiman RF. JAMA. 1994;271:1831-1835. Doern GV, et al. AAC. 1996;40:1208-1213. Thornsberry C, et al. DMID. 1997;29:249-
257. Thornsberry C, et al. JAC. 1999;44:749-759. Thornsberry C, et al. CID 2002;34(S1):S4-S16. Karlowsky, et al. CID. Doern, et al. Antimicrob Agents Chemother. 2001;45:1721.
2003;36:963-970. Data on file, Ortho-McNeil Pharmaceutical, Inc.
Critical Pathways for CAP
Critical Pathways or PURPOSE

Provide standardization of treatment and
Guidelines for Treatment of setting for care based upon risk factors by:
CAP: Do they work? Using current literature and guidelines
Identifying best processes
Providing a mechanism for continuous
improvement in these processes
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Critical Pathways Critical Pathways

How well do they work? How well do they work?
• Study of 1743 patients at 19 hospitals in Canada • Critical pathway utilized:
(CAPITAL study) – Diagnosis of pneumonia in ER
• Objective to determine if use of critical pathway – Severity score assigned
improves efficiency of tx without compromising
– Patients treated as OP or hospitalized
well-being of patients
• OP tx consisted of 10 days oral quinolone
• Hospitals were randomly assigned tx regimen • IP tx started with IV quinolone with specific
– Critical pathway or conventional treatment criteria for switch to oral tx and discharge with
• Outcome measures: QOL at 6 weeks, resource oral therapy
utilization (# bed days per patient)
Marrie et al. JAMA 2000;283:749-55.
Marrie et al. JAMA 2000;283:749-55.
CAPITAL Study Design CAPITAL Study Conclusions

19 Canadian Hospitals (1743 patients) •Use of the Critical Pathway resulted in
January 1, 1998–July 31, 1998 – Significantly reduced hospital resource use
(4.4 vs 6.1 BDPM*, P=0.01)
– No adverse effect on patient well-being or
Randomization other clinical parameters including
(Stratified by teaching or community hospital) • Mortality, ICU admissions, re-admissions, community-
acquired pneumonia complications, or health-related quality
of life
– Reduced admission rates
Critical Conventional
• Proportion of low-risk patients admitted,
Pathway Management 31% vs 49% (P=0.01)
*Number of bed days per patient managed.

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CAPITAL Study Conclusions

continued
• Use of the Critical Pathway resulted in

Switching from Intravenous to
– Reduced number of antibiotic classes used Oral Therapy in the Treatment
• Proportion of patients treated with a single antibiotic,
27% vs 64%, (P=0.01)
of CAP
– Reduced number of days of IV therapy
• 4.6 days vs 6.3 days (P=0.01)
– Reduced overall costs
• Potential savings of $1,700 per patient treated
Why Switch to Oral Therapy?

IV/PO Switch Therapy
• Increasing pressure to shorten duration of
hospitalization – Recommended when patients are stable
• Ramirez criteria
• Switch to oral therapy after short course of
– Improved cough, decreased
parenteral therapy facilitates discharge shortness of breath
• Advantages of oral therapy – White blood cell count normalizing
– lower acquisition cost – Decreased temperature
– convenience – Able to take PO
– minimal expertise and time for administration • IDSA criteria
– avoidance of infusion-related complications (e.g., – Stable/improving clinically
phlebitis) – Hemodynamically stable
– few ancillary materials – Able to ingest orally
– Use of highly bioavailable agents recommended
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750-mg, Short-Course Levofloxacin 750-mg, Short-Course Levofloxacin

for CAP for CAP: Clinical Success by PSI Class
• Multicenter, randomized, double-blind, noninferiority 93.4 96.2 89.8 92.6
study n=122 n=106 n=49 86.3 n=27
84.4
n=51
n=32
• Comparison of 500-mg levofloxacin QD x 10 days vs

750-mg levofloxacin QD x 5 days
• Patients stratified according to Pneumonia Severity
Index (PSI)
– Stratum I: PSI >70 but ≤130: Patients treated as inpatients for at
least 24 hours
Patients in Each PSI Class
– Stratum II: PSI ≤70: Patients treated as inpatients or outpatients
Clin Infect Dis. 2003;37:752-760 Clin Infect Dis. 2003;37:752-760
Non-pharmacologic Treatment Treatment of CAP

