###### Section 3

**Nominal mean number of fluoroquinolone resistant *Campylobacter* cases
attributable to chicken, seeking care, treated with a fluoroquinolone
and therefore affected by the fluoroquinolone resistance**

+-------+------------------------------------------+-------------------+
| **Sym | **Description**                          | **Formula**       |
| bol** |                                          |                   |
+-------+------------------------------------------+-------------------+
| p~ca~ | Probability a *Campylobacter* case is    | Based on          |
|       | attributable to chicken                  | referenced        |
|       |                                          | estimates         |
+-------+------------------------------------------+-------------------+
| p~rh~ | Probability a *Campylobacter* case from  | Weighted estimate |
|       | chicken is fluoroquinolone resistant     | based on data     |
+-------+------------------------------------------+-------------------+
| λ3~n~ | Nominal mean number of fluoroquinolone   | =                 |
|       | resistant *Campylobacter* cases          | λ2                |
| λ3~b~ | attributable to chickens (non-bloody,    | ~n~\*p~ca~\*p~rh~ |
|       | bloody, invasive and total cases)        |                   |
| λ3~i~ |                                          | =                 |
|       |                                          | λ2                |
| **λ3  |                                          | ~b~\*p~ca~\*p~rh~ |
| ~T~** |                                          |                   |
|       |                                          | =                 |
|       |                                          | λ2                |
|       |                                          | ~i~\*p~ca~\*p~rh~ |
|       |                                          |                   |
|       |                                          | **= λ3~n~ +       |
|       |                                          | λ3~b~ + λ3~i~**   |
+-------+------------------------------------------+-------------------+
| p     | Probability a person with                | From Section 2    |
| ~mn,~ | campylobacteriosis seeks care            |                   |
| p~mb~ | (non-bloody and bloody)                  |                   |
+-------+------------------------------------------+-------------------+
| p     | Probability a *Campylobacter* case who   | Composite         |
| ~an,~ | has sought care is treated with an       | estimate based on |
| p~ab~ | antibiotic                               | data              |
+-------+------------------------------------------+-------------------+
| p~FQ~ | Probability a *Campylobacter* case who   | Weighted estimate |
|       | has sought care and has been treated     | based on data     |
|       | with an antibiotic is treated with a     |                   |
|       | fluoroquinolone                          |                   |
+-------+------------------------------------------+-------------------+
| λ4~n~ | Nominal mean number of fluoroquinolone   | = λ3~n~           |
|       | resistant *Campylobacter* cases          | \*p~              |
| λ4~b~ | attributable to chicken, seeking care,   | mn~\*P~an~\*P~FQ~ |
|       | treated with a fluoroquinolone and       |                   |
| λ4~i~ | therefore affected by the                | = λ3~b~\*         |
|       | fluoroquinolone resistance ( non-bloody, | p~                |
| **λ4  | bloody, invasive and total cases)        | mb~\*P~ab~\*P~FQ~ |
| ~T~** |                                          |                   |
|       |                                          | = λ3~i~ \*p~FQ~   |
|       |                                          |                   |
|       |                                          | **= λ4~n~ +       |
|       |                                          | λ4~b~ + λ4~i~**   |
+-------+------------------------------------------+-------------------+

**Overview for Section 3.**

##### Epidemiology of campylobacteriosis

Major differences in the epidemiology of common source outbreaks and
sporadic cases have been described in the literature (12, 14, 95). The
majority of *Campylobacter* cases are classified as sporadic cases
(single cases of campylobacteriosis), while outbreaks account for a
small proportion of all cases (11). In outbreaks, where a common source
was identified, the predominant source of infection was consumption of
unpasteurized milk, and less commonly involved contaminated water, or
poultry (9, 16, 95). The seasonality of outbreak related disease differs
from patterns observed for sporadic disease. Outbreaks peak in May and
October while sporadic disease cases occur throughout the year and peak
in the summer (61, 95, 96, 97) The proportion of disease due to person
to person transmission is considered low, as outbreaks of *C. jejuni*
and *C. coli* have rarely been identified in day care or nursing home
settings where transmission of disease may be more likely (96, 97).
Because outbreaks represent a small number of all cases and the
predominant type of infection is sporadic disease, the major focus of
this analysis was on risk factors for sporadic disease.

Sporadic campylobacteriosis accounts for more than 99% of all cases (95)
and consumption of chicken (14, 32, 42, 43, 45, 51, 52) especially
undercooked chicken (35, 45, 55) and handling or preparation of raw
chicken (52, 56, 62) are the major risk factors identified in
epidemiologic investigations. However, one study showed a protective
effect when handling or consuming meals prepared from whole chicken (1).
Cross-contamination of foods from contaminated poultry has been
demonstrated to be associated with certain kitchen practices involved in
the preparation of food (45, 62). Other risk factors for sporadic
disease identified in the literature are; consumption of contaminated
water (84) drinking unpasteurized milk or eating raw milk food products
(61) contact with pets or diarrheic animals (1, 64) and travel to
developing countries (92).

*Campylobacter* *jejuni* is the predominantly isolated *Campylobacter*
spp, accounting for more than 90% of human isolates. Other
*Campylobacter* spp may cause disease but are not routinely isolated
from cases of campylobacteriosis. When methods other than the commonly
utilized enrichment techniques are used in the isolation of
*Campylobacter*, such as filtration, other species are more commonly
found. This indicates that current culture methods are not sufficiently
developed to optimize isolation of all species of *Campylobacter*. The
lack of knowledge of the magnitude of disease caused by unculturable
*Campylobacter* spp potentially creates an unmeasurable impact on the
estimate of risk. In this assessment, we have assessed only the
measurable risk.

##### Sources of Infection and Level of Carriage

*Campylobacter* infections are predominantly foodborne infections
associated with animal derived food products (51). *Campylobacter* spp
are often found as commensal microbes carried in the intestines of food
animals and can contaminate food during slaughter and processing.
USDA-FSIS has recently conducted surveys of recovery rates and estimated
the mean number per unit (gram, cm^2^) of product for some of the major
foodborne pathogens found on raw animal products at slaughter and
processing. Raw product isolation rates vary by species, with turkeys
and chickens appearing to have the highest rates of *Campylobacter*
recovery (Table 1.2) (90, 103). Broilers carry the highest carcass and
ground product load (Most Probable Number \[MPN\]/cm^3^) of
*Campylobacter* when compared to other food animals at slaughter (108,
109) (Table 1.2), consistent with the repeated observations in
epidemiologic studies of the increased risk of campylobacteriosis
associated with exposure to chicken.

In other surveys of retail food products, *Campylobacter* was isolated
from: 2-20% of raw beef; 40% of veal; up to 98% of chicken meat; low
proportions in pork, mutton and shellfish; 2% of fresh produce from
outdoor markets and 1.5% of mushrooms (33).

##### Campylobacter Speciation

In some of the references cited for human campylobacteriosis in this
risk assessment the distinction between *C. jejuni* and *C. coli* was
not made. *Campylobacter* speciation has been difficult to determine and
the methods used to characterize the organisms have changed over time.
Currently methods are not standardized. Due to the lack of
standardization, laboratories have established unique methods for the
identification of *Campylobacter* spp. This can result in discrepancies
between laboratories (77). Often studies that were published in the
literature did not make the distinction between species and when the
distinction was made, the studies often relied solely upon biochemical
hippurate hydrolysis which does not identify hippurate negative *C.
jejuni* (99). Because of the potential for species misclassification,
additional tests using polymerase chain reaction (PCR) primers to
identify the hippuricase gene were added to protocols to identify
hippurase negative *C. jejuni*. Recently, PCR based assays have been
developed to allow genotypic species characterization (47). The majority
of human disease reported in the United States has been *C. jejuni,*
typically comprising over 90% of human isolates (95). The consistently
reported preponderance of *C. jejuni* human isolates made the lack of
speciation in studies of risk factors less relevant to human
campylobacteriosis.

