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Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment

Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment

Veterinary Medicine Advisory Committee
Public Hearing, 25 September 2006

Carl K. Johnson, D.V.M.
Director, Product Development and Regulatory Affairs
Intervet Inc. 
 

Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 1

Slide 2

Agenda

  • An introduction to cefquinome, a 4th generation cephalosporin for use in
    veterinary medicine
  • Overview of the Microbial Safety Assessment of cefquinome (CEQ), following
    FDA/CVM Guidance for Industry #152
  • Experience with 4th generation cephalosporin use in human and veterinary
    medicine in Europe since 1993 (Prof. André Bryskier)
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 2

Slide 3

Cephalosporins Used in Veterinary Medicine

Cefapirin, 1st Generation

Ceftiofur, 3rd Generation

Cefquinome, 4th Generation 

Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 3

Slide 4

Cefquinome

  • Molecular structure of 4GC:  zwitter-ionic
    • beta-lactam nucleus
    • quaternary ammonium
    • aminothiazolyl moeity
    • zwitter-ionic
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 4

Slide 5

Description of Cefquinome (CEQ)

  • Innovative ß-lactam antimicrobial (4th generation cephalosporin, 4GC):
    • Characterized by zwitter-ionic molecular structure
      • faster penetration of outer cell membrane (gram-negatives)
      • lower affinity to ß-lactamases
      • higher affinity to target penicillin binding proteins

                   ? Enhanced antimicrobial activity 

Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 5

Slide 6

Description of Cefquinome (CEQ)

  • Exclusively for veterinary medicine:
    • Europe (EU): since 1994 for prescription only use in cattle, followed
      by swine (1999), and horses (2005)
    • US: pending applications for treatment of bovine respiratory disease
      with two injectable formulations (by prescription only)
    • Not for use in feed and water
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 6

Slide 7

Mode of Action (4GC)

Binding of CEQ to PBP disrupts synthesis of peptidoglycan layer

Integrity of cell wall is compromised

Net result: cell death (bactericidal) 

Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 7

Slide 8

Overview of Microbial Safety Assessment for Cefquinome
(Guidance for Industry #152)
 

 

 HAZARD CHARACTERIZATIONDescription of hazard and conditions that influence its occurrence
RELEASEProbability of emergence of resistance
  • resulting from use of the drug in animals
EXPOSUREProbability of human exposure to bacteria of concern
  • via food-borne transmission
CONSEQUENCEPotential that human exposure to resistant bacteria results in adverse health consequence
  • estimated by medical importance of the drug class
RISK ESTIMATEIntegration of the above assessments to estimate the relative potential of an adverse human health impact
  • resulting from the proposed veterinary use
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 8

Slide 9

Food-borne Pathogens of Concern

  • GI #152: “…antimicrobial-resistant bacteria attributable to an animal-derived food
    commodity and treated with the human antimicrobial drug of interest”
  • Non-typhoidal Salmonella spp. are the relevant food-borne pathogens of interest
    • NARMS survey data
    • Enteric salmonellae are susceptible to CEQ
  • E. coli is also considered in the release assessment
    • E. coli is usually not associated with food-borne infections, except E. coli
      O157:H7 (for which there is zero tolerance in food)
  • Other food-borne pathogens - Campylobacter spp., and Enterococcus spp. - are
    not considered
    • CEQ is not active against these pathogens 
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 9

Slide 10

Hazard Characterization
Risk Assessment Hypotheses

  • The use of CEQ may cause resistance in Salmonella spp. (E. coli) present in the
    intestinal tract of the target animal, and
  • Resistant Salmonella spp. may contaminate the carcass at slaughter and may
    transfer to humans via food, and
  • Resistant Salmonella spp. may cause infections in humans, and when treated
    with a 4 GC, effectiveness may be compromised
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 10

Slide 11

Outcome of CEQ Microbial Risk Assessment

Using Guidance for Industry #152 (“Evaluating the Safety of Antimicrobial New
Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human
Health Concern”), it is shown that :

  • The overall risk estimate is MEDIUM for the proposed veterinary therapeutic use
    of CEQ in cattle
  • The proposed risk management measures minimize this risk and are consistent
    with antimicrobial prudent use guidelines
  • There is reasonable certainty of no harm to public health with regard to the
    proposed use
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 11

Slide 12

 

RELEASE: Emergence of
CEQ resistance in Salmonella and E. coli
Probability is MEDIUM as determined by: 
  1. Conditions of use are limited (therapeutic, parenteral, individual animal use only,
    for short duration)
  2. 4GCs are active against bacteria carrying the AmpC-type ß-lactamase resistance
    mechanism
  3. 4GC resistance is very rare (must have either non-transferable Outer Membrane
    Protein mutation plus enhanced ß-lactamase activity or Extended Spectrum
    ß-Lactamases [ESBLs] that confer resistance to 4GCs); furthermore, ESBLs
    have not been identified in isolates from US livestock 
  4. Susceptibility surveillance data for 4GCs for both human and veterinary 4GCs
    indicates no change in resistance patterns of relevant food-borne
    pathogens (ongoing surveillance in the US and EU since late 1990’s:
    sustained high level of susceptibility)
     
