# Presentation: 693936

## Clinical Trials for 

**Clinical Trials for **
**Bloodstream Infection / Infective Endocarditis**
- G. Ralph Corey, MD
- Vance Fowler, MD
- Duke Clinical Research Institute
- April 15, 2004

## Issues With Bacteremia As an Indication

- CAP

- UTI

- Bacteremia

- Meningitis

- Endocarditis

- Complicated IABD

- Osteomyelitis

##                           1998 Anti-Infective Drugs Advisory     				    Committee 

- 		I. Bloodstream infection (BSI) of known tissue origin
- 		      *Cure of origin leads to cure of bacteremia
- 			UTI
- 			Pneumonia
- 			Intra-abdominal abscess

## 1998 Anti-Infective Drugs Advisory Committee (cont’d)

-      II. Bloodstream infection of known catheter origin
-    Removal of catheter and 1-2 of weeks of antibiotic leads to cure
- 		*S. aureus*
- 		*Enterococcus *spp*.*
- 		Candida
- 		Coagulase Negative Staphylococci

## 1998 Anti-Infective Drugs Advisory Committee (cont’d)

- Committee conclusions became guidelines for trials of anti-infective agents in patients with documented catheter-associated BSI

## Problems With This Approach

-  Requires _proof_ of catheter infection
-  Assumes that origin of BSI defines complication                  	potential
-  Combines virulent and less virulent organisms
-  Allows approval for more benign diseases without 	subsequent requirement for trials in life-threatening  	disease

## Organisms causing Bloodstream Infections

*S. aureus**    *          	Rare	        3+			4+		4+
- Coag Neg Staph         	 4+	       Rare	              1+ * 		4+
*Enterococcus*          	1+	        1+                               1+*		4+
- Gram negative	 	Rare	        4+	                             1+		4+
- Candida:
-        Normal host           	1+	        Rare                             1+*		1+
-        Compromised host      1+	         1+                                2		3+
- 																					* Primarily with intravascular foreign bodies

## Staphylococcus aureus

***Staphylococcus aureus***

**Lowy, FD *****New Engl J Med***** 1998**

## Uncomplicated S. aureus Bloodstream Infection 

**Incremental diagnostic benefit**
- 368 pts   Uncomplicated SAB, any source, no metastatic infection, treated <=14d
- 		Cure			233 (63.3%)
- 		Recurrence		22 (6.0%)
- 		Attributable mortality	27 (6.1%)
- 		Other mortality		73 (19.8%)
- 		Pending/NA		13 (3%)
- 177 pts  Uncomplicated SAB, *Catheter Related, no met infection, treated <=14d
- 		Cure			132 (75%)
- 		Recurrence		8 (4.6%) (5 re-infections)
- 		Attributable mortality	8 (4.6%)
- 		Other mortality		26 (14.7%)
- 		Pending/NA		3 (1.7%)
- 							*Presumed

## Uncomplicated S. aureus Bloodstream Infection 

- 		Cure			73 (81%)
- 		Recurrence		3 (3%) (re-infections)
- 		Attributable mortality	2 (2%)
- 		Other mortality		12 (14%)
-  65 pts   Uncomplicated SAB, Catheter Related, No met infection, treated <=14d 	Defervesce Within 72H and NEG F/U BCX and NEG Echo
- 		Cure			57 (88%)
- 		Recurrence		2 (3%) (re-infections)
- 		Attributable mortality	1 (2%)
- 		Other mortality		5 (7%)

**Uncomplicated *****S. aureus***** Bloodstream Infection **
**Incremental diagnostic benefit (continued)**

## Uncomplicated S. aureus Bloodstream Infection Incremental diagnostic benefit

**	****	****	****	**** ****	****	****	****	****Mortality****	****      Mortality**
**Uncomplicated *****S. aureus***    368		233 (63.3%)          22 (6.0%)	 27 (6.1%)	        73 (19.8%)
**any source, no**
**metastatic infection**
**Treated <=14d**
**Uncomplicated SAB**	         177		132 (75%)	              8 (4.6%)	   8 (4.6%)	         26 (14.7%)
**catheter associated** 		           	                               (5 re-infections)
**(CASAB), no met infection**
**Uncomplicated CASAB**       90	 	73 (81%)	                3 (3%)	     2 (2%)	         12 (14%)
**Defervesce within 72 H****	**                                                 (re-infections)
**and NEG F/U BCX**
**Uncomplicated CASAB**           65		57 (88%)		2 (3%)	       1 (2%)	           5 (7%)
- NEG echo

