REVIEW OF RESPIRATORY INFECTIONS

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REVIEW OF RESPIRATORY INFECTIONS

• John G. Bartlett
• Johns Hopkins University
• School of Medicine
• Conflicts HIV Advisory Boards
• BMS, Abbott, GSK
• Advisory Board J J
• Research Grants Gilead

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REVIEW OF RTIs

• Three categories
• Community-acquired pneumonia
• Acute sinusitis
• Acute exacerbations of chronic bronchitis
• Issues reviewed
• Microbiology
• Diagnostic tests
• Antibiotic trials
• Guidelines
• Challenges

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PATHOGENS IN RESPIRATORY TRACT INFECTIONS IN
ADULTS

• CAP ABS AECB
• Viruses 20 ? 50
• Bacteria
• S. pneumo 20-40 40 20
• H. influ. 5-10 30 50
• M. catarrhalis 1 10 25
• S. aureus 1 5 5
• C. pneumoniae 5-20 Rare Rare
• M. pneumoniae 5-10 Rare Rare

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Distribution of Pathogens in CAP
M pneumoniae 15
H influenzae 4.9
H parainfluenzae 1.9
M Catarrhalis 1.1
S aureus 1.1
C pneumoniae 12
C pneumoniae M pneumoniae 2.1
S pneumoniae 5.9
Unknown 51.6
Bartlett JG, Mundy LM. N Engl J Med.
19953331618 American Thoracic Society. Am J
Respir Crit Care Med. 20011631730 Hall MJ,
Owings, MF. 2000 National Hospital Discharge
Survey. NCHS. 20021 National Vital Statistics
Report. 20014914. Marrie TJ et al. Resp Med.
2005 9960-65.
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EMPIRIC ABX OUTPATIENT

• Uncomplicatedmacrolide or doxycycline
• Complicated (co-morbidity or recent
  antibiotics)macrolide or fluoroquinolone
• Influenza betalactam or FQ
• Aspiration clindamycin or amox-CA

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TREATMENT OF WALKING PNEUMONIA (MALCOLM C AND
MARRIE T ARCH IN 2003163797)

• Pathway Doxy or Macrolide
• Experience 768 patients
• Antibiotic Macrolide
• Macrolide 426 (65)
• Fluoroquinolone 245 (32)
• Doxycycline 4 (0.5)
• Betalactams 15 (2)
• Outcome Hospitalize 17 (2)

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EMPIRIC ABX HOSPITALIZED

• Wardfluoroquinolonemacrolide betalactam
• ICU (S. pneumoniae Legionella)betalactam
  macrolide/FQ (FQ alone)
• Bronchiectasis cover P. aeruginosaPip/imi/mero/c
  efepime FQ
• Influenzabetalactam or FQ
• MRSA Vanco and/or Linezolid rifampin
• Missed pathogens (Hopkins) PCP TB
• (E. Nuermberger)

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ASSOCIATION OF ANTIBIOTIC THERAPY AND DEATH
Analysis of 12,000 Medicare patients Gleason
P et al. Arch Intern Med 19991592562
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DIAGNOSTIC STUDIES

• TEST COMMENT
• Sputum GS No longer standard
• culture Useful if done right
• Blood cult Standard only with ICU
• admissions LOS
• Legionella Good test 80 sens.
• Urinary Ag Outbreaks and lethal
• S. pneumoniae 80 sensitive with
• Urinary Ag bacteremia 30
• Influenza 70 sensitive ?
• Rapid test antiviral Rx

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ETIOLOGIC DIAGNOSIS OF COMMUNITY-ACQUIRED
PNEUMONIA(Templeton KE. CID 200541345)

• Method 105 pts. CAP, conventional tests PCR
• Results Pathogen in 74
• Bacteria Viruses
• S. pneumoniae 22 Rhinovirus 18
• H. Influenzae 6 Coronovirus 14
• Legionella 6 Influenza 12
• Mycoplasma 10 Paraflu 8
• C. pneumoniae 4 Adenovirus 4
• RSV 3

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MACROLIDE BATALACTAM vs. BETALACTAM ALONE FOR
PNEUMOCOCCAL BACTEREMIA