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 12

Slide 13

 

RELEASE: Emergence of
CEQ resistance
in Salmonella
and E. coli
 
1. Conditions of use of the two injectable formulations: 
  • Individual parenteral therapy of bovine respiratory disease data on CEQ-related residues demonstrate that
    • only very small amounts present in the intestinal tract of treated cattle, and
    • gastro-intestinal inactivation of CEQ
       
  • Short duration of treatment (daily injection for <1 week; single injection)
  • Use controlled by prescription only status

Only limited exposure of enteric pathogens to CEQ possible

 

Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 13

Slide 14

 

RELEASE:
Emergence of CEQ resistance
in Salmonella
and E. coli
   
2. 4GC activity against existing ß-lactam  resistance mechanisms 
  • The plasmid-encoded AmpC-like ß-lactamase CMY-2 is the most important ß-lactamase in Salmonella spp. and E. coli isolated from food-producing animals
  • CMY-2 confers resistance to most ß-lactams (including 3GCs), but not for carbapenems and 4GCs
  • CEQ does not induce Amp C-type ß-lactamases in  Salmonella spp., or E. coli
  • Extended Spectrum ß-Lactamases (ESBLs) have not been found in
    Salmonella spp. and E. coli isolated from US livestock

4GCs (incl. CEQ) do not select for most common ß-lactam resistance
mechanisms

 

Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 14

Slide 15

 

RELEASE: Emergence of
CEQ resistance
in Salmonella
and E. coli
 
3. Resistance mechanism relevant for 4GCs 
  • High level 4GC resistance requires:
    • A combination of both
      • changes in outer membrane protein (non-transferable chromosomal
        mutation) which decreases permeability and/or increases efflux, and
      • simultaneous enhanced ß-lactamase activity 
    • Specific ESBLs that confer resistance to 4GC

Low risk of emergence of resistance to 4GCs (as confirmed  by susceptibility
surveillance data)

 

Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 15

Slide 16

 

RELEASE: Emergence
of CEQ resistance
in Salmonella
and E. coli
 
4. Surveillance data (animal isolates) 
  • Sustained high level of susceptibility to CEQ post- approval (EU):
    • in Salmonella and E. coli (EASSA survey, 1999-01) 
  • Sustained high susceptibility to CEQ pre-approval (US):
    •  in bovine Salmonella (NARMS slaughter isolates, since 2000)
    • in bovine E. coli (Intervet feedlot survey, 2002)

No change observed in high level of susceptibility to CEQ

Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 16


Slide 17

 

 

RELEASE:Emergence of
CEQ resistance
in Salmonella
and E. coli
 
Susceptibility surveillance data (animal isolates)
 

Sustained high susceptibility to CEQ pre-approval
(US) in bovine Salmonella (NARMS
slaughter isolates, 2000-2003)

 

Year 2000 2001 2002 2003 
Number of isolates 1,720 897 702 671 
MIC50 (µg/ml) 0.06 0.06 0.120.06 
MIC90 (µg/ml) 0.25 0.5 1.0 0.5
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 17

Slide 18

 

RELEASE: Emergence of
CEQ resistance
in Salmonella
and E. coli
 
Susceptibility surveillance data (human isolates) 
  • Susceptibility to the 4GC cefepime:
    • nearly 100% in US isolates of Salmonella spp. and E. coli (SENTRY,
      1997-1999).
    • consistently above 98% from 1997 to 2003 in E. coli and Salmonella spp.
      obtained from US hospitals (TSN, Focus Bio-Inova)

Sustained high level of susceptibility to 4GC

 

Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 18

Slide 19

 

RELEASE: Emergence
of CEQ resistance
in Salmonella
and E. coli
 
Release Assessment Summary 
  • Exposure of Salmonella spp. and E. coli to CEQ is limited
  • CEQ does not select for the most prevalent beta-lactam resistance mechanisms
    (Amp C); ESBLs have not been found in food producing animals
  • Selective pressure leading to resistance emergence to 4GCs (incl. CEQ)
    is minimal
  • No change observed in high level of susceptibility to 4GCs (incl. CEQ)

The probability of the emergence of CEQ-resistant Salmonella (and E. coli)
in cattle is MEDIUM

 

Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 19

Slide 20

 

RELEASE: Emergence of CEQ resistantSalmonella,
E. coli MEDIUM
 
Probability of human exposure to Salmonella spp. via food-borne transmission
EXPOSURE: Human
exposure
to Salmonella spp.
  • Contamination of beef (USDA/FSIS) and milk (pasteurization)
    with Salmonella spp. is low:

 

Commodity % prevalence Salmonella Qualitative ranking 
Cows / bulls 

2.4 Low  

(<5%) 

Steers / heifers 

0.6 Low 

(<5%)
 

Ground beef 

2.8 Low 

(<5%) 

  • However, US per capita beef consumption is high 
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 20

Slide 21

 

RELEASE: Emergence of
CEQ-resistant
Salmonella
MEDIUM 
Exposure Assessment Summary
EXPOSURE:
Human exposure to Salmonella
MEDIUM
 
