Acute Pneumonia

1
Acute Pneumonia

• The most widespread and fatal of all acute
  diseases, pneumonia is now Captain of the Men of
  Death.
• The Principals and Practice of Medicine
• Sir William Oscar, 1901

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Principles and Practice of Infectious Diseases
3
Principals and Practice of Infectious Diseases
4
Diagnosis of CAP

• Chest radiograph is the most important diagnostic
  tool
• Clinical presentation is not diagnostic of an
  etiology
• Yield of pathogens from Gram stain of
  expectorated sputum from patients with CAP is
  only 3040.

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Diagnosis Chest Radiograph
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Gram Stains Role in CAP Diagnosis
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CAP Treatment Issues

• Causative pathogen frequently not found
• Treatment predominantly empiric
• Pneumococcal and atypical coverage important
• Increasing antibiotic resistance
• Clinical significance in question
• Use double-coverage for pneumococci?
• If outcomes are similar, which agent do we choose?

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CAP Changing Presentation

• Aging of the population
• Increased number of nursing home beds
• Increased number of AIDS cases
• Increased number of organs transplanted

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Key Bacterial Pathogens in CAP

• Up to 60 of cases have an unknown etiology
• Up to 15 with 2 etiologies

Clin Infect Dis 200031347-82 Ramirez et al.
IDSA 2000
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The reported age-related mortality per 100,000 US
population from pneumonia and influenza in
individuals gt15 yr, 1982-1990
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ASCAP Guidelines for Outpatient Treatment of CAP

• Otherwise healthy patients (all ages)
• First-line
• Azithromycin PO
• Alternative first-line
• Moxifloxacin PO (preferred) or levofloxacin PO or
  clarithromycin PO or gatifloxacin PO

The ASCAP 2002 Consensus Panel. Hosp Med
Consensus Rep. 20021-32 Emerman CL, Bosker G.
In Bosker G, ed. Textbook of Adult and Pediatric
Emergency Medicine. 2nd ed. Atlanta, Ga American
Health Consultants. 2002375-395.
12
Indications for Hospitalization

• Pulse gt140, SBP lt90 mm Hg, and/or respiratory
  rate gt30/min
• Altered mental status
• Hypoxemia (PO? lt60 mm Hg)
• Suppurative complication
• Metabolic abnormality

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ASCAP Guidelines for Inpatient Treatment of CAP

• Hospitalized, non-ICU
• First-line
• Ceftriaxone PLUS azithromycin IV
• Alternative first-line
• Moxifloxacin or levofloxacin IV or gatifloxacin
• ICU Patients
• First-line
• Ceftriaxone IV PLUS levofloxacin IV ()
  aminoglycoside or ceftriaxone IV PLUS
  azithromycin IV () an antipseudomonal agent
• Alternative first-line
• Ciprofloxacin IV PLUS an aminoglycoside IV PLUS
  azithromycin IV

The ASCAP 2002 Consensus Panel. Hosp Med
Consensus Rep. 20021-32 Emerman CL, Bosker G.
In Bosker G, ed. Textbook of Adult and
Pediatric Emergency Medicine. 2nd ed. Atlanta,
Ga American Health Consultants. 2002375-395.
14
ASCAP Guidelines for Inpatient Treatment of CAP
Special Considerations

• Nursing home acquired
• First-line
• Ceftriaxone IV PLUS azithromycin IV
• Alternative first-line
• Ceftriaxone PLUS doxycycline or moxifloxacin or
  levofloxacin IV or gatifloxacin
• Severe, bacteremic CAP with documented
  Streptococcus pneumoniae
• First-line
• Ceftriaxone PLUS moxifloxacin or ceftriaxone IV
  PLUS levofloxacin IV
• Alternative first-line
• Vancomycin PLUS azithromycin IV

Showing high-level or complete resistence to
macrolides, cephalosporins and/or penicillin.
If S. pneumoniae demonstrates complete
resistance to extended-spectrum quinolones (very
rare), third generation cephalosporins and
macrolides, then vancomycin may be required as
part of initial therapy, although this would be
necessary only in rare circumstances. The ASCAP
2002 Consensus Panel. Hosp Med Consensus Rep.
20021-32 Emerman CL, Bosker G. In Bosker G,
ed. Textbook of Adult and Pediatric Emergency
Medicine. 2nd ed. Atlanta, Ga American Health
Consultants. 2002375-395.
15
Infections caused by S. pneumoniae, USA 1997
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Worldwide Prevalence Rates for Penicillin
Resistant S.pneumoniae
Doern CID 1998 Felmingham JAC 1996 and
2000. Zhanel Low and Hoban AAC 1999.
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Penicillin Resistance with S pneumoniae in the
United States
Antimicrob Agents and Chemother 2001451721 and
submitted
18
S. pneumoniae Resistance Rates Selected Agents,
1999-2000
Antimicrobial Resistance
Macrolides 25.9
Clindamycin 8.8
Tetracycline 16.4
Chloramphenicol 8.6
TMP/SMX 30.3
Fluoroquinolones 1.2
n1,531 isolates 33 U.S. medical centers,
winter (1999-2000)
Antimicrob Agents and Chemother 2001451721
Clin Infect Dis 200234330
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PRSP-Mechanism