##### Campylobacter Strains and Epidemiologic Typing Methods

Subtyping of *Campylobacter* strains using phenotypic methods such as
biotyping, serotyping, phage typing, and genotypic methods using pulsed
field gel electrophoresis, restriction endonuclease analysis,
ribotyping, multilocus enzyme electrophoresis (MLEE) and PCR
fingerprinting have all been used to characterize strains for
epidemiologic studies (34). Serotyping has identified similar strains
present in *C. jejuni* isolated from chickens, cattle and human cases
(76). For serotyped *C. coli* isolates, similar strains have been
identified in humans, swine and poultry (76). Using genotypic strain
typing methods, similar strains were identified in humans and poultry
(34, 64, 78).

Some researchers have proposed that genomic rearrangement may occur in
*Campylobacter* (44) suggesting that identification of strains using
genotypic methods may have less sensitivity and specificity than was
previously thought. However, in laboratory studies genomic instability
was not demonstrated in in-vitro and in-vivo tests (44, 121). Strain
typing using a gene, for example the *flaA* and *flaB* genes with
PCR-RFLP typing, is considered a sound epidemiologic tool for strain
identification (73, 75).

##### Other Sources of Human Exposure to Campylobacter:

#### Pet associated cases 

Acquisition of puppies and kittens and contact with diarrheic animals
has been shown to be associated with human campylobacteriosis (1, 85).
Cats and dogs, especially puppies and kittens have been identified as
potential sources of human infections (15, 79). Exposure to diarrheic
animals was a risk factor in one study and approximately 6.3% of cases
were attributed to this exposure (OR 4.3, 95% CI 1.9 to 9.7). Analysis
of isolates obtained from animals and ill persons in the same household
indicated the presence of similar Penner serotypes from both sources
(85).

#### Cattle (beef and raw milk) associated cases

*C. jejuni* is a commensal bacteria inhabiting the intestinal tract of
cattle (61). In Canada and Denmark, Penner serotypes and biotypes
identified in *C. jejuni* and *C. coli* isolated from cattle were
similar to and commonly isolated from human sources (39, 41). In one of
the surveys (39). *Campylobacter* spp were recovered from 50% of steers,
40% of bulls and heifers and 22% of cows. Carcasses are contaminated
with *Campylobacter* during slaughter and processing and the results of
recent estimates of prevalence and load surveys conducted by FSIS are
shown in Table 1.2.

Consumption of contaminated milk has often been associated with
outbreaks of disease (9, 97). Contamination of milk most often occurs
via exposure to feces but mammary excretion of *Campylobacter* has been
demonstrated (61, 65). In a survey of Tennessee dairies *C. jejuni* was
recovered from 12.3% of bulk tank raw milk samples (61).

A reduction in the number of outbreaks and associated cases has been
observed since 1987 when the FDA implemented a ban on the interstate
marketing of raw milk (46). The mean annual number of reported outbreaks
was much lower for the period after the 1987 ban compared to the period
before 1987 (1.3 vs. 2.7) (46). In 1995, for the 28 states that allowed
the intrastate sale of raw milk, it was stated that approximately 1% of
total milk sold was unpasteurized, although a source for this
consumption data was not provided. In Iowa, cases associated with the
consumption of raw milk were the result of the ready availability of
unpasteurized milk on farms where it was produced, never entering a
market (87). The number of reported outbreaks per 10 million
person-years in states that allowed the sale of raw milk was 0.14,
compared to 0.03 outbreaks per 10 million person-years in states where
the sale was illegal (46). It is difficult to assess whether a reduction
in disease rates may have changed after the 1987 FDA ban because raw
milk consumption data is not readily available and outbreaks associated
with exposure to raw milk have not been reported since 1992.

#### Water associated cases

Contaminated surface water has been associated with human outbreaks,
sporadic campylobacteriosis and as a source of infection for animals. In
the U.K., a spring was contaminated with *C. jejuni* that was only
present when other fecal indicator species were concurrently isolated.
The spring was monitored for a 12-month period and some biotypes of the
*C. jejuni* strains isolated from the groundwater were identical to
strains isolated from a dairy farm located within the same rainwater
catchment area (93). Contamination of municipal water sources has been
reported and is typically associated with large outbreaks in the
community. Drinking water contamination may occur from wild animal
reservoirs, especially birds and domestic animal sources by
contamination with feces (71, 84).

Isolation of *Campylobacter* from ground water occurs predominantly in
the spring and fall. *Campylobacter* in water may be difficult to
isolate as they may be present in low numbers, sub-lethally injured by
temperature extremes, osmotic stress, nutrient depletion, and by
competition from other organisms (68). They may enter a "viable but
non-culturable" state but maintain the ability to infect and cause
disease in people and animals (68). *Campylobacter* has been isolated
from stream water at 4 degrees C for 4 weeks. Isolation was temperature
dependent and duration of isolation was less at 25 degrees C compared to
4 degrees C. This indicates that environmental exposures may be
temperature dependent and the environment may provide a source of
*Campylobacter* that is the result of fecal contamination from animal
sources (57).

In a wastewater survey in the Netherlands, three sources of water were
tested for the presence of resistant *Campylobacter*. Poultry abbatoir
effluent and two sewage purification plants, one receiving mixed sewage
from poultry and humans and one not receiving meat-processing sewage,
isolated *Campylobacter* and conducted susceptibility testing.
Fluoroquinolone resistance in *Campylobacter* isolates was identified at
levels of 29%, 18% and 11% respectively, indicating that water can be a
medium for resistant and susceptible *Campylobacter* (87).

## [Turkey associated cases]{.underline}

The presence of *Campylobacter* in the intestinal tract of turkeys is
common. Of 650 cecal samples taken from turkeys on eight farms, 100%
were positive for *Campylobacter* and contamination of raw product can
occur during slaughter and processing (67). In the King County study,
cases exposed to processed turkey sandwich meats demonstrated an
increased risk of infection (RR 1.7, 95% CI 1.0 to 2.9) compared to
controls. In a companion survey of retail meats, fresh turkey samples
were contaminated with *Campylobacter* in 1.8% of samples (45). In a
study of members of a Southern California Health Maintenance
Organization, a significantly higher proportion of 11 bacteremic cases,
not associated with enteric symptoms, compared to 22 controls had
consumed processed turkey meat (45, 89). FDA has shown the persistence
of *C. jejuni* in processed meat for up to 21 days at 4 degrees C (57,
89). In an USDA-FSIS survey of turkey carcasses (110) and ground turkey
(109) the recovery of *Campylobacter* was 90% and 25% respectively.
Although the prevalence of carcass isolation was slightly higher than in
broilers, the level of contamination of the carcass was lower than the
level found on chicken carcasses and approximately half that of the
ground product.

[Swine associated cases]{.underline}

The majority of *Campylobacter* isolated from swine under currently used
microbial species typing is *C. coli* (4, 76) and is usually present in
pigs without signs of disease. *C. coli* recovered from swine and typed
using Penner serotyping indicated that pig serotypes do not appear to
overlap with human: serotypes in Denmark (76); biotypes in the
Netherlands (7); and biotypes and serotypes in the United States (72).
*C. coli* reportedly represents approximately 4 and 6 % of human disease
in the U.S. and Denmark respectively (23, 76). In studies to determine
risk factors for human disease, the finding of an association between
human illness and the consumption of pork is rare. One study in Norway
identified risk associated with consumption of sausages at a barbecue
that could not be attributed to cross-contamination from poultry (62).

[Sheep associated cases]{.underline}

Few investigations of *Campylobacter* have been conducted in sheep to
determine the frequency of isolation from sheep and sheep food products.
Little work characterizing strain serotypes, biotypes or use of genetic
typing methods has been reported for ovine associated *Campylobacter*
(4, 61).

[Shellfish and other associated cases]{.underline}

Few studies have shown an association between disease and exposure to
shellfish and other fish (45). *Campylobacter* have been isolated from
mushrooms (33) but little is known of other produce nor the magnitude of
human cases from exposures to these sources.

## [Human to human transmission]{.underline}

The amount of human-to-human transmission of *Campylobacter* is
considered to be low and infrequent outbreaks in day care settings and
nursing homes confirm the low risk of human to human spread of disease
(95).