• Time to initial response & duration of tx:
• Hydration – Some improvement is expected within 48-72 hr
• Antipyresis • Delayed resolution with increasing age multiple
underlying illnesses, & increasing severity of
• Supplemental O2 (humidified) infection
• Bronchodilators – Usual duration of tx: 7 - 10 days
• Pulmonary Physiotherapy • Longer (14 days) with organisms causing necrosis
(e.g., S. aureus, K. pnemoniae) or atypical pathogens
• L. pneumophila: 21 days
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Therapeutic Monitoring Management of Failure

– Consider cause
• Resistant pathogen
• Resolution of signs and symptoms
(typical or unusual organism)
Hospitalized patients: • Complication (metastatic infection, empyema,
• Vital signs obstruction)
• Superinfection
• CBC (WBC) • Noninfectious cause
• O2 saturation – Evaluation
• Chest x-ray • CT scan
• Arterial Blood Gases • Bronchoscopy
• Biopsy
When to Change to Oral CAP: Treatment Failures

Antibiotics – 444 patients admitted for CAP (Spain)
Patient started on – 49 (11%) failed to respond within 72 hours
IV antibiotics • 30 had nonresponding pneumonia
• 19 had progressive pneumonia
• Symptoms are
improving – Causes of failure:
Afebrile ≥ 4 hours Patient demonstrating • 34-Infectious
•WBC stabilizing clinical improvement – Pathogens-S. pneumoniae (6), GNB (5),
Legionella (1); Resistance (6)
– Empyema-6; Aspiration-7
•Taking other po
Patient able to take medications • 9-Noninfectious
– Malignancy-3; Interstitial Lung Disease
oral medications •Functioning GI
(BOOP)-3
– Heart Disease-2; Foreign Body-1
Mandell et al. Clin Infect Dis • 8-Nondiagnostic
2003;37:1405-33. BOOP=bronchiolitis obliterans-organizing pneumonia
Usually within 3 days Arancibia F et al. Am J Respir Crit Care Med. 2000;162:154-160.
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Processes of Care and Outcome Influenza

Process Outcome
• Influenza virus subdivided into 3 types:
Outpatient vs Inpatient Increased resolution1
– A: causes severe & widespread epidemics &
Early antimicrobials (<8h) Decreased 30d mortality2 pandemics (most prevalent)
Blood cultures within 24h Decreased 30d mortality2 • Subtypes classified based on antigenic differences
O2 assessment Increased 30d mortality2 in 2 surface glycoproteins (hemagglutinin; H1-15
and neuraminidase; N1-9)
Appropriate antimicrobials Decreased 30d mortality3,4
– B: causes regional and widespread epidemics
Early IV to PO switch Decreased LOS/Cost5
– C: causes sporadic outbreaks of mild disease
Critical pathway Decreased LOS/Cost6
• Mortality in USA estimated at 36,000 per
1FineMJ et al. J Gen Intern Med. 1995;7:359-368.
year
2Meehan T et al. JAMA. 1997:278:2080-2084.
3Gordon et al. Chest. 1996
4Gleason PP et al. Arch Intern Med. 1999;159:2562-2572.
5Rameriz JA et al. Arch Intern Med. 1999;20:2449-2454. MMWR. 2005;54(RR-8):1-40.
6Marrie T et al. JAMA. 2000;283:749-755.
See also: http://www.cdc.gov/flu
Influenza - Epidemiology Influenza A Virus

• Worldwide, ~20% of children and 5% of adults Hemagglutinin (H)–16 subtypes
(attachment, penetration)
develop symptomatic flu yearly
• Course of illness is affected by the patient’s:
Neuraminidase (NA)–9 subtypes
– Age
(release)
– Degree of pre-existing immunity
– Properties of the virus 8 viral genes
– Smoking (assembly, replication)
– Co-morbidities
M2 protein
(penetration)
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Antigenic Drift & Shift Influenzal Pneumonia