• Retrospective review of 409 cases
• Betalactam alone 171 (42)
• Betalactam and Macrolide 238 (58)
• OR for risk of death
• Macrolide 0.4
• Age gt 65 yrs 2.5
• Shock 18.3
• Martinez JA. CID 2003 36 389

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CAP MRSA, 2003-4 FLU SEASON (Hageman JC. Em
Infect Dis 200612894)

• S. aureus CAP 2003-4 17 cases, 9 states
• No. MRSA 15 (88)
• Median age 21 yrs
• Lab evidence influenza 12 (71)
• Mortality 5/17 (29)
• PVL genes 11/15 (85)

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STREPTOCOCCUS PNEUMONIAE

• ? PCV7 vaccine reduced resistant
• S. pneumoniae by 10 yrs.
• ? Rate of 19A in children lt5 yrs. increased
  3x from 1999 to 2004
• ? Serotype 19A is resistant to betalactams and
  macrolides
• ? Children limited treatment options
• Adults Fluoroquinolones
• ? FQ sensitivity prob stable unless used in
  children
• ? Wyeth vaccine (19A) 2008-10

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ANTIMICROBIAL ISSUES IN CAP

• 1. Diagnostics
• 2. Antibiotics
• S. pneumoniae
• MRSA (USA 300)
• (Influenza)
• 3. Miscellaneous issues
• Macrolide role
• Pulmonary Pharmacology
• Time to administer
• Mega databanks

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RECOMMENDATIONS FOR MANAGEMENT OF SINUTSITIS

• Imaging not recommended for uncomplicated cases
• Bacterial cultures are not recommended
• Indication for antibiotics
• Nasal pus, severe symptoms
• Symptoms gt 7 days
• Greatest barrier to efficient antibiotic
  treatment is lack of a simple test
• ACP, CDC, IDSA (Ann Intern Med 2001134495)

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Duration of Symptoms in Rhinovirus Upper
Respiratory Tract Infections (URTIs)
Worsening of symptoms at57days in pts with
APBRS complicating a viral URTI
70
60
50
40
Patients With Symptoms
30
20
10
0
1
2
3
4
5
6
7
8
9
10
11
12
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Day of Illness
APBRS diagnosis may be made in a patient with a
viral URTI that is not better after 10 days or
worsens after 57 days and is accompanied by
associated symptoms. Adapted from Sinus and
Allergy Health Partnership (SAHP). Otolaryngol
Head Neck Surg. 2004130(1 Suppl)1-45 Adapted
from Gwaltney JM. JAMA. 1967202158-164.
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SINUSITIS PLACEBO-CONTROLLED TRIAL (van Buchen
FL et al. Lancet 1997349683)

• Method Symptoms x-ray evidence of sinusitis
  randomized to amoxicillin (750 mg tid) vs.
  placebo
• Outcome (2 wks) Placebo Amox.
• n106 n108
• Clinical response 77 83
• Side Effects 9 21
• Relapse 17 21

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SINUSITIS COCHRANE LIBRARY REVIEW
(2003CD000243)

• Method 49 studies, 13,660 pts
• Studies 20 blinded, 5 placebo controlled
• Criteria Radiology aspirate
• Results Clinical cure x-ray
• RR
• Amoxicillin vs. placebo 2.07
• Non-penicillins vs. amox 1.07
• Non-pencillins vs. Amoxclav 1.03
• ADR ceph. Vs. Amoxclav 0.47
• Conclusion Amoxicillin x 7-14 d

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SYSTEMATIC REVIEW OF HEALTH RELATED QUALITY OF
LIFE FOR ADULTS WITH ACUTE SINUSITIS(Linder JA,
et al. J Gen Intern Med 200318390)

• Rationale Evaluation of outcome in acute
  sinusitis
• ? X-ray and CT scans poor
• ? Microbiology impractical
• ? Symptoms and health-related
• quality-of-life (HRQL)

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OUTCOME INSTRUMENT USED

• Rinosinusitis Outcome 2
• Chronic Sinusitis Survey 7
• Sinonasal Outcome Test 16 1
• Short form-36 7
• McGill Pain questionnaire 1
• Short Form -12 2
• Rhinosinusitis Disability Index 2
• Quality of Well-being scale 2
• Sinonasal Outcome Test 20 5
• Modified McGill Pain Question 1

