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

2. Issues With Bacteremia As an Indication CAP UTI Bacteremia Meningitis Endocarditis Complicated IABD Osteomyelitis

3. 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

4. 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

5. 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

6. 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

7. Contaminant Septic Shock Metastatic Infection Resistance 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+ 23+ * Primarily with intravascular foreign bodies Organisms causing Bloodstream Infections

8. Staphylococcus aureus Lowy, FD New Engl J Med 1998

9. Uncomplicated S. aureus Bloodstream Infection Incremental diagnostic benefit 368 pts Uncomplicated SAB, any source, no metastatic infection, treated <=14d Cure233 (63.3%) Recurrence22 (6.0%) Attributable mortality27 (6.1%) Other mortality73 (19.8%) Pending/NA13 (3%) 177 pts Uncomplicated SAB, *Catheter Related, no met infection, treated <=14d Cure132 (75%) Recurrence8 (4.6%) (5 re-infections) Attributable mortality8 (4.6%) Other mortality26 (14.7%) Pending/NA3 (1.7%) *Presumed

10. 90 pts Uncomplicated SAB, Catheter Related, No met infection, treated <=14d Defervesce Within 72H and NEG F/U BCX Cure73 (81%) Recurrence3 (3%) (re-infections) Attributable mortality2 (2%) Other mortality12 (14%) 65 pts Uncomplicated SAB, Catheter Related, No met infection, treated <=14d Defervesce Within 72H and NEG F/U BCX and NEG Echo Cure57 (88%) Recurrence2 (3%) (re-infections) Attributable mortality1 (2%) Other mortality5 (7%) Uncomplicated S. aureus Bloodstream Infection Incremental diagnostic benefit (continued)

11. Total Patients Cure RecurrenceAttributable Other Mortality Mortality Uncomplicated S. aureus 368233 (63.3%) 22 (6.0%) 27 (6.1%) 73 (19.8%) any source, no metastatic infection Treated <=14d Uncomplicated SAB 177132 (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 6557 (88%)2 (3%) 1 (2%) 5 (7%) NEG echo Uncomplicated S. aureus Bloodstream Infection Incremental diagnostic benefit

12. 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)

13. 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

14. Inappropriate for studies: 1. S or S of metastatic disease on presentation 2. Removable focus not removed 3. Hardware in place*** 4. Neutropenia

15. *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

16. 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

17. Proposal 1. Change Definitions a. Uncomplicated BSI b. Complicated BSI c. Others

18. 2. Change Trial Design Proposal

19. 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.

20. 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

21. 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