• virus has ability to genetically change its
antigenic structure
– which is why we don’t develop immunity
• Antigenic composition includes 16 hemag- Primary Influenza Viral Pneumonia
glutinin and 9 neuramidase subtypes
vs.
• Accumulation of mutations to surface proteins:
ANTIGENIC DRIFT Secondary Bacterial Pneumonia
• substantial change in surface antigens:
ANTIGENIC SHIFT
– human populations has no previous exposure →
Pandemic
Primary Influenza Viral Pneumonia Secondary Bacterial Pneumonia

• Occurs predominantly in persons with • Occurs especially in elderly and/or those
cardiovascular disease (esp. rheumatic with chronic pulmonary, cardiac and
heart disease with mitral stenosis) and metabolic disease
pulmonary disorders • Clinically, typical course of influenza
• Clinically, typical flu symptoms followed followed by improvement (4-14 d) then
quickly with sx of pneumonia progressing return of symptoms of pneumonia
to ARDS • Predominant organisms:
• Mortality is high – S. pneumoniae, H. influenzae
PNEUMONIA
PHMPR-732
Approved Antiviral Agents for

Antiviral Therapies for Influenza Influenza Treatment and Prophylaxis
Neuraminidase (NA)
NA Inhibitors Amantadine* Rimantadine* Zanamivir Oseltamivir
• Oseltamivir Protein
M2 M2 NA NA
• Zanamivir target
Activity A only A only A and B A and B
Adults and Adults and Adults and

Matrix protein (M2 ) Therapy children of
Adults
children of
only children of
³1 year ³5 years ³1 year
Adults and
M2 Inhibitors Prophylaxis Yes Yes children(Symmetrel)
of ³ Yes
*CDC recommends that the previously approved M2 inhibitors amantadine and rimantadine
• Amantadine (Flumadine) not be used for the treatment or chemoprophylaxis of7influenza
years A infections in the United
States for the remainder of the 2005-2006 season (CDC. MMWR Dispatch. January 17, 2006).
• Rimantadine
Treanor J. Influenza Virus. In Mandell, Douglas, and Bennett's Principles and Practice of Infectious
diseases. 6th ed. New York: Elsevier/Churchill Livingstone; 2005:2072.
http://www.fda.gov/bbs/topics/NEWS/2006/NEW01341.html.
Prevention of CAP
– Smoking cessation
– Preventative vaccines
• S. pneumoniae
– Vaccines
• Influenza
– Vaccines
– Antiviral drugs
Kyaw MA. NEJM 2006;354:1455-63
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Trivalent Inactivated and

Live Attenuated Influenza Virus Vaccines
Live Attenuated
Trivalent
Category Influenza Virus
Inactivated (TIV)
(LAIV)
Intranasal 
Administration & IM 
Mucosal
immune response Serum antibodies
immunity
Formulation Inactivated Live attenuated
Safety (side effects) Sore arm Coryza
Growth medium Chick embryos Chick cells
Storage Refrigerated Frozen
Indication ≥6 m (healthy & HR) 5–49 y (healthy)
Kyaw MA. NEJM 2006;354:1455-63
CDC. MMWR Recomm Rep. 2005;54(RR-8):1-40.
Vaccination Recommendations 2007-08 Vaccine Coverage

Advisory Committee on Immunization Practices (ACIP) (Adults ≥ 65 years)
• Persons at high risk for influenza-related complications and
severe disease, including
• Those aged 18-49 yoa with high risk (of complications)
conditions
• Children aged 6–59 months
• Pregnant women
• Persons aged ≥50 years
• Persons who live with or care for persons at high risk,
including
• Health care workers
• Anyone who doesn’t want to get the flu or transmit it to
others
CDC. MMWR. 2007;56(37):953-9.
CDC. MMWR. 2007;56(37):953-9.
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Vaccine Coverage in Adults

2005-06
CDC. MMWR. 2007;56(37):953-9.

