J Vet Intern Med 2006;20:245–249

Antibiotic Sensitivity Profiles Do Not Reliably Distinguish

Relapsing or Persisting Infections from Reinfections in Cats
with Chronic Renal Failure and Multiple Diagnoses
of Escherichia coli Urinary Tract Infection
Thurid Freitag, Richard A. Squires, Jan Schmid, Jonathan Elliott, and Andrew N. Rycroft

Older cats with chronic renal failure (CRF) commonly develop urinary tract infections (UTI). Uropathogenic Escherichia coli
(UPEC) is identified as the causal agent of UTI in most affected cats. Infections are often complicated, and UPEC infections
may persist or recur in these cats. Antibiotic sensitivity profiles have been used to distinguish relapsing or persisting UTI from
reinfection by different clones of the same species. However, the accuracy with which antibiograms discriminate different
urinary E coli clones in cats is uncertain. We studied 17 cystocentesis-derived UPEC isolates collected from 5 cats with stable
CRF and multiple diagnoses of UTI. UTIs were classified as relapses versus persistent infections or reinfections using
antibiograms determined by Kirby-Bauer discs and EtestsH.a Subsequently, clonality of UPEC isolates was determined by
pulsed-field gel electrophoresis (PFGE). A comparison of PFGE results with antibiograms indicated that antibiotic resistance
patterns varied considerably within several individual E coli clones. Both antibiotic susceptibility tests differentiated between
relapsing or persistent infections and reinfections with only 58% overall efficiency. Thus, antibiotic sensitivity profiles cannot
be relied upon to distinguish between persisting or relapsing infections as compared to reinfections in cats with CRF and
multiple diagnoses of E coli UTI.
Key words: Antibiogram; Antibiotic resistance; Antibiotic susceptibility; Cat; Persistent infection.

scherichia coli urinary tract infection (UTI) has
E been reported to occur frequently in older cats that
show signs of feline lower urinary tract disease.1–3 One
factor predisposing older cats to development of UTI is
declining renal function. Approximately two-thirds of
older cats with UTI concurrently may be affected by
chronic renal failure (CRF).2 A prospective study
conducted at the Royal Veterinary College showed that
11/36 (30.5%) cats with stable CRF developed at least 1
E coli UTI.b During a study period of 2 years, repeat
diagnoses of infection were made in 6/11 (54.5%)
patients after an initial UTI episode. Repeated diagnoses
of UTI in an individual cat may be made because of
incomplete eradication of the initial infection (ie,
relapsing or persistent infection)4 or later episodes of
UTI may be caused by different bacterial strains (ie,
reinfections). Antibiotic treatment is advocated in cats
with confirmed UTI.5 Prompt antimicrobial treatment
may reduce the severity of microbial-induced inflamma-
tory damage to the kidneys.6–9 To design a treatment
plan for a cat with multiple diagnoses of E coli UTI, it
may be useful to determine whether each diagnosed
infection is a relapse or reinfection.4,10 Comparison of
From the Institute of Veterinary, Animal and Biomedical Sciences
(Freitag, Squires), and Institute of Molecular Biosciences (Schmid),
Massey University, Palmerston North, New Zealand; and De-
partment of Veterinary Basic Sciences (Elliott) and Department of
Pathology and Infectious Diseases (Rycroft), Royal Veterinary
College, London, United Kingdom. Previously presented in part as
an oral presentation at the 22nd Annual American College of
Veterinary Internal Medicine Forum, Minneapolis, MN, June 9–12,
2004.
Reprint requests: Richard A. Squires IVABS, Massey University,
Private Bag 11 222, Palmerston North, New Zealand; e-mail:
R.A.Squires@massey.ac.nz.
Submitted August 28, 2005; Accepted August 31, 2005.
Copyright E 2006 by the American College of Veterinary Internal
Medicine
0891-6640/06/2002-0005/$3.00/0
antibiotic susceptibility patterns of UPEC from different
UTI episodes in a given cat commonly has been used to
predict uropathogenic E coli (UPEC) clonality, because
other phenotypic or genotypic information about
infecting UPEC strains often is limited in a clinical
setting. However, the precision with which antimicrobial
susceptibility patterns distinguish UPEC clones in cats
has not been thoroughly investigated. We studied 17
cystocentesis-derived UPEC isolates from 5 cats with
multiple diagnoses of UTI and CRF. Antibiograms were
compared with genomic fingerprints, performed by
pulsed-field gel electrophoresis (PFGE), to evaluate
whether antibiotic sensitivity profiles can reliably predict
E coli clonality.
Materials and Methods
Patients
Six female domestic shorthair cats with E coli UTI and
concurrent stable CRF were included in this study. The cats were
diagnosed and treated between January 1999 and February 2002 at
2 central London clinics, where investigators of the Royal
Veterinary College conduct geriatric cat clinics. In all cases, UTI
was diagnosed on culture of E coli from cystocentesis-derived
urine. Urine was routinely collected as part of an evaluation
of geriatric cats with suspected or confirmed chronic kidney
disease. Signs of UTI5 were present on only 2/18 occasions (ie,
cat A, infection 1; cat D, infection 1). All other UTIs occurred in
the absence of noticeable clinical signs. Cats A–C, E, and F
were concurrently treated for hyperthyroidism. In cat E,
abdominal ultrasonography showed diffuse thickening of the
bladder wall. Permission to biopsy the bladder wall was not
granted.
Five of the cats studied had multiple diagnoses of UTI (Fig 1,
cats A–D and F). One cat (E) with a single diagnosis of UTI lived
in the same household as a cat that had 2 diagnoses of UTI (cat D).
Of the 5 cats with multiple UTI diagnoses, 3 cats were found to be
infected on 2 occasions, 1 cat on 3 occasions, and 1 cat on 8
occasions over a period of 23 months. The interval between
successive diagnoses in individual cats ranged from 6 weeks to
2.5 years. Cats received antibiotic therapy based on antibiotic

