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 

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Aspects under review

1. Characterization of C3’quaternary ammonium cephalosporins class (4GCs)
2. Clinical indications of 4GCs in Europe
3. Mechanisms of resistance of 4GCs
4. Susceptibility surveillance programs for E.coli and non typhoidal Salmonella
5. Summary and conclusions
    

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I. Classification - b-lactam family

• Penams (Penicillins)
•  Cephems (Cephalosporins, Cephamycins, Oxa-1-cephems, Carbacephems,
  Isocephems)
•  Monocyclic ß-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) 

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    I. Characterization – Chemical structure of ESC

Monoanionic cephems (3GCs)
Cefotaxime
Ceftriaxone
Ceftiofur*
Cefovecin*

Zwitterionic cephems (4GCs)
Cefepime
Cefpirome
Cefquinome*

Dianionic cephems (3GCs)
Ceftazidime

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     I. Characterization – Dual mode of action

• Rapid penetration of the outer membrane
• Rapid crossing of the periplasmic space
• Low affinity for ß-lactamases
• High affinity for Penicillin Binding Proteins (PBPs)

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II. Clinical indications of 4GCs in human
medicine in Europe

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II. Clinical indications of cefquinome in
veterinary medicine in Europe

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III. Resistance mechanisms  

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III. Resistance mechanisms – Major ß-lactamases

ß-lactamases are divided in four classes
(Ambler classification)

- Class A: Narrow- spectrum ß-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) 
 

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III. Mechanisms of resistance – Characteristics of
ESBLs and AmpC

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III. Mechanisms of resistance – Prevalence of AmpC
in Europe

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III. Mechanisms of resistance - Prevalence  of
ESBLs in Europe  

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III. Mechanisms of resistance – Variety  of  ESBLs
and AmpC 

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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 livestock in 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

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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) 
     

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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

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IV. Cefepime susceptibility surveillance for E.coli

• T.E.S.T data
  Cefepime susceptibility data and percent of resistant Enterobacteriaceae and E.coli
  human clinical isolates collected in Europe in 2004-2005

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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

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IV. Cefepime susceptibility surveillance for
E.coli and Salmonella

• EASSA data
  Susceptibility of E.coli and Salmonella spp. isolates collected from
  healthy livestock at slaughter to cefepime 

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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
     

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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

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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  

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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 

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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%) 

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V. Summary and  conclusions

• 4GC structure confers a low affinity for most ß-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.