Fluoroquinolones have been available for human use since 1986 when the
first drug was approved in the United States (91, 92). Emergence of
fluoroquinolone resistant human *Campylobacter* infections occurred
between 1996-8 (92). Although human fluoroquinolone use can lead to the
emergence of resistant isolates, human to human transmission of
*Campylobacter* is uncommon and is unlikely to contribute to a greater
proportion of resistant human infections relative to the contribution of
poultry associated resistant infections (91).

[Travel Associated Cases]{.underline}

In numerous studies, travel to developing countries has been associated
with increased risk of *Campylobacter* infection and since the late
1980's with quinolone resistant *Campylobacter* infections (13, 81, 91).

In the CDC FoodNet *Campylobacter* Case Control Study preliminary
results of 580 cases, the proportion of cases that traveled was 12.1%.
The level of fluoroquinolone resistance in the travelers was 37.5%,
higher than the overall level of *Campylobacter* fluoroquinolone
resistance in 1998 of 13.6% (23, 28).

##### Overview Summary

To summarize, sporadic disease represents the greater proportion of
human campylobacteriosis and although many other sources of infection
have been determined, consumption of chicken has been the most
consistently identified risk factor in epidemiologic studies. Strain
typing of isolates has confirmed epidemiologic findings, that similar
strains are present in humans and chickens, as well as other animal
species. Prevalence surveys indicate a high prevalence and burden of
*Campylobacter* *jejuni* and *C. coli* on chicken carcasses (Table 1.2).
*C. jejuni* is isolated from approximately 95% of human cases. The risk
assessment question was to determine the measurable impact of
fluoroquinolone resistant *Campylobacter* associated with the
consumption of chicken on the treatment of human campylobacteriosis.
This section determines the number of fluoroquinolone resistant human
cases attributed to consumption of chicken that are treated with a
fluoroquinolone.

The number of fluoroquinolone resistant cases attributed to chicken
related exposures was determined from the total number of cases using
the following parameters, (refer to Appendix B for summary reference to
mean expected estimates of each parameter):

-   Probability a *Campylobacter* case is attributable to chicken

-   Probability a *Campylobacter* case from chicken is fluoroquinolone-
    resistant

[Output]{.underline}: Nominal mean number of fluoroquinolone resistant
*Campylobacter* cases attributable to chicken

-   Probability a person with campylobacteriosis seeks care (Bloody
    diarrhea, Non-bloody diarrhea and invasive cases)

-   Probability a *Campylobacter* case who has sought care is treated
    with an antibiotic (no stool submitted or culture; culture confirmed
    cases: Bloody diarrhea and Non-bloody diarrhea; and invasive cases)

-   Probability that, for a *Campylobacter* case who has sought care and
    has been treated with an antibiotic, the antibiotic is a
    fluoroquinolone (no stool submitted or culture; culture confirmed
    cases: Bloody diarrhea and Non-bloody diarrhea; and invasive cases)

[Output]{.underline}: Nominal mean number of fluoroquinolone resistant
*Campylobacter* cases attributable to chicken, seeking care, treated
with a fluoroquinolone and therefore affected by the fluoroquinolone
resistance

**Parameter estimations**

[3.1 (p~ca~ ) Probability a *Campylobacter* case is attributable to
chicken: Chicken associated cases (Studies 1-2)]{.underline}[^1]

STUDY 1, Seattle-King County Study:

A case control study was conducted to explore a wide variety of
potential risk factors associated with sporadic campylobacteriosis
(travel, food, water, animal and human contacts) and to evaluate the
degree to which consumption of various meats played an etiologic role in
disease (45). The study was conducted from April 1982 to September 1983
of enrollees in the Group Health Cooperative (GHC), a 320,000 member
health maintenance organization located in Western Washington State.
Cases and controls were GHC enrollees and residents of King, and
southwest Snohomish Counties. Cases were identified as persons from whom
*C. jejuni* or *C. coli* was isolated from stool. Cases were excluded if
they did not have a telephone, had moved from the study area or did not
speak English. Only the first case from each household was included in
the study. Cases were matched to controls by age and month of case
interview and were interviewed an average of two weeks after onset of
symptoms. Of 32 randomly selected controls out of the total number of
526 controls and 90 contacts of controls that were cultured, no enteric
pathogens were isolated from either group. Risk factors identified in
this study were chicken consumption (relative risk (RR) 2.4, 95% CI 1.6
to 3.6), eating undercooked chicken (RR 7.6, 95% CI 2.1 to 27.6),
consumption of Cornish game hen (RR 3.3, 95% CI 1.1 to 9.8), processed
turkey meats (RR 1.7, 95% CI 1.0 to 2.9), shellfish (RR 1.5, 95% CI 1.1
to 2.1) and raw or rare fish (RR 4.0, 95% CI 1.1 to 14.5). (Table 3.1)

This study also surveyed practices relating to food preparation surfaces
on a "cutting board scale" that ranged from 0-10 points, higher scores
indicating safer practices. Controls scored higher on average than cases
and a linear trend in risk (p[\<]{.underline}0.02) was associated with
decreasing score on the "cutting board scale" that was strongest in
chicken consumers and absent in non-chicken eaters. Chicken consumption
was quite common in the study population and the estimate of the
etiologic fraction, the proportion of cases that would not have occurred
had chicken not been consumed, was **48.5%**, (CI 27.9 to 63.2). No
other fresh red meats or poultry were associated with
campylobacteriosis. Another survey conducted in King County was unable
to isolate *Campylobacter* from fresh fish and shellfish (45).

This study was limited to cases with enteric illness, submitting stools
for culture. The authors indicated a potential non-respondent bias due
to lack of participation by controls that may have resulted in a higher
estimate of the relative risk (RR 3.0) associated with chicken
consumption. The results of this study are now 17 years old and
exposures and other factors may have changed in the interim, potentially
affecting the level of risk attributable to chicken. Demographic
characteristics of the population, the frequency, preparation and amount
of chicken consumption, the proportion of the population consuming
chicken and many other factors may have changed since this study. For
example, the amount of chicken consumed has increased since 1982, and in
1998 people consumed 64.8% (77.5/47.02) more chicken, calculated in RTC
pounds consumed per capita (102, 103).

Table 3.1. Odds Ratios and etiologic fraction associated with
statistically significant exposure variables for campylobacteriosis,
April 1982-September 1983, Group Health Cooperative, King County,
Washington (Adapted from Table 4, Ref. 85)

  --------------------------- --------- ------------------- --------------
  Risk Factor                 Odds      95% Confidence      Etiologic
                              Ratio     Interval            Fraction

  Chicken Consumption         2.4       1.6-3.6             48.2

  Non-household member with   2.5       1.6-4.0             11.7
  enteritis                                                 

  Travel to underdeveloped    32.9      10.2-133.6          9.0
  countries                                                 

  Household member with       1.9       1.2-3.0             8.0
  enteritis                                                 

  Non-home well or surface    1.8       1.1-2.9             7.6
  water                                                     

  Any animal with diarrhea    4.3       1.9-9.7             6.3

  Raw Milk Consumption        4.6       2.1-10.4            5.2
  --------------------------- --------- ------------------- --------------

STUDY 2, University of Georgia Study:

In 1983-1984 at the University of Georgia a case control study was
conducted to identify risk factors for *C. jejuni* enteritis (32). Cases
were students ill with diarrhea that submitted a stool sample from which
*C. jejuni* or *C. coli* was isolated. Controls that were not ill were
matched to the cases by sex, residence and age (+/-5years). Interviews
were conducted by local public health personnel covering demographic,
clinical and other potential exposures. 95 students submitted stools
during the fall and winter quarters, all met the case definition and 45
were included in the study. In a breakdown of the 50 exclusions: 27
students were excluded because they could not be contacted, 11 refused
to be interviewed, five because a matching control was not found and for
seven cases a reason for exclusion was not given. Those excluded from
the study did not differ significantly from the included cases based
upon date of illness, sex, age, or campus residency.

Overall, 40 cases reported consumption of chicken, 9 undercooked chicken
and 11 reported contact with a cat. In an evaluation of the demographic
characteristics between the cases and controls, males were at greater
risk of infection than female students. One explanation proposed for
this difference was that male student cooking practices were less safe
than those of the female students.

