# Presentation: 782954

## Bacteremia and CRBSI as Labeled BSI Indications: A Regulatory History 

- Alfred Sorbello, DO
- Medical Officer
- CDER/Division of Anti-Infective Drug Products

## 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

## BSI Terminology for Antimicrobial Labeling

- Historical Terminology
- Bacteremia
- Septicemia
- Bacteremia/Septicemia
- Bacterial Septicemia
- Septicemia (including Bacteremia)

- Current Terminology
- Site-specific infection (with Bacteremia)

## 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** ****	****	**

## 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**

## 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

## 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

- Critical Care Medicine 1992; 20: 864-874

## SIRS, Infection, and Sepsis

- Sepsis

- Bacteremia

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

- Non-infectious:
- Burns, ischemia,
- Pancreatitis, others

## 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?

## 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

## 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

## 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**

## 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

## 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

## 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**

## 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**

## 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

## 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

## 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