REVIEW OF RESPIRATORY INFECTIONS John G. Bartlett Johns Hopkins University School of Medicine Conflicts: HIV Advisory Boards – BMS, Abbott, GSK Advisory.

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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