CDC. MMWR. 2007;56(37):959-63.
Vaccination of Hospitalized Nosocomial Pneumonia

Patients Epidemiology
• 300,000 cases/year
IDSA recommends that patients
hospitalized for CAP that are candidates for • 20-30,000
influenza and pneumococcal vaccines receive deaths/year
vaccinations prior to discharge (C-III). • Estimated $2 billion
in excess costs
related to
hospitalization/year
Mandell et al. Clin Infect Dis 2003;37:1405-23.
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Risk Factors for HAP Drugs Increasing Risk of HAP

• Severe illness • Cigarette smoking • Sedatives
• Advanced age • Alcoholism • Steroids
• Prolonged • Major organ
• Immunosuppressive agents
hospitalization dysfunction
• Coma • Nasogastic tubes • Antacids
• Malnutrition • Endotracheal tubes • H2-receptor antagonists
• Hypotension • Enteral feeding • Prior antibiotic exposure
• Metabolic acidosis • Certain drugs – Infection with resistant organisms
Mean Mortality Rates in Patients

With CAP, HCAP, HAP, and VAP Etiology: early onset HAP
Mortality Rate (% patients)
• S. pneumoniae
• H. influenzae
• S. aureus
• Gram-negative bacilli
E. coli Proteus spp
10.0 19.8 18.8 29.3 Klebsiella spp Serratia marcescens
Enterobacter spp P. aeruginosa
(n=2,221) (n=988) (n=835) (n=499)
CAP, community-acquired pneumonia;

HCAP, health care-associated pneumonia. Kollef M, et al. Chest. 2005;128:3854-62.
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Antimicrobial Resistance in
Nosocomial Infections
Etiology: late onset HAP Gram-Negative Pathogens
• Similar organisms but more likely to

include:
– P. aeruginosa
– Acinetobacter spp
– Strenotrophomonas maltophilia ICU Patients
Non-ICU Patients
– MRSA
Source: NNIS Data.

Clin Chest Med. 20:303-315.
Antimicrobial Resistance of Nosocomial

Infections
Gram-Positive Pathogens
Clinical Presentation of HAP
• Similar symptoms to CAP

• Signs and symptoms may be
masked by comorbid illnesses
ICU Patients
Non-ICU Patients
Source: NNIS data.

Clin Chest Med. 20:303-315.
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Diagnosis of HAP
Additional Diagnostic Tests for HAP
(based on 5 criteria)
1. Unexplained new or worsening fever • Chest x-rays
2. New or unexplained increased WBC • Gram’s stain and culture of
3. Change in quantity or quality of – Sputum (deep expectorated)
sputum – Endotracheal aspirate (mechanically
ventilated patients)
4. Worsening respiratory function
• RR, oximetry, PFTs • Blood cultures
5. New or worsening infiltrates on CXR
Risk Factors for Increased Risk of

Prognosis with Nosocomial Pneumonia
Increased Mortality in HAP
• Bacteremia
• Mortality rate: 38 - 52% • Dysfunction of other organs
• Mortality rate in critically ill patients • Severe underlying diseases
with severe complications: >70%
• Transfer from another ICU
– e.g., ARDS
• Late onset pneumonia with resistant
pathogens
• Inappropriate initial antibiotics
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Impact on Inadequate Initial

Treatment of Nosocomial Pneumonia
Therapy on Outcome in VAP
• 132 patients with VAP1 • Time to initial response & duration of tx:
– Mortality with adequate initial tx: 38% – Some improvement is expected within 48-72 hr
– Mortality with inadadequate initial tx: 91% • Delayed resolution with increasing age multiple
underlying illnesses, & increasing severity of
– Mortality with no tx: 60% infection
• Immunocompromise and inadequate in- – Usual duration of tx: 14 days
itial tx independent risk factors for • Longer with severe infections with difficult to treat
mortality2 organisms (e.g., P. aeruginosa) or complicated by
abscesses
Luna et al. Chest 1997;111:676-85.
Kollef & Ward 1998;113:412-20.
Empiric Antibiotic Therapy for HAP “Limited Spectrum” Empiric Therapy
• Ceftriaxone or
• Levofloxacin, moxifloxacin, or
ciprofloxacin or
• Ampicillin/sulbactam or
• Ertapenem
ATS/IDSA. Am J Respir Crit Care Med 2005;171:388-416.
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“Broad Spectrum” Empiric Therapy

