# Presentation: 324905

## Healthcare-Associated Pneumonia (HAP):Issues For Clinical Trials

**Donald E. Craven, MD**
**Professor of Medicine **
**Infectious Diseases Department **
**Lahey Clinic Medical Center**
**donald.e.craven@lahey.org**** **

**HAP-FDA 11/02**

**Notes:**
Major Hospital-acquired infection: Scariest
	Principles apply to NP  
	Prinicples apply to CAP
         Principles apply to other NI due to devices 
	VAP ==
	Themes:   Know how to begin and to STOP ABs

## HAP: Issues For Clinical Trials in 2002

**Epidemiology: definitions, emerging resistance  **
**	****      ****Early vs late, VAP, study populations            **
**	****      ****MDR strains; superinfection **
**Dx: HAP vs VAP: colonization vs infection**
**	****	****       ****Clinical Dx & CPIS ****	**
**            ****Quantitative cultures for VAP**
**3.    ****Rx:**** ****early, appropriate antibiotics **
**            ****Streamlining of broad spectrum AB Rx**
**            ****Duration of AB, microbiology, endpoints & outcomes**

## HAP Facts

**ET = 6 to 21-fold > risk **
**>50% ICU ABs **
**Early vs late onset**
**Crude mortality 20% to 50%**
**Attributable mortality ~ 30%**
**Cost in billions**

## Nosocomial Infections in Medical ICUs in the United States

**NNIS Data from 1992 to 1997 **
** ****181,993 Patients in 112 Medical ICUs**

**Richards  1999**

**Nosocomial Infections ****in Medical ICUs in the United States**

## Early HAP Players: No Risk Factors (< 5 to 7 Days of Intubation)

**Early HAP Players: No Risk Factors**** (**_**<**_** 5 to 7 Days of Intubation)**

**Pneumococcus**
**Haemophilus**
**Anaerobes***
**S. aureus**
**Mixed common**

**Fewer MDR strains **
**  ****Lower mortality**

## Late VAP Players (> 7 days): Risk Factors>MDR Pathogens & >Mortality

**MRSA (VRSA) **
**KES (ESBL)**
***P. aeruginosa***
***A. baumanii***** **
**B. cepacia**
**Stenotrophomonas**
**Legionella**
**Candida spp**

**The Dark Side**

## Risk Factors for MDR Pathogens

**135 pts with VAP; 57% had MDR pathogens**
**Risk Factors:**
** ****Late onset VAP: OR = 6.0**
** ****Prior AB (<16 days): OR = 13.5**
** ****Quinolones, 3rd cephs, imipenem: OR = 4.1 **
**Need broader spectrum initial VAP Rx**
**    ****Trouillet, *****AJRCCM***** 1998:157:531:**

## Etiology & Resistance by Site 

**%**

**Rello, AJRCCM, 1999**

## Genes & Virulence In All SpeciesWhich has greater genetic similarity? 

***E. coli***** K1 vs Toxigenic *****E. coli*****  0:157?**
**OR **
**The Two Individuals in the Next Slide? **** **

## E. coli strains = 50%

**Genetic Similarity of These Two = 98%**

**E. coli strains = 50%**

## Bacterial Virulence Among Species

**    ****MRSA & VISA genome**
**    ****70 virulence factors:**
**  ****toxin islands**
**  ****capsules**
**  ****resistance**
**     ****Hiramatsu, *****Lancet*****  2001**

***     ******P. aeruginosa e*****xotoxins**
**     ****S, T, U or PcrV****+****  **
** ****>**** ****cytotoxicity **
** ****< phagocytosis**
** ****> mortality (7-fold) **
**       ****Roy-Burman, *****J Infect Dis***** 2001**

## VAP: Colonization & Pathogenesis 

- Craven, Sem Resp Dis, 1996

## Diagnosis of VAP

**Diagnosis of VAP**

**Clinical Diagnosis**
**vs **
**Quantitative Cultures**

## Methods of Diagnosis 

**Clinical & CPIS score**
**Sputum GS, C & S**
**Urine antigens**
**QEA, *****blind***** BAL/PSB**
**     ****B-BAL, B-PSB****  **
**Assess outcomes **_**NOT**_** sensitivity or specificity**

**Gram Stain**

## Clinical Dx of  HAP 

***Clinical: fever, WBC, sputum;  (GS & C/S) ***
***New & persistent infiltrate***
**BCs or pleural fluid **
**CPIS **
**Dx = poor specificity**

**Empyema**

## Quantitative Bacteriology - VAP 

**UTIs >100,000 CFU/ml**** **
**IV catheters  **
** ****15 CFU - PVC **
** ****>100–1000 CFU - CVC**
**Wounds >1000/g of tissue**
**VAP  (CFU/ml)**
**PSB > 1,000**** **** **
**BAL > 10,000****  **
**QEA >100,000 **

## Blind Bronchoalveolar Lavage (BAL)

**Blind Bronchoalveolar Lavage (BAL)**

**CFU/ml**
** ****BAL > 10****4**

## Mortality

**Cost**

**Morbidity**

**Decreased**
**Device**
**Days**

**Decreased NI &**
**Superinfections**

**Decreased**
**Resistance**

**Stopping **
**Inappropriate**
**Antibiotics**

**HAP:**
**CPIS,**
**VAP: **
**Quantitative **
**Diagnosis**

## French Multicenter Study:Clinical vs “Invasive” Dx

**RCT of VAP outcomes; 413 pts in 31 ICUs**
**Clinical Dx (n=204) vs B-PSB/BAL (n=209)**
**Microbiology  **
**Outcomes **
**Fagon *****Ann Intern Med***** 2000; 132: 621**

