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U.S. Food and Drug Administration. Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated. . Epidemiological Evidence of Pathogen Load Effects.

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u s food and drug administration
U.S. Food and Drug Administration

Notice: Archived Document

The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

epidemiological evidence of pathogen load effects

Epidemiological Evidence of Pathogen Load Effects

Scott A. McEwen DVM DVSc


Department of Population Medicine

Ontario Veterinary College

University of Guelph

  • Plausible mechanisms of pathogen load effects
  • Relevant information from non-food animal species
  • Characteristics of the epidemiological studies reviewed
  • Summary of evidence from food animal studies (excluding those with resistance as the outcome)
possible mechanisms
Possible Mechanisms
  • Increased susceptibility of animals to infection – reduced infectious dose
    • Treatment before exposure to the pathogen increases susceptibility to infection by suppression of normal flora, diminishing colonization resistance
    • Treatment during exposure to a resistant pathogen facilitates infection by the selective effect of resistance
possible mechanisms5
Possible Mechanisms
  • Increased duration of shedding &/or concentration in feces
    • Perhaps due to greater degree of colonization (intra- or extra-intestinal) &/or disruption of normal enteric flora
  • Decreased prevalence / duration of shedding due to treatment
epidemiological studies
Epidemiological Studies
  • Observational in nature
    • Natural exposure / infection
    • drug treatment as it occurs on real farms
  • Multiple causal factors can be investigated
    • Related to agent, host, environment
    • Can assess hierarchical / group effects
  • Must design & analyze carefully to avoid biases
  • Different study designs have strengths & limitations re: causal inferences
related evidence humans and companion animals
Related Evidence – Humans and Companion Animals
  • Several case-control studies in humans showed prior antimicrobial use as a risk factor for salmonellosis, and recently, campylobacteriosis (perhaps diminished “colonization resistance”)
  • Similar findings in hospitalized horses, dogs
  • Some evidence for causal role of antimicrobial treatment in clostridial enterocolitis of horses and rabbits
  • The above observations involve clinical disease, not subclinical infection
example human studies
Example – Human Studies
  • Case-control study - outbreak due to AM-sensitive strain of Salmonella havana
  • Antimicrobials taken a mean of 15.9 days before and stopped a mean of 7.9 days before onset
  • 31% of 35 case-patients had taken antimicrobials within 30 days of onset compared with 13% of age- and neighborhood-matched controls (matched odds ratio 4.3)

Pavia AT et al. J Infect Dis. 1990;161:255-60

example horses
Example – Horses
  • Case-control study - Salmonella saintpaul infection in hospitalized horses
  • Horses receiving parenteral antimicrobials were at 10.9 times greater risk of having S. saintpaul isolated than were horses not receiving parenteral antimicrobials

Hird DW et al. Am J Epidemiol. 1984 Dec;120:852-64

food animal epidemiological studies effect measures
Food Animal Epidemiological Studies - Effect Measures
  • Most studies measured farm-level culture status (prevalence)
  • A few assessed individual-animal status or proportion of herd shedding
  • Duration of infection/shedding, and concentration of pathogen in feces not measured explicitly (although prevalence is a function of incidence and duration of infection)
  • Most outcomes relatively unrefined (multiple serotypes, etc)
antimicrobial exposure measures risk factors
Antimicrobial Exposure Measures (Risk Factors)
  • Most studies also measured treatment at the herd level
    • Drug used for growth promotion yes/no
    • Some named specific drugs; others not
    • Groups treated therapeutically yes/no
  • A few assessed individual-animal treatment (not drug-specific)
  • None measured duration of treatment
  • Most treatment variables relatively unrefined
summary of study results pathogen load
Summary of Study Results – Pathogen Load

[+,- = direction of effect; NS = not significant; (# in parentheses = # of studies)]

example 1 e coli in cattle
Example 1 – E. coli in Cattle
  • Longitudinal study of 36 Pacific Northwest dairy herds; monthly fecal culture of heifer cattle
  • “Tentative” association of E. coli O157 prevalence with feeding of ionophores in heifer rations (p=0.1)

Herriott DE et al. J Food Prot. 1998;61:802-807

example 2 e coli in cattle
Example 2 – E. coli in Cattle
  • Cross-sectional study of U.S. feedlots identified factors associated with shedding of E. coli 0157
  • 63 of the 100 feedlots had at least one positive sample
  • No association between positive fecal samples and ionophore use, or with feeding antimicrobials

Dargatz DA et al. J Food Prot. 1997;60:466-470

example 3 salmonella in swine
Example 3 – Salmonella in Swine
  • Cross-sectional study of 353 Dutch pig farms – outcome was proportion of seropositive samples
  • Use of tylosin as an antimicrobial growth promoter in finishing feed associated with higher Salmonella seroprevalence

van der Wolf PJ. Vet Microbiol. 2001 78:205-219

example 4 salmonella in broilers
Example 4 – Salmonella in Broilers
  • Cross-sectional study of 3923 Danish broiler flocks – 12.6% S. typhimurium +ve
  • Use of unspecified antimicrobials was associated with reduced risk of Salmonella infection (in flocks from Salmonella-negative parent flocks)
  • Growth promoters not significantly associated with Salmonella infection

Chriel M et al. Prev Vet Med. 1999;40:1-17

  • A modest number of epidemiological studies assessed the effects of antimicrobials on fecal shedding with enteropathogens; none assessed carcass contamination
  • Most evaluated Salmonella, fewer Shiga toxin-producing E. coli and Campylobacter
  • Most studies sought to evaluate a broad range of potential risk factors; none were specifically designed to assess pathogen load
  • Given the exploratory nature of these studies, and the comparatively unrefined exposure and outcome variables used, important associations may have gone undetected
  • Future epidemiological studies should be specifically designed to assess pathogen load effects
  • Such studies are inherently post-approval
  • Most studies found no evidence of a pathogen load effect
  • Some found evidence of a protective effect; fewer found a positive effect
  • Overall, current epidemiological evidence suggests that undesirable pathogen load effects of antimicrobials used in Europe and North America, if they exist, are probably minor

Bibliography (For reference - not to be shown at meeting)

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  • Dargatz, D.A., Wells, S.J., Thomas, L.A., Hancock, D.D., Garber, L.P. Factors associated with the presence of Escherichia coli O157 in feces of feedlot cattle. J. Food Prot. 1997;60:466-470
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  • Hird DW, Pappaioanou M, Smith BP. Case-control study of risk factors associated with isolation of Salmonella saintpaul in hospitalized horses. Am J Epidemiol. 1984 Dec;120(6):852-64.
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