• PBP alterations - not ?-lactamaseproduction -
  mediate penicillin resistance in
  pneumococcusthus ?- lactamase inhibitors do not
  enhance activity of ?-lactam agents against
  penicillin-resistant pneumococci

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Drug-Resistant S. pneumoniae

• Age gt 65 years or lt 5 years
• Exposure to a child in a day care center
• Multiple medical comorbidities
• Alcoholism
• Recent use of antibiotics
• Immunosuppression
• Recent hospitalization

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MIC Interpretive Criteria for S. pneumoniae
Susceptibility to Ceftriaxone Effective January
1, 2002

• Meningeal Breakpoints Nonmeningeal Breakpoints
• Sensitive ?0.5 ?g/mL ?1 ?g/mL
• Intermediate 1 ?g/mL 2 ?g/mL
• Resistant ?2 ?g/mL ?4 ?g/mL

For cerebrospinal fluid isolates, report only
meningitis interpretations.For all other
isolates, report interpretations for both
meningitis and nonmeningitis. NCCLS. 2002. M100.
22
Mortality of Hospitalized Patients With Invasive
Pneumococcal Disease

Years N Mortality Reference
Austrian Gold Kings County Brooklyn Hospital 1952-62 1130 13 Annals Int Med 1964
Fine Meta-analysis of 127 cohorts 1966-95 4432 12 JAMA 1996
Feikin Population-based, active surveillance 1995-97 5837 12 Am J Public Health 2000
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Mortality Due to Pneumococcal Pneumonia / Sepsis
Location Year Patients with DRSP () Mortality () Mortality () P Study
Location Year Patients with DRSP () Pen-S Pen-NS P Study
Ohio 1991-94 39/499 (8) 19 21 NS Plouffe, JAMA 1996
Israel 1987-92 67/293 (23) 11 16 NS Rahav, Medicine 1997
Barcelona 1984-93 145/504 (29) 24 38 NS Pallares, NEJM 1995
South Africa 1993-94 35/108 (32) 16 24 NS Friedland PIDJ 1995
Atlanta 1994 44/192 (23) 11 23 NS Metlay, CID 2000
Barcelona 1996-98 49/101-Pen (49) 12/101-Mac (12) 6 14 16 7 NS NS Ewig, AJRCCM 1999
N. America 1995-97 741/4193 (18) 11 14 NS Feikin AJPH 2000
Mac-S Mac-NS Children
Bishai, JAC 2001
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New NCCLS Breakpoints for Streptococcus
pneumoniae
Overall Rates of Resistance (I R) Overall Rates of Resistance (I R) Overall Rates of Resistance (I R)
Drug Old Breakpoints New Breakpoints
Amoxicillin 24.2 6.3
Amoxicillin/clavulanate 24.2 6.3
Ceftriaxone/cefotaxime 24.0 4.0
Cefuroxime 29.1 27.3
Antimicrob Agents Chemother 2001451721-29 NCCLS,
M100 document January 2002
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Time gt MIC90 for Selected ?-Lactams vs. S.
pneumoniae
TgtMIC90, of dosing interval TgtMIC90, of dosing interval TgtMIC90, of dosing interval
?-lactam Pen S Pen I Pen R
Amoxicillin 23 mg/kg bid 100 61 46
Amoxicillin 13 mg/kg bid 100 59 41
Cefotaxime/ceftriaxone 100 100 71
Cefuroxime 75 35 0
Clin Infect Dis 200031(Suppl 2)S29-34
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Antibiotic Activity Against H. influenzae
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H. influenzaeIncreasing ?-Lactamase Production
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Atypical Pneumonia

• AP encompasses pneumonias due to Mycoplasma
  pneumoniae, Chlamydia pneumoniae and Legionella
  spp
• Prospective studies have failed to identify the
  cause of 40 to 60 of CAP cases
• Today, AP implies
• An often benign course (ambulatory)
• Gradual onset
• Systemic complaints often greater than
  respiratory complaints
• AP often a mixed infection

File TM Jr, et al. Infect Dis Clin North Am.
199812572,570,579. Reimann HO. JAMA.
19381112377,2384. Bartlett JG, et al. Clin
Infect Dis. 199826813. Levison ME. Harrisons
Principles of Internal Medicine. McGraw-Hill
19981439.
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Pharmacokinetics and Pharmacodynamic Parameters
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(No Transcript)
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Pharmacodynamic parameters as a guide to
antibiotic decision making
Cmax (peak)

• For optimal antimicrobial effect Cmax/MIC
  should be gt 8-10 AUIC should be gt 50-125
• To minimize resistance AUIC ratio should
  be gt 50-125