• Cefepime or ceftazidime or
• Imipenem or meropenem or Other Pharmacotherapeutic
• Piperacillin/tazobactam
PLUS
Issues and Considerations
• Ciprofloxacin or levofloxacin or
• Aminoglycoside
Plus, if MRSA a consideration
• Linezolid or vancomycin
Duration of Antibiotic Treatment Duration of Antibiotic Treatment

• Prospective, randomized, multicenter trial • 401 patients: 197 “short” vs 201 “long”
• Comparing the outcome of therapy with a short (8 • Mortality: 18.8 vs 17.2% (NS)
d) or a long (15 d) course of antibiotic in patients • Pulmonary infection recurrence: 28.9 vs 26.0% (NS)
– with microbiologically proven VAP (bronchoscopic BAL • Antibiotic use: number of antibiotic-free days,
PSB or Combicath) 13.1±7.4 vs 8.7±5.2 days (p<0.0001)
– receiving appropriate initial empirical treatment • No differences with regard to the number of
– double blind until day 8 ventilator-free days, the number of organ failure-
• Major end-points (day 28): free days, the duration of ICU stay, and mortality at
– mortality day 60
– recurrence of pulmonary infection • Emergence of multiresistant pathogens for patients
– antibiotic use who had pulmonary infection recurrence: 42.1 vs
62.3%, p=0.04)
Chastre J, Wolff M, Fagon JY; ATS 2003
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Rationale for Combination Therapy Add Vancomycin?

• Broad spectrum of activity
• Institutional rate of MRSA?
• Synergistic activity
– yes, if rate is >20%
• Delay or prevent emergence of resistance
• Other agents in the empiric regimen
• N.B. not proven more effective than mono-therapy – Many other ß-lactams are adequate for
but strongly recommended with: MSSA
– Nosocomial pneumonia with mechanical ventilation of > • Pip/tazo, cefepime, imipenem, meropenem
7 days duration, presence of empyema or bacteremia,
use of broad-spectrum antibiotics within previous 2
weeks, and/or profound neutropenia
Non-pharmacologic Treatment Dealing with Therapeutic Failure

• Mechanical ventilation • r/o nosocomial sinusitis
• Supplemental O2 • Expand antibacterial spectrum
• Hydration – Cover MRSA, anaerobes, other Gram-
• Nutritional support negatives
• Antipyretics • Add antiviral agents?
• Bronchodilators (for bronchospasm) • Add antifungal agents?
• Ipratropium (to dry respiratory secretions)
• Chest physiotherapy
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Therapeutic Monitoring Prevention of Nosocomial Pneumonia

• Signs & symptoms of infection • Infection control procedures
• Vital signs – Handwashing
– Isolation (patients with resistant organisms)
• Hemodynamic status
• Maintenance/restoration of good
– Mental status, urine output, etc
pulmonary mechanics
• CBC (WBC count and diff.) – Ambulation, incentive spirometers, etc
• O2 saturation, ABG’s • Avoidance of drugs increasing gastric pH
• Chest x-ray • ± selective digestive decontamination
Example Case-1 Example Case-1 (continued)

GC is a 62 year old white female who was well up until 24 hours prior to
GC is a 62 year old white female who was well up until 24 hours prior to presentation. Past medical history is positive for type II diabetes
presentation. Past medical history is positive for type II diabetes mellitus mellitus and hypertension (well controlled with glyburide and enalapril,
and hypertension (well controlled with glyburide and enalapril, respectively). She presents to the outpatient department with
respectively). She presents to the outpatient department with complaints complaints of fever and difficulty breathing. On physical exam, she is
of fever and difficulty breathing. On physical exam, she is noted to be in noted to be in moderate respiratory distress with a respiratory rate of 33
moderate respiratory distress with a respiratory rate of 33 bpm, mild bpm, mild perioral cyanosis, and a temperature of 40.1oC. Chest
perioral cyanosis, and a temperature of 40.1oC. Chest auscultation auscultation reveals decreased breath sounds over the right lower lobe.
reveals decreased breath sounds over the right lower lobe. Laboratory Laboratory test results: WBC 19,000/mm3 with a left shift, sputum
test results: WBC 19,000/mm3 with a left shift, sputum contains many contains many WBCs and Gram-positive cocci in chains, and oxygen
WBCs and Gram-positive cocci in chains, and oxygen saturation of 90% saturation of 90% on room air. A presumptive diagnosis of community-
on room air. A presumptive diagnosis of community-acquired pneumonia acquired pneumonia is made.
is made.
3. What intitial antibiotic therapy would you recommend?
1. What is the most likely bacterial etiology for this patient’s pneumonia? 4. What are the appropriate monitoring parameters in this case?
2. Where should this patient’s treatment be initiated? 5. How would you determine whether this patient is a candidate for
switch therapy?