Probability of human exposure to Salmonella spp. from applicable food animal source
 Amount of food commodity being consumed    
Commodity contamination High Medium Low 
High (> 25%) 
Medium (5-25%) L
Low (< 5 %) 
Default values provided in FDA/CVM GI #152 for beef result in MEDIUM human exposure
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 21

Slide 22

 

RELEASE: Emergence of
CEQ-resistant
Salmonella
MEDIUM

Consequence Assessment Summary

 

EXPOSURE:
Human exposure to Salmonella
MEDIUM
CONSEQUENCE:
Human health
consequences
of R-salmonella
infection
Qualitative estimate of human medical importance of drug class

 

  • Potential human health consequences are assessed according to the relative
    importance of 4GCs in human medicine (Appendix A, GI #152)
  • Only 4GC approved in US for human use is Maxipime® (cefepime HCl)
  • Cefepime’s primary use in human medicine
    • sole agent approved for empiric monotherapy for neutropenic fever
    • used to treat enteric pathogens of non-food-borne disease
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 22

Slide 23

Rationale for ranking 4GCs as HIGHLY IMPORTANT (from
Appendix A, GI #152)

 

Criteria 

4GCs

Antimicrobial used to treat enteric pathogens that cause food-borne disease 

-
 

Sole therapy or one of few alternatives to treat serious human disease or drug is essential component among many antimicrobials in treatment of human disease 

+
(only for neutropenic fever associated with nosocomial infection)
 

Antimicrobials used to treat enteric pathogens in non-food-borne disease 

No cross resistance within drug class and no linked cross-resistance with other drug classes 

 - 

Limited risk in transmission of resistance elements within/across genera and species of organisms 

 - 


4GCs are classified as HIGHLY IMPORTANT

 

Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 23

Slide 24

 

RELEASE: Emergence of
CEQ-resistant
Salmonella
MEDIUM
  
EXPOSURE:
Human exposure to Salmonella
MEDIUM
Ranking may be conservative when noting the range of alternatives to 4GCs for treating infections associated with Salmonella spp. and E. coli as indicated by the Sanford Guide (2003)
CONSEQUENCE:
Human health
consequences
of R-salmonella
infection
HIGH

Salmonella spp.

E. coli
 

FluoroquinolonesBeta-lactams combined with beta-lactamase inhibitors
 CeftriaxoneFluoroquinolones
 ChloramphenicolTrimethoprim/sulfonamide combination
 Trimethoprim / sulfonamideNitrofurantoin
 AzithromycinCarbapenems
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 24

Slide 25

 

RELEASE: Emergence of
CEQ-resistant
Salmonella
MEDIUM
 

Overall Risk Estimation 

EXPOSURE:
Human exposure to Salmonella
MEDIUM
 
  • Consistent with GI #152 the overall risk estimate is MEDIUM (Category 2)
  • This estimate is conservative:
    • Design of GI #152 is conservative
CONSEQUENCE:
Human health
consequences
of R-salmonella
infection
HIGH
 
  • Release Assessment ranking of MEDIUM is related to resistance mechanism that is not prevalent
Overall Risk Estimate
MEDIUM
(Category 2)
 
  • While 4GCs are important for human medicine, there is a range of treatment alternatives to 4GCs
 
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 25

Slide 26

RISK
Management
Considerations

 

Approval conditions

Category 1 (High)
 

Category 2 (Medium)
 

Category 3 (Low)
 

Marketing statusa
 

Rx
 

Rx/VFD

Rx/VFD/OTC

Extra-label use (ELU)

ELU Restrictions

Restricted in some casesb

ELU permitted

Extent of use

Low

Low, medium

Low, medium, high
 

Post-approval monitoring (e.g. NARMS)

Yes

Yes

In certain cases

VMAC review considered

Yes

In certain casesb

No
 

a Prescription (Rx), Veterinary Feed Directive (VFD), over-the-counter (OTC)
b These risk management steps may be appropriate for certain Category 2 drugs that were ranked critically important for consequence assessment and ranked “high” for release or exposure assessment.
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 26

Slide 27

 

RISK
Management
Considerations
 
Conditions of use for the two injectable formulations of CEQ
limit the risk of the emergence of resistance
 
  • Both parenterally administered products will be used in individual animals for
    short duration, by prescription only
  • The extent of use is ranked LOW in accordance with FDA/CVM GI #152
  • CEQ will continue to be tested against isolates from the NARMS susceptibility
    surveillance program
  • The microbial safety of CEQ has been reviewed by FDA/CVM and by VMAC
  • Consistent with GI #152 no extra-label use limitations are deemed appropriate 
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 27

Slide 28

Conclusions

  • The overall microbial food safety risk estimate is MEDIUM
  • The conditions of use and proposed risk management measures are
    appropriate to minimize this risk and are consistent with prudent use guidelines
  • There is reasonable certainty of no harm to public health with   regard to
    microbial food safety for the proposed veterinary therapeutic use of CEQ
Introduction to Cefquinome (CEQ) and Overview of Microbial Safety Assessment - Slide 28