REVIEW OF RESPIRATORY INFECTIONS
John G. BartlettJohns Hopkins University
School of Medicine
Conflicts: HIV Advisory Boards –BMS, Abbott, GSK
Advisory Board: J & J
Research Grants: Gilead
REVIEW OF RTIs
Three categoriesCommunity-acquired pneumoniaAcute sinusitisAcute exacerbations of chronic bronchitis
Issues reviewedMicrobiologyDiagnostic testsAntibiotic trialsGuidelinesChallenges
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 RareM. pneumoniae 5-10% Rare Rare
Distribution of Pathogens in CAP
Bartlett JG, Mundy LM. N Engl J Med. 1995;333:1618; American Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730’ Hall MJ, Owings, MF. 2000 National Hospital Discharge Survey. NCHS. 2002:1; National Vital Statistics Report. 2001;49:14. Marrie TJ et al. Resp Med. 2005; 99:60-65.
H parainfluenzae1.9%
H influenzae4.9%
M pneumoniae15%
M Catarrhalis1.1%
Unknown51.6%
S pneumoniae5.9%
C pneumoniae +M pneumoniae
2.1%
S aureus1.1%
C pneumoniae12%
EMPIRIC ABX: OUTPATIENT
Uncomplicatedmacrolide or doxycycline
Complicated (co-morbidity or recent antibiotics)macrolide or fluoroquinolone
Influenza: betalactam or FQAspiration: clindamycin or amox-CA
TREATMENT OF
“WALKING PNEUMONIA” (MALCOLM C AND MARRIE T: ARCH IN 2003;163:797)
Pathway: Doxy or MacrolideExperience: 768 patientsAntibiotic: Macrolide
Macrolide: 426 (65%)Fluoroquinolone: 245 (32%)Doxycycline: 4 (0.5%)Betalactams: 15 (2%)
Outcome: Hospitalize 17 (2%)
EMPIRIC ABX: HOSPITALIZED
Ward*fluoroquinolonemacrolide + betalactam
ICU* (S. pneumoniae + Legionella)betalactam + macrolide/FQ (FQ alone)
Bronchiectasis: cover P. aeruginosaPip/imi/mero/cefepime + FQ
Influenzabetalactam or FQ
MRSA: Vanco and/or Linezolid + rifampin
*Missed pathogens (Hopkins): PCP & TB (E. Nuermberger)
ASSOCIATION OF ANTIBIOTIC THERAPY AND DEATH**
Antibiotic Odds Ratio* Reduction
Cephalosporin 1.0
Cephalosporin + macrolide
0.74 26% reduction
Fluoroquinolone alone
0.64 36% reduction
*Analysis of 12,000 Medicare patients
**Gleason P et al. Arch Intern Med 1999;159:2562
DIAGNOSTIC STUDIES TEST COMMENTSputum GS No longer standard
& culture Useful if done rightBlood cult Standard only with ICU
admissions; LOSLegionella Good test; 80% sens.
Urinary Ag Outbreaks and lethalS. pneumoniae 80% sensitive with
Urinary Ag bacteremia $30Influenza 70% sensitive; ?
Rapid test antiviral Rx
ETIOLOGIC DIAGNOSIS OF COMMUNITY-ACQUIRED PNEUMONIA
(Templeton KE. CID 2005;41:345)Method: 105 pts. CAP, conventional tests
+ PCRResults: Pathogen in 74%
Bacteria VirusesS. pneumoniae22 Rhinovirus 18 H. Influenzae 6 Coronovirus 14Legionella 6 Influenza 12Mycoplasma 10 Paraflu 8C. pneumoniae 4 Adenovirus 4 RSV 3
MACROLIDE + BATALACTAM vs. BETALACTAM ALONE FOR PNEUMOCOCCAL
BACTEREMIA
Retrospective review of 409 casesBetalactam alone 171 (42%)Betalactam and Macrolide 238 (58%)
OR for risk of deathMacrolide 0.4Age > 65 yrs 2.5Shock 18.3
*Martinez JA. CID 2003; 36: 389
CAP: MRSA, 2003-4 FLU SEASON (Hageman JC. Em Infect Dis 2006;12:894)
S. aureus CAP 2003-4: 17 cases, 9 states
No. MRSA = 15 (88%)Median age: 21 yrsLab evidence influenza: 12 (71%)Mortality: 5/17 (29%)PVL genes: 11/15 (85%)
STREPTOCOCCUS PNEUMONIAE
● PCV7 vaccine reduced resistant S. pneumoniae by 10 yrs.
● Rate of 19A in children <5 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
ANTIMICROBIAL ISSUES IN CAP
1. Diagnostics
2. AntibioticsS. pneumoniae
MRSA (USA 300)(Influenza)
3. Miscellaneous issuesMacrolide rolePulmonary PharmacologyTime to administerMega databanks
RECOMMENDATIONS FOR MANAGEMENT OF SINUTSITIS*
1. Imaging not recommended for uncomplicated cases
2. Bacterial cultures are not recommended3. Indication for antibiotics:
• Nasal pus, severe symptoms• Symptoms > 7 days
4. Greatest barrier to efficient antibiotic treatment is lack of a simple test
*ACP, CDC, IDSA (Ann Intern Med 2001;134:495)
Duration of Symptoms in Rhinovirus Upper Respiratory Tract Infections (URTIs)
Worsening of symptoms at5–7days in pts with APBRS complicating a viral URTI
% P
atie
nts
Wit
h S
ymp
tom
s
Day of Illness
0
10
20
30
40
50
60
70
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Nasal Discharge Sore Throat
Cough Fever
APBRS diagnosis may be made in a patient with a viral URTI that is not better after 10 days or worsens after 5–7 days and is accompanied by associated symptoms.
