# Presentation: 050691

## Epidemiological Evidence of Pathogen Load Effects

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

## 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)**

## 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 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

**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

**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

**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

**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 

**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)

**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

|  | Poultry | Swine | Cattle | Fish |
| --- | --- | --- | --- | --- |
| Salmonella | -, NS (3) | +, NS (3) | -, NS (3) |  |
| E. coli O157:H7 (STEC) |  |  | -, “+”, NS (4) |  |
| Campylobacter | -, NS (2) |  | NS (1) |  |

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

## 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

**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

**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

**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 **

## 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**

## 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**

## 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**

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

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- Chriel M, Stryhn H, Dauphin G. Generalised linear mixed models analysis of risk factors for contamination of Danish broiler flocks with Salmonella typhimurium. Prev Vet Med. 1999;40:1-17.
- 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.
- Irwin, R.J., McEwen, S.A., Clarke, R.C. and Meek, A.H. 1989  The prevalence and antimicrobial resistance patterns of verocytotoxin and non-verocytotoxin-producing *Escherichia coli* and* Salmonella* in Ontario broiler chickens. Can. J. Vet. Res. 53:411-418.
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