In univariate analysis of potential risk factors, three statistically
significant factors were identified; consumption of chicken within six
days of onset of illness (odds ratio=4.7, p[\<]{.underline}0.02),
consumption of raw or undercooked chicken (odds ratio=9.10,
p[\<]{.underline}0.05) and contact with a cat in the week before onset
of illness (odds ratio 9.0, p[\<]{.underline}0.05). Multivariable
analysis indicated the same risk factors as in univariate analysis;
eating any undercooked chicken (odds ratio 48.7, 95% confidence interval
\[CI\] 2.1 to 1,135), eating any chicken (cooked only) (odds ratio 7.2,
95% CI 1.2-43.7) and contact with a cat (odds ratio 28.2 95% CI
1.02-777) (32). Those who had eaten raw or undercooked chicken were more
likely to have eaten barbecued chicken than the cases who had eaten
completely cooked chicken. No foreign travel or raw milk consumption was
reported by any of the respondents. Illness was not associated with
untreated water, contact with a dog or puppy, exposure to another person
with diarrhea, consumption of pork, beef, or turkey or place of food
preparation. The number of chicken meals consumed by cases peaked in the
period two to four days before onset of illness compared to the controls
where frequency of consumption was more consistent and only half as
frequent as cases. Illness was not associated with preparation of
chicken, consumption of chickens cooked whole or the duration between
preparation and consumption of chicken. Overall **66.7%** (95% CI 20.2
to 86.1) of cases were attributed to eating chicken (95).

Limitations of this study include the lack of representativeness of the
study population and the absence of some exposures, such as travel and
raw milk that are frequently associated with risk in the population at
large. In addition, the study was limited to enteric illnesses because
more invasive infections were not eligible for inclusion in the study,
although these usually comprise less than 1% of cases. These differences
result in difficulty in generalizing the findings to the United States
population but may represent the level of risk in some subgroups of the
population.

DISCUSSION: In the two case control studies there was an increased risk
of illness associated with consumption of chicken especially consumption
of undercooked chicken. One study indicated a risk associated with raw
milk consumption although the proportion of attributable risk was much
less than that attributed to chicken. The proportions of disease
attributable to chicken consumption were 48.5% and 66.7%. The higher
estimate of attributable risk from study 2 of 66.7% in the university
student population indicates that in some subgroups of the population
exposures are likely to differ and risk attributable to consumption of
chicken will vary accordingly. These estimates of the etiologic fraction
represent a range of risk that is likely to reflect the level of risk in
the early 1980's. More recent data do not exist for United States
populations.

ASSUMPTION: The current level of risk of contracting campylobacteriosis
from consumption of chicken is contained within the range of risk
ascertained from studies conducted in the 1980's.

DISCUSSION: The definition of the attributable risk included all cases
of disease which may be attributed to a specific risk factor (122, 83).
One limitation of epidemiologic tools used to determine the attributable
risk or etiologic fraction is that those cases that were exposed to the
risk factor of interest, even though the exposure may not have been the
cause of the disease, would be included in the calculated level of risk,
thereby potentially overestimating the level of actual risk. Conversely,
another limitation of the epidemiologic tools used to determine the risk
from the specific exposure of interest is that spread from the primary
source of the pathogen, in this case chickens, is not included in the
calculation of the level of risk. The magnitude of the bias introduced
by false associations with chicken exposures (false positive
associations) may well be much smaller than the lack of inclusion of the
undeterminable cases from spread of the chicken associated resistant
*Campylobacter* to other sources of human exposure as such a large
proportion of the population, over 80%, consumes chicken. In addition,
the risk assessment does not take into account the spread of the
pathogen from chicken to other food sources. This can occur from cross
contamination of other foods (29) or spread from chicken sources more
proximate to the farm. For example: from chicken litter to birds, insect
and water; use of chicken litter in aquaculture to fertilize fish ponds
and to increase the non-protein nitrogen content of cattle feeds.
Therefore, the risk assessment is likely to underestimate the overall
risk of acquiring a resistant *Campylobacter* infection from exposure to
chicken due to the spread of *Campylobacter*.

ASSUMPTION: The level of risk as calculated does not account for cases
originating from chicken and contaminating other foods or the spread
from chicken to other animal hosts and resulting in human exposure.

A Uniform distribution was used to model the uncertainty in the
proportion of *Campylobacter* illness attributed to domestically
consumed chicken, p~ca~. The Uniform distribution assigns the same
probability to all parameter values in its range, indicating maximum
uncertainty about the true parameter value. The lower and upper bounds
of the range of the Uniform are themselves unknown parameters. These
parameters were estimated from the confidence intervals for the
attributable risks from the two studies as follows.

Walter (122) demonstrated that for attributable risk estimator θ and ξ =
1 - θ, the log of ξ is asymptotically Normal. This is the basis for the
derivation of the confidence intervals for θ. If, then, θ~L~,θ~U~ are
the limits of a 95% confidence interval for θ, the uncertainty
distribution of log~10~(ξ) is modeled as

Normal {log~10~(1-θ),\[ log~10~(1-θ~L~) -- log~10~(1-θ~U~)\]/1.96}.

The uncertainty distribution for p~ca-min~ is based on the estimated 95%
confidence interval for the smaller attributable risk point estimate
48.5%, from Study 1, and is 10\^Normal(-0.66, 0.34). The uncertainty
distribution for p~ca-max~ is based on the estimated 95% confidence
interval for the larger attributable risk point estimate 66.7%, from
Study 2, and is 10\^Normal(-1.10, 0.89). These two Normal distributions
overlap very slightly; the smaller of p~ca-min~ and p~ca-max~ was taken
as the sampled value for the lower bound of the Uniform and the larger
was taken as the sampled value for the upper bound of the Uniform
uncertainty distribution for p~ca~.

That is,

p~ca-min~ = 10\^Normal(-0.66, 0.34),

p~ca-max~= 10\^Normal(-1.10, 0.89), and

p~ca~ = Uniform(MIN(p~ca-min~, p~ca-max~),MAX(p~ca-min~, p~ca-max~)).

[3.2 (p~rh~) - Probability a *Campylobacter* case from chicken is
fluoroquinolone resistant:]{.underline}

Ciprofloxacin is one of two antimicrobials used to monitor losses of
susceptibility to the class of fluoroquinolone drugs in the National
Antimicrobial Resistance Monitoring System: Enteric Bacteria (NARMS:EB)
and represents the most widely used member of the class in human
medicine. The breakpoint below which isolates are considered
susceptible, 4 mcg/ml, was formally established for other
*Enterobacteriaceae* by NCCLS and is used as a predictor of
*Campylobacter* susceptibility to Ciprofloxacin. The breakpoint
indicating loss of clinical effectiveness has not been set for
fluoroquinolone drug use in *Campylobacter* infections but a breakpoint
of 4 mcg/ml is used by many diagnostic labs and surveillance systems to
monitor shifts in susceptibility.

E-Test strips (AB BIODISK, Solna, Sweden) contain an antimicrobial
gradient on the opposite surface of a scale indicating increasing
concentrations of the test drug. Growth along the strip is inhibited
where the concentration of the drug exceeds the minimum inhibitory
concentration (MIC) of the microorganism being tested. *Campylobacter*
E-test MIC's to Ciprofloxacin have been compared with agar dilution
susceptibility testing and although the E-Test tended to produce lower
results, indicating higher activity than that observed on agar dilution
testing, the overall correlation of MIC's between methods was good at
90.4% of the tests in one study (53).

Fluoroquinolone resistance has been significantly associated with human
infections that are travel related (80, 92) foodborne, particularly
chicken associated infections (71) and treatment of human illness with a
fluoroquinolone (88).

580 isolates were obtained from the FoodNet catchment area from cases
enrolled in the *Campylobacter* Case Control Study. *C. jejuni*
comprised 92.4%, *C. coli* 2.7% and *C.* "other" 4.8% of the total
number of isolates. The isolates were cultured and speciated in clinical
laboratories and forwarded to the FoodNet State Health Department where
susceptibility testing was performed. Isolates (150/580) were forwarded
to CDC for NARMS:EB surveillance susceptibility testing using E-Test and
compared to state health department findings. The correlation of
susceptibility testing results between laboratories was good.

