Bacteremia and Endocarditis: Products and Guidance

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Bacteremia and Endocarditis Products and Guidance

• Janice Soreth, MD
• Director
• Division of Anti-Infective and Ophthalmology
  Products

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PDR Search Products Labeled for
Endocarditis/Bacteremia

• Imipenem
• Cefazolin
• Gentamicin
• Vancomycin
• Nafcillin
• Oxacillin

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Imipenem

• Bacterial septicemia. Enterococcus faecalis,
  Staphylococcus aureus (penicillinase-producing
  strains), Enterobacter species, Escherichia coli,
  Klebsiella species, Pseudomonas aeruginosa,
   Serratia species, Bacteroides species including
  B. fragilis
• Endocarditis. Staphylococcus aureus
  (penicillinase-producing strains)

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Cefazolin

• Septicemia   Due to S. pneumoniae, S. aureus, P.
  mirabilis, E. coli .
• Endocarditis   Due to S. aureus (including
  (beta)-lactamase-producing strains) and S.
  pyogenes .

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Vancomycin

• Vancomycin is indicated for the treatment of
  serious or severe infectionscaused by susceptible
  strains of methicillin-resistant
  (beta-lactam-resistant) staphylococci. It is
  indicated for penicillin-allergic patients, for
  patients who cannot receive or who have failed to
  respond to other drugs, including the penicillins
  or cephalosporins, and for infections caused by
  vancomycin-susceptible organisms that are
  resistant to other antimicrobial drugs.
  Vancomycin is indicated for initial therapy when
  methicillin-resistant staphylococci are
  suspected, but after susceptibility data are
  available, therapy should be adjusted
  accordingly.
• Vancomycin is effective in the treatment of
  staphylococcal endocarditis.
• Its effectiveness has been documented in other
  infections due to staphylococci, including
  septicemia, bone infections, lower respiratory
  tract infections, skin and skin structure
  infections.
• When staphylococcal infections are localized and
  purulent, antibiotics are used as adjuncts to
  appropriate surgical measures.

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Gentamicin

• Gentamicin has been found effective when used in
  conjunction with a penicillin-type drug for the
  treatment of endocarditis caused by group D
  streptococci.
• Gentamicin has also been shown to be effective in
  the treatment of serious staphylococcal
  infections. While not the antibiotic of first
  choice, gentamicin may be considered when
  penicillins or other less potentially toxic drugs
  are contraindicated and bacterial susceptibility
  tests and clinical judgment indicate its use.
• In the neonate with suspected bacterial sepsis or
  staphylococcal pneumonia, a penicillin-type drug
  is also usually indicated as concomitant therapy
  with gentamicin.

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Oxacillin
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Nafcillin

• Nafcillin is indicated in the treatment of
  infections caused by penicillinase-producing
  staphylococci which have
• demonstrated susceptibility to the drug.
• Culture and susceptibility tests should be
  performed initially to determine the causative
  organism and its susceptibility to the drug.
• Nafcillin may be used to initiate therapy in
  suspected cases of resistant staphylococcal
  infections prior to the availability of
  susceptibility test results.
• Nafcillin should not be used in infections caused
  by organisms susceptible to penicillin G.

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Design of Previous Studies for Bacteremia and
Endocarditis Claims (pre-1990s)

• Multicenter study of the comparative efficacy,
  safety, and tolerance of drug X and drug Y in the
  parenteral therapy of infections in hospitalized
  patients caused by susceptible pathogenic
  bacteria
• Infections studied in one trial included lower
  respiratory, skin, gynecologic, UTI, bone and
  joint, septicemia, and endocarditis, with
  treatment duration ranging from a week to a month
  or longer
• Experience in bacteremia or endocarditis usually
  in a handful, sometimes supplemented with case
  series or data from uncontrolled study

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1992 Points to Consider Document Endocarditis

• One open trial of at least 50 patients that
  establishes a predetermined overall clinical and
  microbiologic success rates is suggested.
• If there is not a reasonable mix of artificial
  and native valve, right and left sided disease,
  and acute versus subacute clinical presentations,
  such should be noted in the approved labeling by
  restricting the labeling in the INDICATIONS AND
  USAGE section of the product labeling to just
  those types of infection and populations actually
  studied.
• This trial should involve at least two
  investigators in different geographic areas.
  Pathogens listed would be determined on a
  case-by-case basis, taking into account various
  expected success rates for the treatment of
  specific pathogens.

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Anti-infectives approved for endocarditis post
1992 Guidance

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2004 AIDAC Recommendations to FDAon S. aureus
bacteremia indication

• Re-write the draft guidance on catheter related
  bloodstream infections to reflect the current
  reality of patient/public health needs and
  resources for drug development.
• Balance good science with practicalities of
  clinical trial design and conduct.
• Study patients with S. aureus bacteremia,
  including in a development program patients with
  defined sites of infection and concurrent
  bacteremia, as well as those without an
  identified organ site (primary).

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The Study

• Sponsor, Cubist Pharmaceuticals, designed and
  conducted a study in the treatment of patients
  with S. aureus bacteremia and endocarditis.
• Sponsor and FDA agreed upon the study design
• a randomized, open-label, controlled trial of
  daptomycin versus standard of care in a group of
  patients who have S. aureus in the blood, some of
  whom have endocarditis
• The study echos what physicians face the
  management of patients with staphylococcal
  bacteremia, including patients with endocarditis.
  

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Todays Agenda

• Overview
• Clinical Trial (Sponsor and FDA talks)
• Charge to the Committee

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Critical Path Initiative

• An attempt to bring attention and focus to the
  need for targeted scientific efforts, to address
  unmet medical need, and to improve the techniques
  and methods used to evaluate the safety, efficacy
  and quality of medical products as they move from
  product selection, design, mass manufacture, and
  use.