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u s food and drug administration
U.S. Food and Drug Administration

Notice: Archived Document

The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

aspects of the use of 4 gcs in human and veterinary medicine in europe

Aspects of the use of 4 GCs in human and veterinary medicine in Europe

Veterinary Medicine Advisory Committee

Public Hearing, 25 September 2006

Pr. André Bryskier, MD

aspects under review
Aspects under review
  • Characterization of C3’quaternary ammonium cephalosporins class (4GCs)
  • Clinical indications of 4GCs in Europe
  • Mechanisms of resistance of 4GCs
  • Susceptibility surveillance programs for E.coli and non typhoidal Salmonella
  • Summary and conclusions
slide4

I. Classification - -lactam family

    • Penams (Penicillins)
    • Cephems (Cephalosporins, Cephamycins, Oxa-1-cephems,
  • Carbacephems, Isocephems)
    • Monocyclic β-lactams (monobactams)
    • Penems (carbapenems)
  • C3’quaternary ammonium cephalosporins (4GCs) belong to the Cephem group.
  • Together with 3GCs, they are identified as extended spectrum cephalosporins (ESC)
slide5

I. Characterization – Chemical structure of ESC

CH

CO

N

H

CH

CO

S

N

H

S

R7

R7

R

N

N+

N

O

O

COO-

COO-

Monoanionic cephems (3GCs)

Zwitterionic cephems (4GCs)

Cefotaxime

Ceftriaxone

Ceftiofur*

Cefovecin*

Cefepime

Cefpirome

Cefquinome*

CH

CO

N

H

S

COO-

N+

N

O

COO-

Dianionic cephems (3GCs)

Ceftazidime

*Cephems only used in veterinary medicine

i characterization dual mode of action
I. Characterization – Dual mode of action
  • Rapid penetration of

the outer membrane

  • Rapid crossing of the

periplasmic space

  • Low affinity for β-

lactamases

  • High affinity for

Penicillin Binding

Proteins (PBPs)

Nikaido et al., 1990; Pucci et al. 1991

iii resistance mechanisms
III. Resistance mechanisms
  • Outer-membrane Minor epidemiological

impermeability relevance in Gram negative

  • Efflux pump
  • β-lactamasesMajor epidemiological relevance in Gram negative
  • Penicillin Binding Relevance in Gram positive

Protein (PBP)

alterations

iii resistance mechanisms major lactamases
III. Resistance mechanisms – Major β-lactamases

β-lactamases are divided in four classes

(Ambler classification)

  • Class A: Narrow- spectrum β-lactamases: TEM-1, TEM-2, SHV-1

ESBLs: TEM, SHV-derivatives, CTX-M

  • Class B: Metallo enzymes: carbapenemases
  • Class C: AmpC: FOX, MOX, CMY, ACC, etc.
  • Class D: Oxacillinases

Most important beta-lactamases are cephalosporinases (AmpC) and Extended Spectrum Beta-Lactamases (ESBLs)

iii mechanisms of resistance prevalence of ampc in europe
III. Mechanisms of resistance –Prevalence of AmpC in Europe

(-): sporadic cases have been reported

Philippon A et al., 2002

iii mechanisms of resistance prevalence of esbls in europe
III. Mechanisms of resistance - Prevalence of ESBLs in Europe

(-): sporadic cases have been reported

Lahey.org; Batchelor M et al., 2005; Miriagou V et al., 2004

iii mechanisms of resistance variety of esbls and ampc
III. Mechanisms of resistance – Variety of ESBLs and AmpC

ESBL

AmpC

Great variety in human medicine

Lahey.org; Batchelor M et al., 2005

iii mechanisms of resistance conclusions
III. Mechanisms of resistance - Conclusions
  • ESBL:
      • Broad spectrum of hydrolysis except carbapenems
      • Identified since 1988 in E.coli in human medicine
      • Great variety in human isolates
      • Sporadic cases in livestockin Europe
  • AmpC
      • Broad spectrum of hydrolysis except 4GCs and carbapenems
      • Identified since 1990 in human medicine
      • Some variants in human isolates
      • Sporadic cases in livestock in Europe
iv susceptibility surveillance programs for e coli and non typhoidal salmonella
IV. Susceptibility surveillance programs for E.coli and non typhoidal Salmonella
  • Published susceptibility surveillance data to

4GCs (cefepime) are limited

      • T.E.S.T and SENTRY surveillance programs identified as sources for human medicine
      • EASSA surveillance program for veterinary medicine
  • European surveillance programs are testing