**Uncomplicated *****S. aureus***** Bloodstream Infection Incremental diagnostic benefit**

## New Definitions

**Uncomplicated BSI (all of the following):**
- 1. Health care associated BSI
- 2. No signs or symptoms of metastatic infection
- 3. Follow up blood cultures negative (24-48 hours)
- 4. Defervesce within 72 hours
- 5. No valvular disease (demonstrated preferably by 	 TEE for adults, TTE for children)*
- 6. Removable focus removed **
- 7. No hardware in place ***
- 8. Non-neutropenia (>500 neutrophil/cc or if known 	HIV patient CD4>200 cell/mm3)

## Complicated BSI:

-    A. For study purposes
-        1. Follow up blood culture positive despite removal of all 	      intravascular devices after initial blood culture
-        2. No signs and symptoms of metastatic disease upon 	      enrollment (exception-uncomplicated IE)
-        3. No hardware***
- Note:
-  Length of fever may be either less or greater than 72 hours
-  Echo not necessary before enrollment

## Inappropriate for studies:

- 	1. S or S of metastatic disease on presentation
- 	2. Removable focus not removed
- 	3. Hardware in place***
- 	4. Neutropenia

##  *Significant valvular heart disease is defined (by TTE or TEE) as:

- 	1. More than trivial insufficiency and/or more than mild 	    stenosis
- 	2. Congenital heart disease (not including mitral valve 	    prolapse unless meeting above criteria)
**** Primarily intravenous catheters**
***** Non-removable hardware is defined as:**
- 	1. Joint prostheses, plaques, screws, and rods
- 	2. Intravascular valves, vein filters, and stents/grafts placed 	    within 6 weeks of BSI

## Present Guidance 

**Present Guidance**
- 	1. Phase 2: randomized double blind study of cSSSi
- 	2. Phase 2: 2 randomized double blind studies of 	   		        uncomplicated BSI
- 			        (preferably superiority)
- 	3. Phase 3: randomized double blind study of 			                  complicated BSI
- Assumption I:
- 	Step 1 predicts success / failure in step 2
- 	Step 2 predicts success / failure in step 3
- Assumption II: Completion of step 1 leads to step 2 and step 2 leads to step 3

## Proposal

-        1. Change Definitions
-      a. Uncomplicated BSI
- 	 b. Complicated BSI
- 	 c. Others

## Proposal

**Proposal**

## 				 Fast Track

- 				 **Fast Track**
**  **    1. Phase 2: randomized double blind study of cSSSi
- 	2. 50 patient open label consecutive series with new
- 	     anti-infective in uncomplicated bloodstream infections
- a. Cure > 85% then proceed to large randomized,           	    double blind, Phase 3 trial in patients with both 	    complicated and uncomplicated disease
- b. Cure < 85% then proceed to randomized, double 	    blind Phase 2 trial in patients with uncomplicated          	    bacteremia only. After showing non-inferiority 	    proceed to Phase 3 trial with both uncomplicated  	    and complicated BSIs.

##                               Middle of the Road

- 	1. Phase 2: randomized double blind study of cSSSi
- 	2. Phase 2/3: large open label randomized study of 	    		 _all_  patients with SAB with adjudication 			every 5 cases

##                 Mimic Cardiology

- 	1. Test the drug in the disease of interest
- 	2. Start with both uncomplicated and complicated      	      BSI with case by case adjudication
- 	3. Prevents having the drugs “tested” in the 		     sickest patient with off label, unsupervised 		     use by practicing physicians