From the 580 isolates collected for the *Campylobacter* Case Control
study, the proportion of travelers and persons taking fluoroquinolones
prior to culture was calculated for susceptible and resistant isolates
for each state in the study, see Table 3.2 located at the end of Section
3 or the worksheet labeled "Data" in the Excel model. These proportions
were used to remove travelers and persons taking fluoroquinolones prior
to culture, adjusting total susceptible and total resistant NARMS:EB
isolates from each site for 1998 and 1999 (23, 24). Because the number
of isolates that were tested was disproportionately distributed by site
and the rate of resistance varied by site, the level of resistance was
weighted by the site population size to better represent the relative
contributions of each FoodNet site, Table 3.3 below (21, 22).

^Table\ 3.3\ Weighted\ levels\ of\ domestically\ acquired\ resistance\ by\ FoodNet\ site,\ 1998\ and\ 1999^1

  ------- -------- -------- -------- -------- -------- -------- -------- -------- ------------
  State   CA^2^    CT       GA       MD       MN       NY       OR       TN       Level of DA
                                                                                  Resistance
                                                                                  (%)

  1998    0.0176   0.0285   0.0241   0.0363   0.0164   0.0133   0.0059   ND       14.2

  1999    0.0172   0.0375   0.0587   0.0286   0.0288   0.0131   0.0064   0.0059   19.6
  ------- -------- -------- -------- -------- -------- -------- -------- -------- ------------

^1^See model data sheet for calculation of weighted levels of
domestically acquired resistance or Table 3.5 at the end of this section
^2^CA-California, CT-Connecticut, GA-Georgia, MD-Maryland, MN-Minnesota,
NY-New York, OR-Oregon, DA-Domestically Acquired, ND-Not Determined

DISCUSSION: It is difficult to know what proportion of resistance in
human campylobacteriosis may be attributable to a single commodity or
source of human illness when human exposures are multiple and varied. A
single source of resistant bacteria may be disseminated from its origins
or maintained in secondary hosts further spreading resistant
*Campylobacter* to additional sources of human exposure.

Fluoroquinolone use has been associated with the development of
fluoroquinolone resistance in *Campylobacter* in clinical trials in
poultry production units (58) in the Netherlands (36) and in the United
States (92) after the introduction of veterinary fluoroquinolones. In
countries where fluoroquinolones have been approved for human and
companion animal use but are not allowed in food animals the level of
fluoroquinolone resistance in food animals and human clinical cases is
low (8, 54)

An Extra Label Use Prohibition of fluoroquinolone use in food-producing
animals was published in 1997 (21CFR530.41), limiting food animal drug
use to species listed on the product label. Approvals of fluoroquinolone
drugs for use in animals include feline and canine oral and canine
injectable products (available beginning in 1989), poultry water soluble
and in-ovo injectable products (available in 1995) and feedlot cattle
injectable products (available beginning in October 1998). There are no
fluoroquinolones currently approved for use in swine.

Although drugs were used in humans and companion animals in the U.S.
since the late 1980's, domestically acquired levels of fluoroquinolone
resistance were not reported until 1996, after approval of the poultry
fluoroquinolones. The level of domestically acquired resistance in
Minnesota has increased annually from 0.8%, in 1996, to 4.2% in 1999
(92, personal communication K. Smith).

Campylobacteriosis is primarily an animal derived foodborne disease,
with the predominant source of human infections attributed to poultry
(32, 45, 51, 85). There is little surveillance data available to
describe the level of fluoroquinolone resistance in *Campylobacter*
isolated from other animal derived food and other food products in the
United States, either before or after the approval of these drugs for
food animal use. Chicken *Campylobacter jejuni* isolates collected in
1998 and 1999 indicated a level of 9.4% resistance to Ciprofloxacin (see
Section 4.2). Because there was no food animal fluoroquinolone use other
than use in poultry until late 1998, and only rare sporadic and isolated
resistance was observed prior to 1992 in human cases[^2] it is unlikely
that the increase in domestically acquired fluoroquinolone resistance
observed in people since 1996[^3] can be attributed to origins other
than poultry.

ASSUMPTIONS: The fluoroquinolone resistance observed in persons ill from
campylobacteriosis, (after removal of travelers, those who took a
fluoroquinolone prior to culture and those for whom the time of taking
the fluoroquinolone was unknown) is largely attributed to chickens.

DATA GAP: Quantification of the proportion of human disease attributable
to various sources and the determination of the level of resistance
carriage within the specific exposures would more precisely allow the
determination of the relative contributions of the various exposures to
fluoroquinolone resistant human disease. A model intended to determine
the human health impact of the level of resistance in *Campylobacter*
attributable to fluoroquinolone use in food animals will need to
distribute the burden of susceptible and resistant human disease amongst
many different food animal species and potentially other food sources.

From the CCC study the number of resistant cases: 1) who had traveled
internationally within the past 7 days; 2) who had taken
fluoroquinolones prior to submitting cultures; and 3) who did not
remember when the fluoroquinolone was taken, was known per catchment
site for the total number of resistant cases and the total number of
cases tested. From that it was possible to estimate the proportion of
all resistant isolates that came from cases who had either traveled
internationally or had taken a fluoroquinolone prior to culture at site
j. Call those proportions a~j~. Conversely, it was possible to estimate
proportion of all susceptible isolates that came from cases who had
either traveled internationally or had taken a fluoroquinolone prior to
culture at site j. Call those proportions b~j~. G~j~ is the number of
human isolates that tested positive for resistant *Campylobacter* for
site j, shown in Table 3.2 at the end of this section. F~j~ is the
number of human isolates that were tested for resistance that is found
by adding the number susceptible and the number resistant in the table.
F~j~ - G~j~ is therefore the number of susceptible isolates.

The parameter p~rh~ is then modeled as:

$$\begin{array}{r}
p_{\text{rh}} = \sum_{j}^{}{W_{j}\text{Beta}(g_{j} + 1,f_{j} - g_{j} + 1)} \\
\text{              }
\end{array}$$

for g~j~ = G~j~\*(1-a~j~)

and f~j~ = g~j~ + Binomial (ROUND(F~j~-G~j~)\*(1-b~j~),0),p~ca~)

[3.3 (λ3~n~, λ3~b~, λ3~i~, **λ3~T~**) -- Nominal mean number of
fluoroquinolone resistant *Campylobacter* cases attributable to chickens
(non-bloody, bloody, invasive and total cases):]{.underline}

The nominal mean number of people with fluoroquinolone resistant
*Campylobacter* infection from chicken is estimated as the nominal mean
number of *Campylobacter* illnesses times the proportion that are
chicken associated times the proportion of *Campylobacter* infections
from chicken that are resistant to fluoroquinolone. This is determined
separately for enteric *Campylobacter* infections with non-bloody
diarrhea, enteric *Campylobacter* infections with bloody diarrhea and
invasive *Campylobacter* infections and lastly, the three estimates are
summed.

