Epidemiological Evidence of Pathogen Load Effects

1
Epidemiological Evidence of Pathogen Load Effects

• Scott A. McEwen DVM DVSc
• Professor
• Department of Population Medicine
• Ontario Veterinary College
• University of Guelph

2
Overview

• 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)

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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

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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

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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

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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

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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. 1990161255-60
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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
Dec120852-64
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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)

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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

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Summary of Study Results Pathogen Load
,- direction of effect NS not
significant ( in parentheses of studies)
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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 (p0.1)

Herriott DE et al. J Food Prot. 199861802-807
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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. 199760466-470
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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 78205-219
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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. 1999401-17
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Summary

• 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

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Summary

• 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

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Conclusions

• 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

19

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