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U.S. Department of Health and Human Services

Animal & Veterinary

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Comments on CVM Approach: Microbiologist Perspective

SLIDE 1: A Microbiologist’s Perspective on the CVM Approach

Daniel F. Sahm, Ph.D.
MRL

SLIDE 2: Focus of Presentation

  • Background in clinical microbiology and antimicrobial resistance among human pathogens
  • Resistance is a complex microbiological and ecological issue
  • Presentation will focus on concerns regarding the strategic decision to use risk assessment modelling to address the issue

 

SLIDE 3: Resistance Among Human Pathogens 

With all the focus and attention there remain few, if any, definitive answers.

For example:

  • How truly prevalent are different resistance patterns?
  • How extensively are different resistance patterns distributed?
  • What are the ‘causes’?
  • Are they changing? If so, in what way and how fast?
  • To what extent are they clinically relevant?
  • Can they really be prevented ? Controlled?
  • Are proposed interventions sound ones?
  • How do we measure the success of interventions?


SLIDE 4:

Complexity of Resistance Among Human Pathogens

  • The emergence and dissemination of antimicrobial resistance, and its ultimate impact on human health, result from several complex interactions of human physiology, medical practices and advances, healthcare finances and policies, social and economic variables AND microbial genetics, physiology, and ecology.
  • Others are attempting to model this resistance


SLIDE 5:

  • Antimicrobial Use Alone = Resistance
  • Even if we had practiced “appropriate use” from the inception of the antimicrobial era, how do we know the resistance situation would be any different than it is today?

 

SLIDE 6: Antimicrobial Use Alone ¹ Resistance

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SLIDE 8: Impact of Veterinary Antimicrobial Use on Resistance in Human Pathogens?

 

Organism Antimicrobial Y2K %R Vet. Congener
S. pneumoniae Erthromycin 33% Tylosin, spiramycin
S. aureus Ciprofloxacin 38% Enrofloxacin, difloxacin
E. coli Ciprofloxacin 4% ß
  Ceftriaxone 0.4% Ceftiofur
C. freundill Ceftriaxone 11% ß
E.cloacae Ceftriaxon 22% ß
E.faecium Vancomycin 73% Avonarcin

How can risk be measured if resistance already exists in organisms of human origin?

 

SLIDE 9: Impact of Veterinary Antimicrobial Use on Resistance in Human Pathogens of Animal Origin?

SLIDE 10: Dume et al. JAMA 284:3151 (2000)

  • From 1996 to 1998, 13 of 4093 (0.3%) isolates found to be ceftriaxone-resistant (CMY-2 beta-lactamase)
  • Based on both our data and that of Dume et al. this resistance phenotype remains rare. Can the risk of such a rare event to human health be accurately modeled ?
  • Is the cause and the path of development of this resistance really known ?

 

SLIDE 11: Considering the Emergence of Ceftriaxone Resistance in Salmonella

  • CMY-2 is an AmpC-type beta-lactamase of Citrobacter origin
  • The enzyme is located on a transferable plasmid
  • Transfer of CMY-2 from Citrobacter to E.coli and Klebsiella has been well documented among human isolates
  • The AmpC enzyme is rare among Salmonella, but is intrinsic to C.freundii

 

SLIDE 12: Potential Paths to Ceftriaxone Resistance

 

SLIDE 13: Potential Paths to Ceftriaxone Resistance (Continued)

 

SLIDE 14: Fey et al. NEJM. 17:1242 (2000)

  • Using molecular typing (PFGE) documented apparent transfer of CMY-2 containing Salmonella from livestock to child
  • Not all isolates contained CMY-2 so penetration of plasmid(s) was not extensive (sporadic transfer from Citrobacter ?)
  • Could not establish use of ceftiofur in the herd

 

SLIDE 15:

  • The findings of Dume and Fey document that ceftriaxone-resistant Salmonella exist and may be, albeit rarely, encountered in humans in the United States
  • However, in neither report was “cause and effect” related to animal or human use of cephalosporins established

 

SLIDE 16: Issues

  • Without being able to model the emergence of resistance in either human or animal bacterial populations, how can we expect to reasonably model the risk of drug use in the animal population to human health
  • With regard to human health, the model approach is further complicated by the fact that for the vast majority of Salmonella infections antimicrobial therapy is not required. Also, how does the fact that other antimicrobial choices still exist enter into risk assessment ?

 

SLIDE 17: Issues

  • With the microbiological, ecological, and genetic phenomena surrounding antimicrobial resistance not well understood for human or veterinary medicine, alternatives to risk assessment models should be seriously considered.

 

SLIDE 18: Issues

  • More extensive and timely surveillance (e.g. NARMS) would provide one such alternative that could allow:
    • Monitoring of population shifts in MICs over time to detect subtle but perhaps significant shifts prior to emergence of frank resistance
    • Identify new resistance profiles in the context of the environment (e.g. drug use patterns)
    • Put resistance that is found in a clearer context of prevalence, geographical differences, etc. that would help us avoid unnecessarily sensationalizing findings

 

SLIDE 19:

Surveillance: Can be a key step in the process of gaining the knowledge necessary for making informed decisions.

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