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U.S. Food and Drug Administration
Notice: Archived DocumentThe 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 It was current when produced, but is no longer maintained and may be outdated.
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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
I. Characterization of C3’quaternary ammonium cephalosporins class (4GCs)
II. Clinical indications of 4GCs in Europe
III. Mechanisms of resistance of 4GCs
IV. Susceptibility surveillance programs for E.coli and non typhoidal Salmonella
V. Summary and conclusions
4
• Penams (Penicillins)
• Cephems (Cephalosporins, Cephamycins, Oxa-1-cephems, Carbacephems, Isocephems)
• Monocyclic β-lactams (monobactams)
• Penems (carbapenems)
I. Classification - -lactam family
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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S
N
NH
COCH
R7
COO-
O
N+
Zwitterionic cephems (4GCs)
CefepimeCefpiromeCefquinome*
S
N
NH
COCH
R7
COO-
O
R
Monoanionic cephems (3GCs)
CefotaximeCeftriaxoneCeftiofur*Cefovecin*
S
N
NH
COCH
COO-
COO-
O
N+
Dianionic cephems (3GCs)
Ceftazidime
*Cephems only used in veterinary medicine
I. Characterization – Chemical structure of ESC
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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 β- lactamases
High affinity for Penicillin Binding Proteins (PBPs)
Nikaido et al., 1990; Pucci et al. 1991
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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
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II. Clinical indications of cefquinome in veterinary medicine in Europe
Cattle
injectable
Pig
injectable
Horse
injectable
Cattle
Intra-mammary
Clinical indications
Respiratory tract infectionsNeonatal E.coli septicemiaAcute E.coli mastitisFoot infections
Respiratory tract infectionsMastitis Metritis Agalactiae (MMA)MeningitisEpidermitisArthritis
Respiratory tract infectionsNeonatal E.coli septicemia
Clinical mastitis
Clinical
introduction
1994 1999 2005 1998
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III. Resistance mechanisms
• Outer-membrane Minor epidemiological impermeability relevance in Gram negative
• Efflux pump
• β-lactamases Major epidemiological relevance in Gram negative
• Penicillin Binding Relevance in Gram positiveProtein (PBP) alterations
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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)
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III. Mechanisms of resistance – Characteristics of ESBLs and AmpC
ESBL AmpCSelection All beta-lactams All beta-lactams (except 4GCs,
carbapenems)
Spectrum of hydrolysis
•Aminopenicillins-Carboxy-penicillins•Narrow spectrum cephalosporins•Extended spectrum beta-lactams
•Aminopenicillins •α-carboxy- and ureidopenicillins •Cephamycins •oximino-cephalosporins •aztreonam
Location Plasmid Chromosomal or plasmid
Nordmann P, 1998
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III. Mechanisms of resistance – Prevalence of AmpC in Europe
Bacterial species
AmpC
Human Vet (livestock)
E.coli +(since 1994)
(-)
Salmonella
enterica+
(since 1990)
(-)
(-): sporadic cases have been reported
Philippon A et al., 2002
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III. Mechanisms of resistance - Prevalence of ESBLs
in Europe
Bacterial species
ESBLs
Human Vet (livestock)
E.coli +(since 1988)
(-)
Salmonella
enterica+
(since 1992)
(-)
(-): sporadic cases have been reported
Lahey.org; Batchelor M et al., 2005; Miriagou V et al., 2004
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III. Mechanisms of resistance – Variety of ESBLs and AmpC
0
30
60
90
120
150
180
SHV TEM CTX-M CMY
N o
f va
rian
ts
Human
Veterinary
Great variety in human medicine
ESBL AmpC
Lahey.org; Batchelor M et al., 2005
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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
Hoban D et al., E-326, ICAAC 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
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IV. Cefepime susceptibility surveillance for E.coli and Salmonella
• SENTRY dataPercent of resistant E.coli and Salmonella spp. isolates collected in pediatric infections in Europe in 2004 to cefepime
Fedler KA et al., 2006
Bacterial species(Number of isolates)
% R cefepime
E.coli(663)
2.1
Salmonella spp.(73)
0
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IV. Cefepime susceptibility surveillance for E.coli and Salmonella
• EASSA dataSusceptibility of E.coli and Salmonella spp. isolates collected from healthy livestock at slaughter to cefepime
Animal species
E. coli(MIC90 µg/ml)
Salmonella spp.(MIC90 µg/ml)
1999-2001 2002-2003* 1999-2001 2002-2003*
Cattle 0.032(n = 664)
0.063(n = 490)
ND 0.125(n = 15)
Pig 0.063(n = 652)
0.063(n = 494)
0.125(n = 146)
0.125(n = 128)
Chicken 0.063(n = 802)
0.125(n = 481)
0.125(n = 118)
0.125(n = 62)
Bywater et al., 2004; *: unpublished data
No resistant isolate reported
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IV. Susceptibility surveillance - European surveillance programs
EARSSEuropean 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
In 2004 : 30119 isolates collected
Average resistance rate : 2.9%
Resistance breakpoints 1-32 µg/ml
• EARSS dataProportion of invasive E.coli isolates with resistance to 3GCs in 2004
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IV. Susceptibility surveillance - European surveillance programs
0
10
20
30
40
50
2001 2002 2003 2004*
% r
es
ista
nc
e
AmpicillinR>16 µg/mlCefotaximeR> 1 µg/ml
N=6396 N=10145 N=8669 N=10078
• 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
*: European enlargement and inclusion of Australia
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IV. Susceptibility surveillance - European surveillance programs
• Enter-net dataPercent 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
No resistance to ESC in Europe
cefotaxime R breakpoint > 1µg/ml
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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 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.