# Presentation: 201151

## 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

**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**

## I. Classification - -lactam family

-  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)**

## I. Characterization – Chemical structure of ESC

- S

- N

- N
- H

- CO

- CH

**R7**

**COO****-**

- O

**N****+**

**Zwitterionic cephems (4GCs)**

**Cefepime**
**Cefpirome**
**Cefquinome***

- S

- N

- N
- H

- CO

- CH

**R7**

**COO****-**

- O

**R**

**Monoanionic cephems (3GCs)**

**Cefotaxime**
**Ceftriaxone**
**Ceftiofur***
**Cefovecin***

**S**

**N**

**N**
**H**

**CO**

**CH**

**COO****-**

**COO****-**

- O

**N****+**

**Dianionic cephems ****(3GCs)**

**Ceftazidime**

- *Cephems only used in veterinary medicine

**I. Characterization – Chemical structure of ESC**

## 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

## 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 |

## 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 | 1994 | 1999 | 2005 | 1998 |

## 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 positive**
**	****Protein (PBP) **
**	****alterations ****	****	****	****	****	****	****	****	**

## 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 – Characteristics of ESBLs and AmpC

|  | ESBL | AmpC |
| --- | --- | --- |
| Selection  | 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

## 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

## 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

## III. Mechanisms of resistance – Variety  of  ESBLs and AmpC

**Great variety in human medicine**

**ESBL**

**AmpC**

- Lahey.org; Batchelor M et al., 2005

## 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**

## 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

**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

**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 |

## 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

| Bacterial species
(Number of isolates) | % R cefepime |
| --- | --- |
| E.coli
(663) | 2.1 |
| Salmonella spp.
(73) | 0 |

## 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**

| 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**

## 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

**In 2004 : 30119 isolates **
**collected**
**Average resistance rate : 2.9%**
- Resistance breakpoints 1-32 μg/ml

-  EARSS data
- 	**Proportion of invasive *****E.coli *****isolates with resistance to 3GCs in 2004**

## IV. Susceptibility surveillance - European surveillance programs

**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

## 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 |

**No resistance to ESC in Europe**

- cefotaxime R breakpoint > 1μg/ml

## 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

**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.**