Pneumonia: Epidemiology: Pneumonia PHMPR-732 John A. Bosso, Pharm.D

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PNEUMONIA

PNEUMONIA • Most common infectious cause of death

Host Defenses of the Respiratory Tract Pneumonia: Pathogenesis

Pneumonia: Pathogenesis Pneumonia: Etiology

Pathogens Associated with CAP

Etiology: “Typical” Pathogens Etiology: “Atypical” Pathogens

Etiology: Anaerobic Pathogens Etiology: Viruses

Patient Characteristics Related

Signs & Symptoms of

Diagnosis: Chest Radiograph

Other Diagnostic Testing

Community-Acquired Pneumonia Factors Predisposing to CAP &

Bacterial Etiology of CAP: In General Bacterial Etiology of CAP:

Ohio Pneumonia Study Bacterial Etiology of CAP:

Age-specific rates of hospital

Streptococcus Mycoplasma 2Excluding Pneumocystis species

Bacterial Etiology of CAP: Effect on Mortality

Prognostic Factors Associated With CAP Management Issues

• Bacteremia • Tachypnea —Pneumococcal and atypical coverage important

30 Serum • Importance of initial therapy (timing

Pneumonia: Considerations for Admission

Pneumonia Severity of Illness Scoring

Step 2 Prediction Rule

Risk Class, PSI Score, Mortality

– Arterial pH < 7.35 +30 I. Low - 0.1 outpatient

Limitations of the Prediction Rule Rules and Policies

• Does not account for continuing patient

Pneumonia Outcome Based on

Gleason PP et al. Arch Intern Med. 1999;159:2562-2572.

Community-Acquired Pneumonia: 2003 IDSA Treatment Guidelines for

Risks for Drug-Resistant

Mandell et al. Clin Infect Dis 2007;44:S27-72.

Trend for Penicillin-Resistant (MIC ≥ 2 µg/ml) *

Critical Pathways for CAP

Critical Pathways or PURPOSE

Critical Pathways Critical Pathways

CAPITAL Study Design CAPITAL Study Conclusions

*Number of bed days per patient managed.

CAPITAL Study Conclusions

• Use of the Critical Pathway resulted in

Marrie TJ, et al. JAMA. 2000;283:749-755.

Why Switch to Oral Therapy?

750-mg, Short-Course Levofloxacin 750-mg, Short-Course Levofloxacin

• Comparison of 500-mg levofloxacin QD x 10 days vs

Clin Infect Dis. 2003;37:752-760 Clin Infect Dis. 2003;37:752-760

Non-pharmacologic Treatment Treatment of CAP

Therapeutic Monitoring Management of Failure

When to Change to Oral CAP: Treatment Failures

Processes of Care and Outcome Influenza

Influenza - Epidemiology Influenza A Virus

Antigenic Drift & Shift Influenzal Pneumonia

Primary Influenza Viral Pneumonia Secondary Bacterial Pneumonia

Approved Antiviral Agents for

Adults and Adults and Adults and

Kyaw MA. NEJM 2006;354:1455-63

Trivalent Inactivated and

Vaccination Recommendations 2007-08 Vaccine Coverage

Vaccine Coverage in Adults

CDC. MMWR. 2007;56(37):953-9.

Vaccination of Hospitalized Nosocomial Pneumonia

Risk Factors for HAP Drugs Increasing Risk of HAP

Mean Mortality Rates in Patients

CAP, community-acquired pneumonia;