Adapted from Sinus and Allergy Health Partnership (SAHP). Otolaryngol Head Neck Surg. 2004;130(1 Suppl):1-45; Adapted from Gwaltney JM. JAMA. 1967;202:158-164.
SINUSITIS: PLACEBO-CONTROLLED TRIAL (van Buchen FL et al. Lancet 1997;349:683)
Method: Symptoms + x-ray evidence of sinusitis randomized to amoxicillin (750 mg tid) vs. placebo
Outcome (2 wks) Placebo Amox.n=106
n=108Clinical response 77% 83%Side Effects 9% 21%Relapse 17% 21%
SINUSITIS: COCHRANE LIBRARY REVIEW (2003;CD000243)
Method: 49 studies, 13,660 ptsStudies: 20 blinded, 5 placebo controlled
Criteria: Radiology + aspirateResults: Clinical cure + x-ray
RRAmoxicillin vs. placebo 2.07Non-penicillins vs. amox 1.07Non-pencillins vs. Amoxclav 1.03ADR ceph. Vs. Amoxclav 0.47
Conclusion: Amoxicillin x 7-14 d
SYSTEMATIC REVIEW OF HEALTH RELATED QUALITY OF LIFE FOR ADULTS
WITH ACUTE SINUSITIS(Linder JA, et al. J Gen Intern Med 2003;18:390)
Rationale: Evaluation of outcome in acute sinusitis
● X-ray and CT scans – poor● Microbiology – impractical● Symptoms and health-related
quality-of-life (HRQL)
OUTCOME INSTRUMENT #USED
Rinosinusitis Outcome 2Chronic Sinusitis Survey 7Sinonasal Outcome Test 16 1Short form-36 7McGill Pain questionnaire 1Short Form -12 2Rhinosinusitis Disability Index 2Quality of Well-being scale 2Sinonasal Outcome Test 20 5Modified McGill Pain Question 1
Linder JA et al
Conclusion (acute sinusitis)1. No measure of outcome has met even
minimal validation requirements2. Virtually all patients respond within 2
weeks-measure must detect rapid change with antibiotics
3. Meta-analyses of sinusitis antibiotic treatment show marginal benefit
ANTIMICROBIAL ISSUES IN SINUSITIS
1. Diagnostics – simple test2. Criteria for response
ACUTE EXACERBATIONS OF CHRONIC BRONCHITIS: PRACTICE GUIDELINES
ACCP, ATS, CTS (Chest 2006;129:104S)
1. Antibiotics are recommended in patients with purulent sputum and more severe illness (increased cough, sputum and dyspnea
ACUTE EXACERBATIONS OF CHRONIC BRONCHITIS: PRACTICE GUIDELINES
ACCP, ATS, CTS (Chest 2006;129:104S)
1. Antibiotics are recommended in patients with purulent sputum and more severe illness (increased cough, sputum and dyspnea
2. FDA 2002: Abx trials done over 40 years are flawed and role of antibiotics is inconclusive
Meta-Analysis of the Benefitsof Antibiotics in AECB
–1.0 1.0–0.5 1.50 0.5
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
Favors Placebo Favors Antibiotic
Effect SizeSaint S et al. JAMA. 1995;274:1131-1132.
SEVERE EXACERBATIONS CHRONIC BRONCITIS:
CONTROLLED TRIAL WITH OFLOXACIN*
Method: Randomized placebo-controlled trial of severe AECB requiring mechanical ventilation
Results: Ofloxacin Placebon=47 n=46
Death 2(4%) 10(22%)Duration mech vent 6.4 d 10.6 dDuration ICU 9.4 d 14.5 d
*
*Nouira S. Lancet 2001;358:220
ROLE OF H. INFLUENZAE IN EXACERBATIONS OF
CHRONIC BRONCHITIS
Method: 104 patients followed 1994-2005, 3009 visits
Results: Rank order bacteria H. Flu > M. cat > S. pneumonia
Exacerbations:• New strain: NEJM 2002;347:465• Serologic response: AJCCM 2004;169:448• Persists: AJRCCM 2004;170:266
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; 347:465
STRAIN SPECIFIC RESPONSETO HAEMOPHILUS INFLUENZAE*
Method: Whole cell EIA and bactericidal assay to homologous H. influenzae with AECB
Results: ResponseNew Strain 22/36 (61%)*Prior strain 7/33 (21%)
*Highly strain specific – bactercidal for 11/92 heterologous strains
*Sethi S AJRCCM 2004; 169:448
NEW METHODS
Bronchoscopy: 4 reports support role(Solar N AJRCCM 1998; 157:1498)
Molecular epidemiology: New strain H. flu(Sethi S AJRCCM 2002;337:465)
Immune response: IgG or IgA vs. infecting strain (Bakri F JID 2002; 185:632;
Sethi S AJRCCM 2004; 169:448)
Airway inflammation: Neutrophilic response + IL-8
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 technologyPlacebo – controlled trialsH. hemolyticus – accounts for 40% of
“H. influenza” (non pathogen)
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