[(λ3~n~, λ3~b~) *Enteric disease:*]{.underline}

##### (λ3~n~)Non-bloody diarrhea

λ3~n~ = λ2~n~\*p~ca~\*p~rh~

(λ3~b~) *Bloody diarrhea*

λ3~b~ = λ2~b~\*p~ca~\*p~rh~

[(λ3 ~i~) *Invasive disease*]{.underline}

λ3~i~ = λ2~i~\*p~ca~\*p~rh~

The distributions have the following characteristics:

  ----------- ----------------- -------------- -------------- --------------
  **Year**    **Model output**  **5^th^        **Mean**       **95^th^
                                percentile**                  percentile**

  **1998**    **λ3~n~**         57,255         106,485        176,009

              **λ3~b~**         11,807         37,454         90,295

              **λ3~i~**         29             46             68

  **1999**    **λ3~n~**         61,966         113,548        188,082

              **λ3~b~**         12,830         39,971         95,580

              **λ3~i~**         39             60             86
  ----------- ----------------- -------------- -------------- --------------

Therefore the sum of nominal mean number of fluoroquinolone resistant
*Campylobacter* cases attributable to chickens for non-bloody, bloody
and invasive cases is:

**λ3~T~ = λ3~n~ + λ3~b~ +λ3~i~**

The distribution has the following characteristics:

  -------------- ----------------- -------------- -------------- --------------
  **Year**       **Model output**  **5^th^        **Mean**       **95^th^
                                   percentile**                  percentile**

  **1998**       **λ3~T~**         77,373         143,985        241,459

  **1999**       **λ3~T~**         83,990         153,580        258,047

  **Difference                                    9,595          
  (99-98)**                                                      
  -------------- ----------------- -------------- -------------- --------------

![](media/image1.wmf){width="5.8in" height="3.6791666666666667in"}

Figure 3.1 Uncertainty distribution for **λ3~T~**

[3.4 (p~mn~, p~mb~) - Probability a person with campylobacteriosis seeks
care (non-bloody and bloody):]{.underline}

In the population survey, described in Section 2.1, the most important
factors in seeking care for acute diarrheal disease included having
fever, vomiting, "how sick they felt", stomach cramps, reporting blood
in stool and duration of diarrhea. The highest rates for seeking care
were amongst children less than 5 years of age, urban residents, and
those with health insurance. This estimate was for all diarrheal
illness, and not specific to campylobacteriosis.

##### (p~mn~)-- Reported **non-bloody** stool rate for seeking care

Of cases with a diarrheal illness and reporting non-bloody stools 20.5%,
a weighted estimate, sought care (131/609) (28).

##### (p~mb~)-- Reported **bloody** stool rate for seeking care

Of cases with a diarrheal illness and reporting bloody stools 33.2%, a
weighted estimate, sought care (9/30) (28).

In the model, these parameters were set equal to those of Section 2.1.
As in Section 2.1, the proportion of those seeking care with invasive
infection was estimated at 100%.

[3.5 (p~ab~, p~an~) - Probability a *Campylobacter* case who has sought
care is treated with an antibiotic (not submitting a stool, submitting a
stool and invasive disease):]{.underline}

Persons ill with campylobacteriosis may take antibiotics for their
illness with or without having sought care. The population survey
indicated 5.9%, a weighted estimate, of persons that do not seek care
with diarrheal illness take antibiotics, 28/524 (26). To assess the
magnitude of impact this group may have on the total number of persons
with a fluoroquinolone resistant illness taking fluoroquinolones, the
total number of persons was estimated. Approximately 153,580 persons
acquired fluoroquinolone resistant illnesses from chicken in 1999. Of
these 88% did not seek care and 5.9% reported taking an antimicrobial
(26). There were no data describing the types or sources of
antimicrobials that were actually used. From data reporting recorded
prescriptions of fluoroquinolones (69) it was determined that the cases
prescribed fluoroquinolones were likely to make a small contribution to
the total number of affected cases and hence were not included in the
modeled estimate of cases.

Those cases that seek care present to the physician with varying
severity of illness and complicating medical conditions. Cases that were
not requested to submit a stool for culture took antimicrobial drugs
less commonly than those submitting stools for culture did. Cases of
invasive disease represented severely ill patients that were all likely
to be prescribed antimicrobial drugs for their illness. Both of these
groups were included in the estimate of the number of affected
individuals.

*Campylobacter* Case Control Study Description, 1998-1999 (28)

A *Campylobacter* case control study was conducted at 7 FoodNet sites in
1998-1999 for a twelve-month period. (The start and end date of the
12-month enrollment period varied between sites). In total, 1,314
matched sets of case patients and controls were enrolled in the study.
The cases were defined as persons with diarrhea residing in the
catchment area with a *Campylobacter* infection identified by a clinical
laboratory isolation of *Campylobacter* from stool. Exclusion criteria
from the case-control study were persons whose primary residence was
outside the catchment area, persons without telephones, persons that
were non-English speaking or unavailable for interview (including dead,
and non-contactable). Additional exclusion criteria were persons not
reporting diarrheal symptoms, or who could not recall the date of onset
of their diarrhea, or whose onset of diarrhea was \>10 days before the
date of culture collection, or persons whose infections were outbreak
associated; persons were also excluded if another member of the same
household had a previous culture-confirmed infection within the past 28
days. A subset of case isolates were tested for antimicrobial
susceptibility, either at the CDC (4 sites CA, GA, MD, OR) or by their
own state public health laboratory as part of the study (3 sites CT, MN,
NY). The number of submissions varied by site and is shown in Section
3.2.

One control per case was interviewed, matched on age and telephone
exchange number of the case. Telephone interviews (using progressive and
sequential telephone digit dialing based on telephone number of the
case) were conducted within seven days of the matched case interview by
trained personnel using standardized questionnaires for cases and
controls. Questionnaires included questions about demographic
characteristics, symptoms of illness, treatment, potentially
complicating medical conditions, possible exposures such as travel,
foods consumed and hygienic practices. For the seven participating sites
during the study period, there were 3,860 reported *Campylobacter* cases
in surveillance; 2,870 were eligible to be in the study (Table 1.3),
1,461 cases were enrolled; 1,314 were matched with a control, resulting
in a 46% (1,314/2,870) enrollment rate for the case-control study.

##### (z) **Not submitting** a stool for culture

From the population survey, in the population seeking care, **38.1%**
(**44**/**116)** of persons not requested to submit a stool sample by
their health care provider took antibiotics for their illness (26). The
estimated probability for taking an antibiotic given that a stool was
not submitted, z, is estimated based upon 38.1%.

ASSUMPTION: The population survey proportion of cases of all acute
diarrheal illness seeking care, not submitting a stool sample and
receiving an antibiotic (38.1%) is similar to that for persons ill with
campylobacteriosis.

DISCUSSION: Severity of illness is one of many factors that lead
physicians to prescribe antibiotics to patients with a diarrheal
illness.

\(y\) ***Submitting** a stool for Culture*

Preliminary analysis of the CDC FoodNet *Campylobacter* Case Control
Study provided estimates of antibiotic use for culture confirmed cases
(28). The proportion of cases treated with antibiotics was 84.4%
unweighted estimate (488/578) and an overall summed weighted estimate of
83.1%. The individual state treatment rates were weighted: CA 8.9%
(11/12), CT 13.3% (162/192), GA 16.5% (30/32), MD 10.3% (19/21), MN
18.7% (199/242), NY 4.6% (59/68) and OR 11.0% (8/11) (28).

ASSUMPTION: Patients who have sought care and been requested to submit
stool cultures and have submitted stool cultures are prescribed
antibiotics at a rate that is the same whether they had bloody or
non-bloody diarrhea. Conversely, if patients have sought care but have
not been requested to submit stool cultures, they are prescribed at
another rate that is the same whether they had bloody or non-bloody
diarrhea.

The parameters p~an~ and p~ab~ are modeled as:

p~an~ = p~cn~\*y + (1-p~cn~)\* z

p~ab~ = p~cb~\*y + (1-p~cb~)\* z

where $y = \sum_{j}^{}{W_{j}\text{Beta}(D_{j} + 1,C_{j} - D_{j} + 1)}$,

z = Beta(116\*0.381+1, 116\*(1-0.381)+1)

and W~j~ are the weights for FoodNet sites as defined in section 1.9;
C~j~ is the number of culture-confirmed cases for whom it is known
whether they received an antibiotic or not for site j; and D~j~ is the
number of culture-confirmed cases who did receive an antibiotic, shown
in Table 3.4 below. z is the antibiotic prescription rate among patients
who have sought care but have not been requested to submit stool
samples.

y is the antibiotic prescription rate among patients who have sought
care and been requested to submit stool samples.

ASSUMPTION: Because of the severity of illness upon presentation, all
cases with invasive disease are presumed to seek care and are presumed
to take antibiotics for their illness. Therefore p~ai~ is taken to be 1.

