Bacteremia and CRBSI as Labeled BSI Indications: A Regulatory

History

Alfred Sorbello, DOMedical Officer

CDER/Division of Anti-Infective Drug Products

October 14, 2004 2

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

October 14, 2004 3

BSI Terminology for Antimicrobial Labeling

Historical Terminology– Bacteremia– Septicemia– Bacteremia/Septicemia– Bacterial Septicemia– Septicemia (including

Bacteremia)

Current Terminology– Site-specific infection

(with Bacteremia)

October 14, 2004 4

Pre-1992/1993 Labeled BSI Indications Bacteremia and septicemia were defined as

infection accompanied by the following laboratory criteria

Bacteremia: one positive blood cultureSepticemia: 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

October 14, 2004 5

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

October 14, 2004 6

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

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 PaCO2<32 torr WBC>12,000 cells/mm3, <4000 cells/mm3 or >10% bands

October 14, 2004 8

SIRS, Infection, and Sepsis

INFECTIONSIRSSepsis

Bacteremia

Adapted from Crit Care Med 1992;20:864-874.

Non-infectious:Burns, ischemia,Pancreatitis, others

October 14, 2004 9

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?

October 14, 2004 10

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

October 14, 2004 11

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

October 14, 2004 12

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

October 14, 2004 13

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

October 14, 2004 14

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

developmentCriteria for catheter removalStrict microbiologic criteria with less

stringent clinical criteria Number and source of blood culturesDNA subtyping

October 14, 2004 15

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

October 14, 2004 16

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 originwww.fda.gov/ohrms/dockets/ac/99/transcript/3558t1a.pdf

October 14, 2004 17

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 removalType of catheterSuspected pathogen

October 14, 2004 18

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

October 14, 2004 19

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