# Presentation: 683031

## 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

## REVIEW OF RTIs

- _Three categories_
- 	Community-acquired pneumonia
- 	Acute sinusitis
- 	Acute exacerbations of chronic 	bronchitis
- _Issues reviewed_
- 	Microbiology
- 	Diagnostic tests
- 	Antibiotic trials
- 	Guidelines
- 	Challenges

## 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

## 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 parainfluenzae**
**1.9%**

***H influenzae***
**4.9%**

***M pneumoniae***
**15%**

***M Catarrhalis***
**1.1%**

- Unknown
- 51.6%

**S pneumoniae**
**5.9%**

***C pneumoniae +***
***M pneumoniae***
**2.1%**

***S aureus***
**1.1%**

***C pneumoniae***
**12%**

**Notes:**
Community-acquired pneumonia (CAP) is a common and serious illness.
Pneumonia is the seventh leading cause of death in the United States1 and the most common cause of death due to infectious disease.2   Up to 5.6 million cases of CAP occur annually, with as many as 1.1 million of these requiring hospitalization.2
Marrie and colleagues conducted an etiological study of CAP in an ambulatory setting.  Despite considerable effort, their etiological diagnosis of CAP treated on an ambulatory basis was made in only half the patients.  The most commonly identified pathogens were M pneumoniae, C pneumoniae, S pneumoniae, and 
H influenzae.3 
Treatment strategies for CAP are complicated by the emergence of bacterial strains that have become resistant to current antibiotics. Resistance is being identified with increasing frequency among S pneumoniae, H influenzae, M catarrhalis, and a number of enteric gram-negative bacteria.2

References:
1. Arias E, Smith BL. Deaths: preliminary data for 2001. National Vital Statistics Reports. March 14 2003;51(5):1-45;         2. Niederman MS, Mandell LA, Anzueto A, et al. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med. 2001;163:1730-1754;  3. Marrie TJ, Poulin-Costello M, Beecroft MD, Herman-Gnjidic Z.  Etiology of community-acquired pneumonia treated in an ambulatory care setting.  Resp Med. 2005;99:60-65.

## EMPIRIC ABX: OUTPATIENT

- _Uncomplicated_macrolide or doxycycline
- _Complicated_ (co-morbidity or recent 	antibiotics)macrolide or fluoroquinolone
- _Influenza_: betalactam or FQ
- _Aspiration_: clindamycin or amox-CA

## TREATMENT OF “WALKING PNEUMONIA” (MALCOLM C AND MARRIE T: ARCH IN 2003;163:797)

- _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%)

## EMPIRIC ABX: HOSPITALIZED

- _Ward*_fluoroquinolonemacrolide + betalactam
- _ICU*_ (S. pneumoniae + Legionella)betalactam + macrolide/FQ (FQ alone)
- _Bronchiectasis_: cover P. aeruginosaPip/imi/mero/cefepime + FQ
- _Influenza_betalactam 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			        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

## ETIOLOGIC DIAGNOSIS OF COMMUNITY-ACQUIRED PNEUMONIA(Templeton KE. CID 2005;41:345)

- _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

## 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 > 65 yrs		2.5
- 	Shock			18.3
- *Martinez JA. CID 2003; 36: 389

## Slide 12

## 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 yrs
- Lab evidence influenza:  12 (71%)
- Mortality:  5/17 (29%)
- PVL genes:  11/15 (85%)

## Slide 14

## Slide 17

## 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.  Antibiotics
- 		S. pneumoniae
- 	MRSA (USA 300)
- 	(Influenza)
- 3.	Miscellaneous issues
- 	Macrolide role
- 	Pulmonary      	Pharmacology
- 	Time to administer
- 	Mega databanks

## RECOMMENDATIONS FOR MANAGEMENT OF SINUTSITIS*

- Imaging not recommended for 	uncomplicated cases
- Bacterial cultures are not recommended
- Indication for antibiotics:
- 	•  Nasal pus, severe symptoms
- 	•  Symptoms > 7 days
- 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 at****5–7days  in pts with APBRS complicating a viral URTI**

**% Patients With Symptoms**

**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**

**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.**

**Notes:**
The duration of symptoms in rhinovirus RTIs is displayed.  Most of the symptoms should be resolved by about day 10-14.  However, if on days 5-7 or later, the symptoms worsen, then APBRS should be considered.

References:
1. Gwaltney JM, Jr., Hendley JO, Simon G, Jordan WS, Jr.  Rhinovirus infections in an industrial population. II. Characteristics of illness and antibody response. JAMA. 1967;202:494-500;  2. Sinus and Allergy Health Partnership (SAHP). Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg. 2004;130(1 Suppl):1-45.

## 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=108
- Clinical response	77%		83%
- Side Effects			  9%		21%
- Relapse				17%		21%

## SINUSITIS:  COCHRANE LIBRARY REVIEW (2003;CD000243)

- _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

## 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			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

## 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

## ANTIMICROBIAL ISSUES IN SINUSITIS

- Diagnostics – simple test
- Criteria for response

## ACUTE EXACERBATIONS OF CHRONIC BRONCHITIS:  PRACTICE GUIDELINESACCP, ATS, CTS (Chest 2006;129:104S)

- 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)

- 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

## Meta-Analysis of the Benefitsof Antibiotics in AECB

**–****1.0**

**1.0**

**–****0.5**

**1.5**

**0**

**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 Size**

**Saint S et al. *****JAMA*****. 1995;274:1131-1132.**

**Notes:**
Antibiotic treatment of acute exacerbation of chronic bronchitis (AECB) leads to improved outcomes.
A meta-analysis of published randomized trials was conducted to determine the effectiveness of antibiotics in treating AECB. The analysis included randomized, placebo-controlled trials that enrolled patients having an exacerbation of chronic bronchitis, those that used an antibiotic in the treatment group and a placebo in the control group, and those that provided sufficient data to calculate an effect size.
The overall summary effect size of the 9 trials satisfying all inclusion criteria was 0.22 (95% CI, 0.10–0.34), indicating a slight benefit in the antibiotic-treated group.
Analysis of 6 studies that included data on changes in peak expiratory flow rate revealed a summary effect size of 0.19 (95% Cl, 0.03–0.35) and a summary change in peak expiratory flow rate of 10.75 L/min (95% Cl, 4.96–16.54 L/min) in favor of the antibiotic-treated group. Hospitalized patients appeared to benefit more than outpatients, perhaps because they exhibit more complicating factors (eg, older age, comorbid illness) at the beginning of therapy.
These analyses demonstrate a statistically significant improvement due to antibiotic therapy in AECB, particularly if patients have at least 2 of the 3 cardinal symptoms: increased dyspnea, increased sputum volume, and increased sputum purulence.

References:
Saint S, Bent S, Vittinghoff E, Grady D. Antibiotics in chronic obstructive pulmonary disease exacerbations: a meta-analysis. JAMA. 1995;273:957-960.

## Slide 31

## Slide 32

## SEVERE EXACERBATIONS CHRONIC BRONCITIS:  CONTROLLED TRIAL WITH OFLOXACIN*

- _Method_:  Randomized placebo-controlled trial of severe AECB requiring mechanical ventilation
- _Results_:			 	Ofloxacin		Placebo
- 						n=47			n=46
- 	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 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 RESPONSETO 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; 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 technology
- Placebo – controlled trials
- H. hemolyticus – accounts for 40% of
- 	“H. influenza” (non pathogen)

## Return

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