Table 3.4 *Campylobacter* Case Control Study, unweighted and weighted
proportions treated with antimicrobials and weighted proportions treated
with fluoroquinolones, 1998-9 (Ref. 28)

+---+-------+-------+----------+-----------+--------+-------+-------+
| S | Weig  | N     | Number   | Number    | Unwe   | Wei   | Wei   |
| i | hting | umber | who were | who were  | ighted | ghted | ghted |
| t | Fra   | for   | treated  | treated   | prop   | propo | propo |
| e | ction | whom  | with     | with      | ortion | rtion | rtion |
|   |       | res   | ant      | Fluoro    | who    | who   | of    |
|   | W ~j~ | ponse | ibiotics | quinolone | were   | were  | those |
|   |       | was   |          |           | t      | tr    | tr    |
|   |       | known | D ~j~    | E ~j~     | reated | eated | eated |
|   |       |       |          |           | with   | with  | with  |
|   |       | C ~j~ |          |           | antib  | a     | antib |
|   |       |       |          |           | iotics | ntibi | iotic |
|   |       |       |          |           |        | otics | rece  |
|   |       |       |          |           | \[%\]  |       | iving |
|   |       |       |          |           |        | (P    | F     |
|   |       |       |          |           |        | ~em~) | luoro |
|   |       |       |          |           |        |       | quin- |
|   |       |       |          |           |        | \[%\] | olone |
|   |       |       |          |           |        |       |       |
|   |       |       |          |           |        |       | (p    |
|   |       |       |          |           |        |       | ~FQ~) |
|   |       |       |          |           |        |       |       |
|   |       |       |          |           |        |       | \[%\] |
+---+-------+-------+----------+-----------+--------+-------+-------+
| C | 0.10  | 12    | 11       | 5         | 85.7   | 8.9   | 4.8   |
| A |       |       |          |           |        |       |       |
+---+-------+-------+----------+-----------+--------+-------+-------+
| C | 0.16  | 192   | 162      | 93        | 84.0   | 13.3  | 9.1   |
| T |       |       |          |           |        |       |       |
+---+-------+-------+----------+-----------+--------+-------+-------+
| G | 0.18  | 32    | 30       | 19        | 91.2   | 16.5  | 11.3  |
| A |       |       |          |           |        |       |       |
+---+-------+-------+----------+-----------+--------+-------+-------+
| M | 0.12  | 21    | 19       | 8         | 87.0   | 10.3  | 5.1   |
| D |       |       |          |           |        |       |       |
+---+-------+-------+----------+-----------+--------+-------+-------+
| M | 0.23  | 242   | 199      | 110       | 82.0   | 18.7  | 12.6  |
| N |       |       |          |           |        |       |       |
+---+-------+-------+----------+-----------+--------+-------+-------+
| N | 0.05  | 68    | 59       | 31        | 85.7   | 4.6   | 2.8   |
| Y |       |       |          |           |        |       |       |
+---+-------+-------+----------+-----------+--------+-------+-------+
| O | 0.16  | 11    | 8        | 5         | 69.2   | 11.0  | 9.5   |
| R |       |       |          |           |        |       |       |
+---+-------+-------+----------+-----------+--------+-------+-------+
| T | 1     | 578   | 488      | 271       | 84.4   | 83.1  | 55.1  |
| o |       |       |          |           |        |       |       |
| t |       |       |          |           |        |       |       |
| a |       |       |          |           |        |       |       |
| l |       |       |          |           |        |       |       |
+---+-------+-------+----------+-----------+--------+-------+-------+

[3.6 (p~FQ~) - Probability a *Campylobacter* case who has sought care
and has been treated with an antibiotic is treated with a
fluoroquinolone (not seeking care, seeking care but not submitting a
stool , submitting a stool]{.underline} [\[non-bloody and
bloody\]):]{.underline}

##### 

##### **Not seeking** care

The 5.9% of persons with a diarrheal illness in the population survey
that do not seek care and take antibiotics are not included in the
assessment of fluoroquinolone treatment because they represent a small
poorly described fraction of cases (See Section 3.4).

##### 

##### **Submitting** a stool for Culture (Non-Bloody and Bloody Diarrhea)

In preliminary results from the *Campylobacter* Case Control Study the
proportion of cases treated with antimicrobials and receiving
fluoroquinolone treatment was 55.5% (271/488) for both crude and
weighted overall estimates. The individual state treatment rates were CA
4.8% (5/11), CT 9.1% (93/162), GA 11.3% (19/30), MD 5.1% (8/19), MN
12.6% (110/199), NY 2.8 % (31/59), OR 9.5% (5/8). (Table 3.4, above)

##### **Not submitting** a stool for culture

ASSUMPTION: Patients with campylobacteriosis who did not submit stools
were treated by their health care provider with fluoroquinolones at the
same frequency as those who submitted stools. (Table 3.4, above)

##### **Invasive** Disease

ASSUMPTION: The proportion of fluoroquinolone prescriptions of total
antibiotic prescriptions is the same for patients with invasive
campylobacteriosis treated by their health care providers as it is for
patients with enteric campylobacteriosis treated by their health care
providers. (Table 3.4, above)

The parameter p~FQ~ was thus modeled as:

$$p_{\text{FQ}} = \sum_{j}^{}{W_{j}\text{Beta}(E_{j} + 1,D_{j} - E_{j} + 1)}$$

where, again, the W~j~ are the FoodNet site weights, E~j~ is the number
of cases who have sought care and been treated with an antibiotic that
is a fluoroquinolone and D~j~ is the number of cases who received
antibiotics, shown in Table 3.4 above.

[3.7 (**λ4~n~, λ4~b~, λ4~i~, λ4~T\ ~**) - Nominal mean number of
fluoroquinolone resistant *Campylobacter* cases attributable to chicken,
seeking care, treated with a fluoroquinolone and therefore affected by
the fluoroquinolone resistance ( non-bloody, bloody and invasive and
total):]{.underline}

This is the number of persons with fluoroquinolone resistant infections
that are attributed to exposure to chicken, that seek care and are
treated with a fluoroquinolone. The sum of non-bloody, bloody and
invasive cases is:

[(λ4~n~, λ4~b~)*Enteric disease*]{.underline}

*(λ4~n~) Non-bloody diarrhea*

**λ4~n~** = λ3~n~\* p~mn~\*P~an~\*P~FQ~

*(λ4~b~) Bloody diarrhea*

**λ4~b~** = λ3~b~\* p~mb~\*P~ab~\*P~FQ~

[(λ4~i~) *Invasive disease*]{.underline}

**λ4~i~ =** λ3~i~ \*p~FQ~

The distributions have the following statistical characteristics[^4]:

  ----------- ----------------- -------------- -------------- --------------
  **Year**    **Model output**  **5^th^        **Mean**       **95^th^
                                percentile**                  percentile**

  **1998**    **λ4~n~**         2,943          5,411          8,895

              **λ4~b~**         1,415          3,241          6,794

              **λ4~i~**         15             25             38

  **1999**    **λ4~n~**         3,187          5,768          9,468

              **λ4~b~**         1,527          3,460          7,147

              **λ4~i~**         21             33             48
  ----------- ----------------- -------------- -------------- --------------

(λ4~T~) - *Estimate of **total** **nominal** **mean** number of people
with fluoroquinolone resistant Campylobacter infection from chicken who
receive fluoroquinolone.*

The distribution of the sum, **λ4~T~ = λ4~n~ + λ4~b~ + λ4~i~** is shown
in Figure 3.2. The distribution has the following statistical
characteristics.

  -------------- --------------- -------------- ------------ -------------- ------
  **Year**       **Model         **5^th^        **Mean**     **95 ^th^      
                 output**        percentile**                percentile**   

  **1998**       **λ4~T~**       4,758          8,678        14,369         

  **1999**       **λ4~T~**       5,227          9,261        15,326         

  **Difference                                  583                         
  (99-98)**                                                                 
  -------------- --------------- -------------- ------------ -------------- ------

**Figure 3.2**. Relative confidence distribution of **λ4~T~.**

**Section Summary**

The model estimates that in 1998 a mean estimate of 8,678 people had
fluoroquinolone resistant *Campylobacter* illnesses from chicken and
received fluoroquinolones. The 5^th^ and 95^th^ percentile estimates for
the number of people who had fluoroquinolone resistant *Campylobacter*
infections from chicken receiving fluoroquinolones is 4,758 and 14,369.
In 1999 the mean estimate was 9,261 with wider 5^th^ and 95^th^
percentile estimates of 5,227 and 15,326 compared to 1998. The fairly
long length of the confidence interval is reflective of the lack of
certainty in the various parameters used in the model up to this point.
Relative contributions of the various components of the model to the
model uncertainty will be presented in Section 5, Sensitivity Analysis.