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Linder JA et al

• Conclusion (acute sinusitis)
• No measure of outcome has met even minimal
  validation requirements
• Virtually all patients respond within 2
  weeks-measure must detect rapid change with
  antibiotics
• Meta-analyses of sinusitis antibiotic treatment
  show marginal benefit

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ANTIMICROBIAL ISSUES IN SINUSITIS

• Diagnostics simple test
• Criteria for response

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ACUTE EXACERBATIONS OF CHRONIC BRONCHITIS
PRACTICE GUIDELINESACCP, ATS, CTS (Chest
2006129104S)

• Antibiotics are recommended in patients with
  purulent sputum and more severe illness
  (increased cough, sputum and dyspnea

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ACUTE EXACERBATIONS OF CHRONIC BRONCHITIS
PRACTICE GUIDELINESACCP, ATS, CTS (Chest
2006129104S)

• Antibiotics are recommended in patients with
  purulent sputum and more severe illness
  (increased cough, sputum and dyspnea
• FDA 2002 Abx trials done over 40 years are
  flawed and role of antibiotics is inconclusive

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Meta-Analysis of the Benefitsof Antibiotics in
AECB
Favors Placebo
Favors Antibiotic
Elmes et al. 1957 Berry et al. 1960 Fear,
Edwards. 1962 Elmes et al. 1965 Petersen et al.
1967 Pines et al. 1972 Nicotra et al.
1982 Anthonisen et al. 1987 Jorgensen et al.
1992 Overall
1.0
1.0
0.5
1.5
0
0.5
Saint S et al. JAMA. 19952741131-1132.
Effect Size
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SEVERE EXACERBATIONS CHRONIC BRONCITIS
CONTROLLED TRIAL WITH OFLOXACIN

• Method Randomized placebo-controlled trial of
  severe AECB requiring mechanical ventilation
• Results Ofloxacin Placebo
• n47 n46
• Death 2(4) 10(22)
• Duration mech vent 6.4 d 10.6 d
• Duration ICU 9.4 d 14.5 d

Nouira S. Lancet 2001358220
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ROLE OF H. INFLUENZAE IN EXACERBATIONS OF
CHRONIC BRONCHITIS

• Method 104 patients followed 1994-2005, 3009
  visits
• Results Rank order bacteria
• H. Flu gt M. cat gt S. pneumonia
• Exacerbations
• New strain NEJM 2002347465
• Serologic response AJCCM 2004169448
• Persists AJRCCM 2004170266

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EVIDENCE FOR NEW STRAINS OF H. INFLUENZAE

• Method Molecular typing of sputum isolates
• Results 81 pts, 1975 visits
• 374 exacerbations
• 
  New Strain
• Exacerbation 33
• Control periods 15
• Sethi S NEJM 2002 347465

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STRAIN SPECIFIC RESPONSETO HAEMOPHILUS
INFLUENZAE

• Method Whole cell EIA and bactericidal
• assay to homologous H.
  influenzae with AECB
• Results Response
• New Strain 22/36 (61)
• Prior strain 7/33 (21)
• Highly strain specific bactercidal
  for 11/92
  heterologous strains
• Sethi S AJRCCM 2004 169448

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NEW METHODS

• Bronchoscopy 4 reports support role
• (Solar N AJRCCM 1998 1571498)
• Molecular epidemiology New strain H. flu
• (Sethi S AJRCCM 2002337465)
• Immune response IgG or IgA vs.
• infecting strain (Bakri F JID 2002 185632
• Sethi S AJRCCM 2004 169448)
• Airway inflammation Neutrophilic response
  IL-8

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ACUTE EXACERBATIONS OF CHRONIC BRONCHITIS ISSUES

• Indications to treat and to evaluate
• are crude
• ? Time to response
• ? Time to next exacerbation
• ? Quality-of-life
• Goal to apply new technology
• Placebo controlled trials
• H. hemolyticus accounts for 40 of
• H. influenza (non pathogen)

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