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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 of the use of 4 GCs in human and veterinary medicine in Europe - Slide 1

Slide 2

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
     
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 2

Slide 3

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)
 
 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 3

Slide 4

    I. Characterization – Chemical structure of ESC

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

Zwitterionic cephems (4GCs)
Cefepime
Cefpirome
Cefquinome*

Dianionic cephems (3GCs)
Ceftazidime

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

Slide 5

     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)
 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 5

Slide 6

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

 

 Cefepime – Cefpirome
(injectable)
Clinical indications

-Respiratory tract infections/pneumonia

-Bacteriemia/septicemia

-Complicated urinary tract infections (UTI)

-Biliary tract infections

Empiric therapy for neutropenic patients

Clinical
introduction
1993
 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 6

Slide 7

II. Clinical indications of cefquinome in
veterinary medicine in Europe

 

 Cattle
injectable
Pig
injectable
Horse
 injectable
Cattle
Intra-mammary
Clinical indications
  • Respiratory tract infections
  • Neonatal E.coli septicemia
  • Acute E.coli mastitis
  • Foot infections
  • Respiratory tract infections
  • Mastitis Metritis Agalactiae (MMA)
  • Meningitis
  • Epidermitis
  • Arthritis
  • Respiratory  tract infections
  • Neonatal E.coli septicemia
  • Clinical   mastitis
Clinical
introduction
1994199920051998
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 7

Slide 8

III. Resistance mechanisms  

 

  • Outer-membrane impermeability 
  • Efflux pump
Minor epidemiological  
relevance in Gram negative
  • ß-lactamases
Major epidemiological relevance in Gram negative 
  • Penicillin Binding Protein (PBP) alterations 
Relevance in Gram positive  
 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 8

Slide 9

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) 
 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 9

Slide 10

III. Mechanisms of resistance – Characteristics of
ESBLs and AmpC

 

 ESBL AmpC 
Selection   All beta-lactams All beta-lactams (except 4GCs, carbapenems
Spectrum of hydrolysis 
  • Aminopenicillins
     
  • a-Carboxy-penicillins
  • Narrow spectrum cephalosporins
  • Extended spectrum beta-lactams
     
  • Aminopenicillins
  • a-carboxy- and ureidopenicillins
  • Cephamycins
  • oximino-cephalosporins
  • aztreonam
     
Location Plasmid Chromosomal or plasmid 
 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 10

Slide 11

III. Mechanisms of resistance – Prevalence of AmpC
in Europe

 

 

AmpC

Bacterial speciesHumanVet (livestock)
E.coli

+
(since 1994)
 

(-)
 

Salmonella
enterica

+
(since 1990)

 

(-)
 

(-): sporadic cases have been reported
 
  
Philippon A et al., 2002
  
 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 11

Slide 12

III. Mechanisms of resistance - Prevalence  of
ESBLs in Europe
 

 

 ESBLs
Bacterial speciesHumanVet (livestock)
E.coli

+
(since 199)
 

(-)
 

Salmonella
enterica

+
(since 1992)

 

(-)
 

(-): sporadic cases have been reported
 
Lahey.org; Batchelor M et al., 2005; Miriagou V et al., 2004
 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 12

Slide 13

III. Mechanisms of resistance – Variety  of  ESBLs
and AmpC
 

 

Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 13

Slide 14

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
 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 14

Slide 15

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) 
       
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 15

Slide 16

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
 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 16

Slide 17

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

 

Bacterial species
(Number of isolates) 
 Cefepime 
Enterobacteriaceae
(3841) 
MIC50
MIC90
%R 
= 0.5 µg/ml
4 µg/ml
6.1 
E.coli
(723) 
MICI50
MIC90
%R 
= 0.5 µg/ml
1 µg/ml
4.4 
 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 17

Slide 18

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

 

Bacterial species
(Number of isolates) 
% R cefepime 
E.coli
(663) 
2.1 
Salmonella spp.
(73) 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 18

 

Slide 19

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
     

 

 E. coli
(MIC90 µg/ml)
Salmonella spp.
(MIC90 µg/ml)
Animal species1999-20012002-2003*1999-20012002-2003*
Cattle0.032
(n = 664)
0.063
(n = 490)
ND0.125
(n = 15)
Pig0.063
(n = 652)
0.063
(n = 494)
0.125
(n = 146)
0.125
(n = 128)
Chicken0.063
(n = 802)
0.125
(n = 481)
0.125
(n = 118)
0.125
(n = 62)
  No resistant isolate reported
 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 19

Slide 20

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
       
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 20

Slide 21

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

Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 21

Slide 22

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
      
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 22

Slide 23

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 

 

Year

Number of isolates

% of resistance

2005

794

0

1st quarter
2006

162

0

cefotaxime R breakpoint > 1µg/ml
 No resistance to ESC in Europe
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 23

Slide 24

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%) 
 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 24

Slide 25

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.
 
Aspects of the use of 4 GCs in human and veterinary medicine in Europe - Slide 25