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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

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• 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.