1. Bacteremia and CRBSI as Labeled BSI Indications: A Regulatory History Alfred Sorbello, DO Medical Officer CDER/Division of Anti-Infective Drug Products

2. October 14, 20042 Historical Timeline   Pre-1992/1993 Labeled BSI Indications   1992 Points to Consider   1993 AIDAC Meeting   1998 AIDAC Meeting   1999 AIDAC Meeting   2004 FDA/IDSA/ISAP Workshop   2004 AIDAC Meeting

3. October 14, 20043 BSI Terminology for Antimicrobial Labeling   Historical Terminology – –Bacteremia – –Septicemia – –Bacteremia/Septicemia – –Bacterial Septicemia – –Septicemia (including Bacteremia)  Current Terminology –Site-specific infection (with Bacteremia)

4. October 14, 20044 Pre-1992/1993 Labeled BSI Indications   Bacteremia and septicemia were defined as infection accompanied by the following laboratory criteria   Bacteremia: one positive blood culture   Septicemia: two positive blood cultures   Data for approval were based on pooling of bacteremia cases from trials involving different sites of infection (lung, urinary tract)   Varied clinical context: transient bacteremias, bacteremias secondary to a known focal infection, and bacteremias of unknown origin

5. October 14, 20045 1992 Points to Consider: Site-specific Indications   1992 Points to Consider: The term “indication” refers to “the treatment of infection at a specified body site(s) due to a specified, susceptible microorganism(s)”   Accounts for differences in drug efficacy at different body sites   Allows demonstration of efficacy and safety from adequate and well-controlled studies   Allows description of drug effect in labeling www.fda.gov/cder/guidance/ptc.htm

6. October 14, 20046 1993 Anti-Infective Drug Advisory Committee   Discussion of the ACCP/Society of Critical Care Medicine Consensus definitions of sepsis and organ failure   Discussion of Bacteremic Sepsis as a proposed indication

7. October 14, 2004 Critical Care Medicine 1992; 20: 864-874 7 ACCP/Society of Critical Care Medicine Consensus Definitions   Infection: microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms   Bacteremia: the presence of viable bacteria in blood   Systemic Inflammatory Response Syndrome (SIRS): Systemic inflammatory response to various clinical insults manifested by 2 or more of:   Temperature >38º C or <36ºC   Heart rate >90 beats/min   Respiratory rate >20 breaths/min or PaCO 2 <32 torr   WBC>12,000 cells/mm 3, 10% bands

8. October 14, 20048 SIRS, Infection, and Sepsis Sepsis Bacteremia Adapted from Crit Care Med 1992;20:864-874. Non-infectious: Burns, ischemia, Pancreatitis, others

9. October 14, 20049 Bacteremic Sepsis   Defined as SIRS with infection associated with positive blood cultures (without concomitant hypotension, hypoperfusion, and organ dysfunction).   Issues: – –Clinically meaningful entity? – –Patient population heterogeneity – –Positive blood culture   adds specificity in confirming the identification of the infecting bacterium   ?represent an independent marker of prognosis – –Source for bacteremia   does efficacy in treating bloodstream infection extrapolate to comparable efficacy within body tissues at the source of the bacteremia?

10. October 14, 200410 1993 Anti-Infective Drug Advisory Committee   Concerns: – –“Bacteremia” and “septicemia” lacked specificity of definition as used pre-1993 – –Heterogeneity of patient populations – –Concerns about pooling data involving bacteremias of various sites of origin – –Insufficient data to clinically distinguish patients with sepsis/SIRS who have positive blood cultures from those without positive blood cultures

11. October 14, 200411 1993 Anti-Infective Advisory Committee   Recommendations: – –In defining an indication for an anti-infective drug, the site of infection was considered to be more important than the presence/absence of bacteremia – –Labeling should include bacteremia in the context of a site-specific indication – –Example: CAP with bacteremia

12. October 14, 200412 1998 Anti-Infective Drug Advisory Committee   Discussion of Bacteremia as an indication, including consideration of catheter-related bloodstream infections (CRBSI) – –Rising incidence of bacteremia due to resistant (Gram-positive) bacteria – –Increased incidence of IV catheter-related bacteremia and bacteremia without an identified source – –Using data involving bacteremic patients to supplement clinical trials data for other types of infections www.fda.gov/ohrms/dockets/ac/98/transcript/3456t2.pdf

13. October 14, 200413 1998 Anti-Infective Drug Advisory Committee   Bacteremia as an indication: – –Secondary bacteremias retained within the context of site-specific label indications – –Primary bacteremia as a potential new indication – –Catheter-related bacteremias as a focus for future studies

14. October 14, 200414 1998 Anti-Infective Drug Advisory Committee   Catheter-related BSI – –Increased incidence of catheter-related BSI – –Growing antimicrobial resistance and limited antibiotic treatment options – –Lack of controlled clinical trials for drug development   Criteria for catheter removal   Strict microbiologic criteria with less stringent clinical criteria   Number and source of blood cultures   DNA subtyping

15. October 14, 200415 1999 Anti-Infective Drug Advisory Committee   Draft Guidance for Industry on the Development of Antimicrobial Drugs for the Treatment of Catheter-related Bloodstream Infections (FDA/DAIDP CRBSI Working Group) www.fda.gov/cder/guidance/3385dft.pdf

16. October 14, 200416 1999 AIDAC: CRBSI Draft Guidance Discussion Issues   Heterogeneous patient population – –Underlying illnesses – –Types of catheters – –Varied causative microorganisms   Large sample size requirement – –Many patients screened to identify CRBSI – –Lack of catheter data – –Patients lack microbiologic data at test-of-cure   Lack of standardized disease definition   Lack of demonstrable treatment effect – –Low virulence bacteria of skin origin www.fda.gov/ohrms/dockets/ac/99/transcript/3558t1a.pdf

17. October 14, 200417 1999 AIDAC: CRBSI Draft Guidance Discussion Issues   Lack of standardized procedures for management of an infected catheter – –Criteria for proof of catheter infection   Lack of standardization – –one catheter-drawn and one peripheral blood culture, two peripheral blood cultures, catheter tip quantitative culture and blood culture, hub cultures – –Criteria for Catheter removal   Type of catheter   Suspected pathogen

18. October 14, 200418 1999 AIDAC: CRBSI Draft Guidance Discussion Issues   Microbiological Issues – –Limited availability of quantitative blood cultures   Differential blood culture time to positivity – –Concordance of catheter and blood culture isolates   Pulse field gel electrophoresis for S. epidermidis – –Test-of-cure blood cultures   would not be necessary in well, stable patients   As a secondary endpoint in patients where the catheter is retained

19. October 14, 200419 Historical Timeline   Pre-1992/1993 Labeled BSI Indications   1992 Points to Consider   1993 AIDAC Meeting   1998 AIDAC Meeting   1999 AIDAC Meeting   2004 FDA/IDSA/ISAP Workshop   2004 AIDAC Meeting