Bacteremia and CRBSI as Labeled BSI Indications: A Regulatory History

1
Bacteremia and CRBSI as Labeled BSI Indications
A Regulatory History

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

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

3
BSI Terminology for Antimicrobial Labeling

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

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

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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

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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
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

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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 gt38º C or lt36ºC
• Heart rate gt90 beats/min
• Respiratory rate gt20 breaths/min or PaCO2lt32 torr
• WBCgt12,000 cells/mm3, lt4000 cells/mm3 or gt10
  bands

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SIRS, Infection, and Sepsis
Bacteremia
Sepsis
Non-infectious Burns, ischemia, Pancreatitis,
others
Adapted from Crit Care Med 199220864-874.
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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?

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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

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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

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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
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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

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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

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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
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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
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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

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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

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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