Table 3.2 *Campylobacter* Case Control study, the proportion of
travellers and persons taking fluoroquinolones prior to culture for
susceptible and resistant isolates by site

+---+----------+--------+------+------+-------+-------+-------+-------+
|   | 1998     | 1998   | 98   | 98   | 98    | 98    | 98    | 98    |
|   | C        | Popu   | T    | T    | CCC   | CCC   | CCC   | CCC   |
|   | atchment | lation | otal | otal | Resi  | S     | Propo | Propo |
|   | Pop.     | Wei    | Sus  | R    | stant | uscep | rtion | rtion |
|   |          | ghting | cept | esis | Trav  | tible | Resi  | S     |
|   |          | Fr     | ible | tant | elers | Trav  | stant | uscep |
|   |          | action |      |      | and   | elers | Trav  | tible |
|   |          |        | F~   | G~j~ | Prior | and   | elers | Trav  |
|   |          | W ~j~  | j~ - |      | FQ    | Prior | and   | elers |
|   |          |        | G~j~ |      | users | FQ    | Prior | and   |
|   |          |        |      |      |       | users | FQ    | Prior |
|   |          |        |      |      |       |       | users | FQ    |
|   |          |        |      |      |       |       |       | users |
|   |          |        |      |      |       |       | a~j~  |       |
|   |          |        |      |      |       |       |       | b~j~  |
+---+----------+--------+------+------+-------+-------+-------+-------+
| C | 2        | 0.10   | 10   | 2    | 1     | 3     | 0.50  | 0.30  |
| A | ,146,096 |        |      |      |       |       |       |       |
+---+----------+--------+------+------+-------+-------+-------+-------+
| C | 3        | 0.16   | 166  | 26   | 15    | 49    | 0.58  | 0.30  |
| T | ,274,069 |        |      |      |       |       |       |       |
+---+----------+--------+------+------+-------+-------+-------+-------+
| G | 3        | 0.18   | 29   | 3    | 2     | 9     | 0.67  | 0.31  |
| A | ,746,059 |        |      |      |       |       |       |       |
+---+----------+--------+------+------+-------+-------+-------+-------+
| M | 2        | 0.12   | 19   | 3    | 0     | 6     | 0.00  | 0.32  |
| D | ,444,280 |        |      |      |       |       |       |       |
+---+----------+--------+------+------+-------+-------+-------+-------+
| M | 4        | 0.23   | 225  | 17   | 13    | 52    | 0.76  | 0.23  |
| N | ,725,419 |        |      |      |       |       |       |       |
+---+----------+--------+------+------+-------+-------+-------+-------+
| N | 1        | 0.05   | 59   | 10   | 4     | 16    | 0.40  | 0.27  |
| Y | ,106,085 |        |      |      |       |       |       |       |
+---+----------+--------+------+------+-------+-------+-------+-------+
| O | 3        | 0.16   | 10   | 1    | 1     | 0     | 1.00  | 0.000 |
| R | ,281,974 |        |      |      |       |       |       |       |
+---+----------+--------+------+------+-------+-------+-------+-------+
| T | 20       | 1.00   | 518  | 62   | 36    | 135   | 0.58  | 0.261 |
| O | ,723,982 |        |      |      |       |       |       |       |
| T |          |        |      |      |       |       |       |       |
| A |          |        |      |      |       |       |       |       |
| L |          |        |      |      |       |       |       |       |
+---+----------+--------+------+------+-------+-------+-------+-------+

Table 3.5. Numbers of culture-confirmed cases with enteric
campylobacteriosis where *Campylobacter* was tested for fluoroquinolone
resistance and number fluoroquinolone resistant, by site, 1998-9.

+--------+-----------+---------------+---------------+-----------------+
| Site   | Catchment | Weighting     | Number tested | Number          |
|        |           | Fraction      |               | fluoroquinolone |
| j      |           |               | F~j~          | resistant       |
|        |           | W~j~          |               |                 |
|        |           |               |               | G~j~            |
+--------+-----------+---------------+---------------+-----------------+
| CA     | 2,146,096 | 0.10          | 8             | 1               |
+--------+-----------+---------------+---------------+-----------------+
| CT     | 3,274,069 | 0.16          | 128           | 11              |
+--------+-----------+---------------+---------------+-----------------+
| GA     | 3,746,059 | 0.18          | 21            | 1               |
+--------+-----------+---------------+---------------+-----------------+
| MD     | 2,444,280 | 0.12          | 16            | 3               |
+--------+-----------+---------------+---------------+-----------------+
| MN     | 4,725,419 | 0.23          | 177           | 4               |
+--------+-----------+---------------+---------------+-----------------+
| NY     | 1,106,085 | 0.05          | 49            | 6               |
+--------+-----------+---------------+---------------+-----------------+
| OR     | 3,281,974 | 0.16          | 10            | 0               |
+--------+-----------+---------------+---------------+-----------------+
| Total  | 2         | 1             | 409           | 26              |
|        | 0,723,982 |               |               |                 |
+--------+-----------+---------------+---------------+-----------------+

[^1]: In the draft risk assessment a third study, Hopkins, R., Olmstead,
    R., and Istre, G., Endemic *Campylobacter jejuni* Infection in
    Colorado: Identified Risk Factors. Am. Jour. Pub. Health. 1984.
    74(3); 249-50.) was used to define the attributable risk of
    campylobacteriosis from consumption of chicken. The study was
    dropped from the final risk assessment because of inconsistencies in
    the reported results.

[^2]: In two surveys encompassing 474 human isolates from 1982 to 1992
    in the United States, only a single Ciprofloxacin resistant isolate
    was identified and subsequently speciated as *C. lari* which is
    intrinsically resistant to fluoroquinolones (91).

[^3]: After removal of persons who had traveled within 7 days of illness
    onset and removal of those taking fluoroquinolones prior to culture,
    quinolone resistance in Minnesota was observed in 0.8% of isolates
    in 1996 and had increased to 3.0% in 1998 (chi square for linear
    trend, 9.8; p[\<]{.underline}0.002) (92). In Minnesota quinolone
    resistance, screened by nalidixic acid disc diffusion was highly
    correlated with resistance to ciprofloxacin using the E-Test,
    (sensitivity 99.6%, specificity 98.4%) (92). A survey of
    *Campylobacter* isolated from 88% of 91 chicken products resulted in
    *C. jejuni* from 67(74%) and *C. coli* from 19 (21%) of samples and
    six samples were the source of both pathogens. Products carrying
    resistant isolates were purchased from 11 stores representing 8
    franchises and originated in seven processing plants in five states
    (91, 92) indicating widespread resistance in chicken *Campylobacter*
    isolates. Molecular subtyping was performed using PCR restriction
    endonuclease length polymorphism typing of the flagellin gene in
    *the C. jejuni* human and chicken product isolates. 12 subtypes were
    identified from 13 *C. jejuni* positive chicken products. Six of
    seven resistant subtypes in the chicken products were also
    identified in the quinolone resistant human isolates. For people
    acquiring infections during 1997, excluding cases that had taken
    fluoroquinolones prior to culture, persons with non-traveler
    resistant infections were more likely to *have C. jejuni* subtype
    also found in the quinolone resistant *C. jejuni* from chicken
    products (odds ratio 15.0, 95% CI 1.9 to 321.8) (91)

[^4]: Values incorporated in these tables will vary very slightly from
    graphed results due to small variations in repeating Monte Carlo
    simulations. The graphs are based on smaller simulation runs while
    the quoted values are based on large simulations and are more
    accurate.