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. 

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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)

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Cephalosporins Used in Veterinary Medicine

Cefapirin, 1st Generation

Ceftiofur, 3rd Generation

Cefquinome, 4th Generation 

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Cefquinome

• Molecular structure of 4GC:  zwitter-ionic
  • beta-lactam nucleus
  • quaternary ammonium
  • aminothiazolyl moeity
  • zwitter-ionic

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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 

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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

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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) 

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

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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 

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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

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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

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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)
    

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• 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

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• 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

 

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• 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)

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• 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

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

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• 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

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• 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

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• Contamination of beef (USDA/FSIS) and milk (pasteurization)
  with Salmonella spp. is low:

• However, US per capita beef consumption is high 

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• 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

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

4GCs are classified as HIGHLY IMPORTANT

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RISK
Management
Considerations

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• 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 

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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