## Microbiology 

**Fagon *****Ann Intern Med***** 2000;132:621**

** ***** p<.01 **

*****

*****

## Outcomes

*****

*****

*****

*** P <0.05**

**26%**

**Fagon *****Ann Intern Med***** 2000; 132: 621**

**16%**

## VAP Dx: Stopping Antibiotics! 

**Patients with (-) cultures; ABs STOPPED!**
**Why decreased mortality?**
** ****Reduced inappropriate AB?     **
** ****Reduced MDR superinfections?**
** ****Earlier evaluation of other sources? **

## Treating VAP

- Guidelines & Reality

## Treating HAP is a Dynamic Process!

**Assess severity (CPIS), risk factors; obtain blood & sputum cultures**
**Begin appropriate ABs**
**Clinical response & **
**     ****adjust AB regimen**

## Mortality Related to Initial AB Therapy 

*****

*****

*****

*****

**Crude Mortality (%)**

*** P<0.05**

## CPIS,Early, Appropriate & Adjusted AB Therapy  

**Singh, AJRCCM, 2000**
**Ibrahim,  Crit Care Med, 2001**
**Dennesen, AJRCCM 2001**

## CPIS Point Scoring 

**Fever****: (1-2 points)**
**WBC****: <4 or >10K (1); bands >50% (1)**
**ETA****: purulent (1-2); + GS**
**Oxygen****: PaO****2****/FiO****2**** mmHg <240; PAW**
**CXR****: diffuse (1); localized (2)**
*** Day 3  ****CXR progression (2)**
******* ****Day 3****  Cultures: pathogen mod (1); GS (1)**

**Pugin, ARRD, 1991:143:121, Singh, AJRCCM 2000; 162:505-511**

## Use of CPIS Score for Short Course Therapy

**Suspected NP/VAP**
**CPIS **_**<**_** 6**

**Cipro x 3 Days**
**N = 39**

**Day 3**
**CPIS > 6**

**OUTCOMES**

**Day 3**
**CPIS **_**<**_** 6**

**Standard Rx**
**N = 42**

**STOP Rx**

**Rx**

**Singh, AJRCCM 2000; 162:505**

## Outcomes for Short Course Therapy 

*****

*****

*****

*****

*** P<0.01**

## Clinical Guideline to Treat VAP  

**48**

**94**

**Appropriate Initial Rx (%)**

**Ibrahim, Crit Care Med; 2001**

**P<0.001**

## Pathogens Not Treated With Appropriate Antibiotic Therapy Before & After A Guideline 

**No. of Patients**

**Ibrahim Crit Care Med 2001**

## HAP: The “Liberal” Approach

**Failure to recognize**
** ****HAP**
**Lack of AB efficacy**
** ****due to resistance**
**Increased mortality due to ineffective antibiotics**

**+**

**Therefore, Use More Antibiotics**

## HAP: The “Conservative” View

**Increasingly ill patients**
**	**
**	****       **
**	****	**** ****MDR pathogens**
**Loss of effective ABs **
**? Secondary to overuse**

***Therefore, Use Fewer Antibiotics***

**+**

## HAP: The Right “Best” Way

**Avoid inadequate Rx of HAP:**
**     ****Use “liberal” ABs  for initial Rx based on clinical Dx, guidelines & local resistance data**
**Avoid excessive ABs:**
**     ****Modify Rx of VAP based on clinical data, cultures**
**     ****Stop therapy if there is no VAP**
**     ****Use ID/Pulmonary consultants**

## Severe VAP: Antibiotics 

**GNR + Pseudomonas**
**Cefepime or ceftazidime**
**+/- aminoglycoside**
**MRSA?**
**Vancomycin**
**Atypicals: Legionella**
**Ciprofloxacin Azithromycin**
**Anaerobes**
**BL/BLI, clindamycin**

## Clinical Response to Antibiotic Therapy

**Dennesen, AJRCCM 2001: 163: 1371-75**

## HAP Suspected

**Check CPIS Score**
**Obtain Cultures***

**Early, Appropriate AB(s)  Therapy: **
**Based on Severity of Disease & Risk Factors **

**Not Improved:****Alter  ABs? Dx?**
** ****Obtain Consult**

**Assess Clinical Response:  24 - 48 hr**
**Culture Data, CPIS, ETC.  **

**Improved:**
**?De-escalation of ABs**
**Rx: 7-14 Days**

## Break The Cycle

**Cost**

**Morbidity**

**Decrease**
**Device**
**Days**

**Decrease NI,**
**Superinfections **
**& Complications**

**Decrease**
**Resistance**

**Inappropriate**
**Antibiotics**

**VAP 2002:**
**Quantitative Dx, **
**CPIS,**
**Early, **
**Appropriate**
**AB(s) **
**&**
**Prevention**

**Break The Cycle**

## Before 

- by a new idea,
- never regains its original dimension.
- -- Oliver Wendell Holmes

**Before **

**After**