3GCs as representatives of ESC

      • EARSS (ceftazidime, ceftriaxone, cefotaxime), Enter-net (cefotaxime)
iv cefepime susceptibility surveillance for e coli and non typhoidal salmonella
IV. Cefepime susceptibility surveillance for E.coli and non typhoidal Salmonella
  • T.E.S.T

Tigecycline Evaluation and Surveillance Trial

    • Collection of human clinical isolates from blood, respiratory tract, urine and other infections (skin, wound, fluids)
    • MIC determination of cefepime as tigecycline comparator by broth micro-dilution technique
    • Cefepime MIC interpretive criteria R≥ 32 µg/ml
  • SENTRY surveillance program
    • Funded 1993,
    • Collection of human clinical isolates
    • MIC determination of cefepime by broth micro-dilution technique
    • Cefepime MIC interpretative criteria R≥ 32 µg/ml
  • EASSA

European Antimicrobial Susceptibility Surveillance in Animals

    • Collection of foodborne and commensals bacteria from healthy animals

at slaughter

    • MIC determination of cefepime by broth micro-dilution technique
    • Cefepime MIC interpretative criteria R≥ 32 µg/ml
iv cefepime susceptibility surveillance for e coli
IV.Cefepimesusceptibility surveillance for E.coli
  • T.E.S.T data
  • Cefepime susceptibility data and percent of resistant Enterobacteriaceae and
  • E.coli humanclinical isolates collected in Europe in 2004-2005

Hoban D et al., E-326, ICAAC 2005

iv cefepime susceptibility surveillance for e coli and salmonella
IV. Cefepime susceptibility surveillance for E.coli and Salmonella
  • SENTRY data

Percent of resistant E.coli and Salmonella spp. isolates collected in pediatric infections in Europe in 2004 to cefepime

Fedler KA et al., 2006

iv cefepime susceptibility surveillance for e coli and salmonella20
IV. Cefepime susceptibility surveillance for E.coli and Salmonella
  • EASSA data

Susceptibility ofE.coli and Salmonella spp. isolates collected from healthy livestock at slaughter to cefepime

No resistant isolate reported

Bywater et al., 2004; *: unpublished data

iv susceptibility surveillance european surveillance programs
IV. Susceptibility surveillance - European surveillance programs
  • EARSS

European Antimicrobial Resistance Surveillance program

    • Funded by European Commission in 1999, partner of WHO
    • On going collection of antimicrobial susceptibility tests of invasive bacteria (Blood culture and CSF)
  • Enter-net
  • International surveillance network for enteric infections Salmonella, verotoxigenic E.coli (VTEC) and Campylobacter
    • Funded by European Commission in 1993, partner of WHO
    • International database of fully characterized bacteria including data on epidemiology and antibiotic resistance
iv surveillance surveillance european surveillance programs
IV. Surveillance surveillance - European surveillance programs
  • EARSS data
  • Proportion of invasive E.coli isolates with resistance to 3GCs in 2004

In 2004 : 30119 isolates

collected

Average resistance rate : 2.9%

Resistance breakpoints 1-32 µg/ml

iv susceptibility surveillance european surveillance programs23
IV.Susceptibility surveillance - European surveillance programs
  • Enter-net data
  • Percent of resistant Salmonella spp isolates to ampicillin (21.7 to 27.5 %)
  • and cefotaxime (0.2 to 0.4%) from 2001 to 2004

N=6396

N=10145

N=8669

N=10078

*: European enlargement and inclusion of Australia

iv susceptibility surveillance european surveillance programs24
IV. Susceptibility surveillance - European surveillance programs
  • Enter-net data

Percent of resistant isolates of E.coli (VTEC, environmental and animal reservoirs) to cefotaxime from 2005 to first quarter 2006

cefotaxime R breakpoint > 1µg/ml

No resistance to ESC in Europe

iv susceptibility surveillance conclusions
IV. Susceptibility surveillance - Conclusions
  • Resistance to ESC in human clinical cases
    • Approximately 3 % in E.coli isolated from invasive infections
    • Very low in Salmonella (< 1%)
    • Not found in VTEC (0%)
v summary and conclusions
V. Summary and conclusions
  • 4GC structure confers a low affinity for most β-lactamases including AmpC
  • Resistance due to ESBL emerged about 15 years ago and evolved to a great variety in human isolates
  • Only sporadic cases reported of ESBL and AmpC in veterinary medicine in Europe
  • No 4GC resistance in E.coli and Salmonella spp. in animals at slaughter

The use of cefquinome for more than 10 years in Europe has not promoted the emergence of resistance in human medicine.