Antibiotic serum concentration
AUC
MIC
Time above MIC
Time (h)
Schentag J and Tillotson, G.S. (1997). Chest.
112(6 Suppl)314S-319S
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AUC/MIC90 Ratio of Major FQ for S. pneumoniae
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FQ Prescription per Capita and Frequency of
Pneumococci with Reduced Susceptibility to FQs in
Canada According to Patients Age (Bars)
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Gatifloxacin vs Ceftriaxone Macrolide in
Hospitalized CAP Patients
Gatifloxacin IV 400 mg QD n141
Gatifloxacin PO 400 mg QD
?2 days
Newly Hospitalized CAP Patients (?18 years)
Ceftriaxone IV 1 or 2 g (32) QD Erythromycin
IV 0.5 or 1 g (39) q6h n142
Clarithromycin PO 500 mg BID
?2 days
Treatment for 7 to 14 days
Fogarty C et al. J Respir Dis. 199920(suppl
11)S60-S69. Please see IMPORTANT SAFETY
INFORMATION slides. Please see full Prescribing
Information.
35
Gatifloxacin vs Ceftriaxone Macrolide in CAP
Clinical and Bacteriologic Response
Gatifloxacin
Ceftriaxone erythromycin/clarithromycin
NSD
NSD
100
97
97
92
90
90
Patients with Cure or Eradication ()
80
70
96/99
96/106
69/71
73/79
0
Clinical Cure
Microbiologic Eradication

• Macrolides were erythromycin IV and
  clarithromycin PO step-down.No. cured/total of
  clinically evaluable patients No.
  eradicated/total of microbiologically evaluable
  patients.
• NSDnot statistically different
• Fogarty C et al. J Respir Dis. 199920(suppl
  11)S60-S69.
• Gatifloxacin efficacy rates in CAP from clinical
  trials used as a basis for approvalup to 90
• Please see IMPORTANT SAFETY INFORMATION slides.
  Please see full Prescribing Information.

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Gatifloxacin vs Ceftriaxone Macrolide in CAP
Clinical Response by Pneumonia Severity
Gatifloxacin
Ceftriaxone erythromycin/clarithromycin
NSD
NSD
NSD
100
100
97
96
92
91
90
90
Patients with Cure ()
80
70
96/99
96/106
28/28
24/26
68/71
72/80
0
All Patients
Mild/Moderate CAP
Severe CAP

• Macrolides were erythromycin IV and
  clarithromycin PO step-down ATS severity
  scores No. cured/total of clinically
  evaluable patients.
• NSDnot statistically different
• Niederman MS et al. Am Rev Respir Dis.
  19931481418-1426 Fogarty C et al. J Respir
  Dis. 1999 20(suppl 11)S60-S69.
• Gatifloxacin efficacy rates in CAP from clinical
  trials used as a basis for approvalup to 90
• Please see IMPORTANT SAFETY INFORMATION slides.
  Please see full Prescribing Information.

37
Role of FQ in Treatment of CAP

• To limit the emergence of FQ-resistant strains,
  the new FQ should be limited to adults
• For whom one of the above regimens has already
  failed,
• Who are allergic to alternative agents,
• OR
• Who have documented infection with highly
  drug-resistant pneumococci (MIC 4 µg/ml)

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Pneumococcal Vaccine

• Older than 2 years with
• functional or anatomic asplenia
• immunocompromise or immunosuppression
• HIV infection
• malignancy
• chronic renal failure, HD, nephrotic syndrome
• chronic cardiovascular or pulmonary illness
• Alaskan natives, American Indians
• Revaccination
• if gt65 years, consider revaccination in 5 yr

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CDC Recommendations Who Should Receive Influenza
Vaccine?

• Persons at increased risk (age ?6 mos)
• Hospital and outpatient employees
• Nursing home employees with patient contact
• Home health care providers working with high-risk
  persons
• Household members of high-risk persons
• Persons desiring to avoid influenza infection

MMWR. 1999485-7.
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Guidelines for CAP
Guideline Inpatient Outpatient
IDSA ?-lactam macrolide or Fluoroquinolone Macrolide or Doxycycline or Fluoroquinolone
ATS IV azithromycin or ?-lactam macrolide or Fluoroquinolone Macrolide or doxy ?-lactam macrolide Fluoroquinolone
CDC ?-lactam macrolide or Fluoroquinolone ?-lactam or macrolide or doxycycline (reserve quinolones)
Clin Infect Dis 200031347-82 Am J Resp Crit
Care Med 20011631730-54 Arch Int Med
20001601399-1408
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• I prefer to decide my prescription strategies for
  CAP on the basis of severity of the patients
  condition, the presence of comorbidities, and the
  epidemiologic pattern in each geographical area.
• J. Rello - Chest (May 98)

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Results of Influenza Vaccination Among Staff
Patients in 12 Scottish Geriatric Long-Term Care
Facilities
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Acknowledgements

• Dr Naiel Nassar MD FACP
• Assistant professor of Medicine
• UTSW Dallas