246 Freitag et al
Fig 1. Timeline of detected E coli clones in 6 cats. Nine different
E coli clones were detected in the 6 cats. Identical shapes indicate
identical clones. Fill colors indicate whether relapsing/persistent
infection or reinfection was predicted using EtestH: Grey, relapsing/
persistent infection; Black, reinfection. Initial infections are shown
in white. An asterisk is shown below each isolate for which disc
diffusion tests disagreed with EtestsH.
susceptibility of isolated E coli strains each time a UTI was
diagnosed. In the majority of cases, therapeutic success was
assessed by bacteriologic urine cultures. These were performed
during antibiotic therapy or no earlier than 5 days after the end of
each period of antibiotic therapy.
Collection of E coli isolates
Urine samples were collected by antepubic cystocentesis. E coli
strains were cultured on sheep blood agar using 2 mL of
uncentrifuged urine. Organisms were identified as E coli
using cultural and biochemical criteria.11 Strains were stored in
20% glycerol in 10% skimmed milk at 294uF (270uC) until
further characterization. Eighteen isolates were collected from the
6 cats.
Macrorestriction Analysis by PFGE
Macrorestriction analysis by PFGE was performed using
a previously described method12 with minor modifications. In
brief, DNA preparations were digested using the restriction enzyme
XbaI.c Samples were run in 1% PFGE agarosed on a clamped
homogenous electric fields–Mapper (CHEF-Mapper)e for 20 hours
with an initial pulse time of 0.5 seconds and a final pulse time of
18 seconds. After image capture, the clonality of the isolates was
determined according to the criteria presented by Tenover et al.13
Using these criteria, a relapsing or persisting UTI was diagnosed
when the E coli isolate causing the current infection had a banding
pattern indistinguishable from that of an isolate that had caused
a previous UTI episode in the same cat. A reinfection was
diagnosed when E coli isolates causing repeated UTI episodes had
#65% of PFGE bands in common.
We determined the discriminatory power14 of PFGE for
distinguishing relapsing or persisting infections from reinfections
by investigating how often identical patterns were observed in the
absence of the possibility of relapse (ie, when comparing isolates
from different cats). Among 119 possible comparisons between
isolates from different cats, there was only 1 instance in which 2
isolates had an indistinguishable PFGE pattern (Fig 1). Thus, the
discriminatory power of the PFGE method among our isolates was
0.991 (ie, the probability that identity between 2 patterns was the
result of a relapsing or persisting infection was .99%). PFGE
categorization of recurrent UTI was used as our gold standard
when evaluating the accuracy of antibiotic susceptibility tests in
distinguishing between relapsing or persisting infections and
reinfections.
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Antibiotic Sensitivity Testing
The antibiotic susceptibility of each isolate was tested using
antimicrobial discs.f The minimal inhibitory concentration (MIC)
of several antibiotics for each isolate was determined using
EtestsH.a Tests were performed according to the National
Committee for Clinical Laboratory Standards (NCCLS) for
antimicrobial disc and dilution susceptibility tests for bacteria.15
Isolates were classified as susceptible, intermediate, or resistant on
the basis of NCCLS standards.
Antibiotic discs used were tetracycline (30 mg), ampicillin
(10 mg), amoxicillin/clavulanic acid (20/10 mg), cephalothin
(30 mg), sulfamethoxazole/trimethoprim (23.75/1.25 mg), enroflox-
acin (5 mg), cefuroxime (30 mg), and ciprofloxacin (5 mg). EtestsH
used were tetracycline (0.016–256 mg/mL), ampicillin (0.016–
256 mg/mL), amoxicillin/clavulanic acid (2/1; 0.016–256), cefurox-
ime (0.016–256 mg/mL), sulfamethoxazole/trimethoprim (19/1;
0.002–32 mg/mL), and ciprofloxacin (0.002–32 mg/mL).
The antibiogram was interpreted as having indicated a relapsing
or persisting infection when the susceptibility pattern of the current
infecting E coli isolate was identical to that of a previous isolate
from the same cat. When the antibiogram of the current infecting
E coli differed from that of previous isolates from the same cat,
a reinfection was diagnosed. Subsequently, categorizations made
using antibiograms (EtestsH and disc diffusion tests) were
compared with those obtained using our gold standard (PFGE).
PFGE or antibiotic sensitivity tests were repeated when results
were markedly discordant, to minimize potential technical errors.
Results
Clinical Evaluation
There was no significant association between severity
of CRF and number of UTI diagnoses in the cats.
Antibiotic Susceptibility Tests
Antibiotic susceptibility results obtained using
EtestsH and disc diffusion tests are shown in Figure 2.
Using the PFGE results as our gold standard, EtestH
antibiograms incorrectly categorized 3/8 relapsing or
persisting infections and 2/4 reinfections in 3/5 cats.
Sensitivity and specificity of EtestH antibiograms for
detection of relapsing or persisting infections were 63%
and 50%, respectively. EtestsH discriminated between
relapsing or persisting infections and reinfections with
58% efficiency. Disc diffusion test–based antibiograms,
which included 2 additional antibiotics, incorrectly
categorized 4/8 relapsing or persisting infections and 1/
4 reinfections in 2/5 cats. Thus, disc diffusion tests
detected relapsing or persisting infections with 50%
sensitivity and 75% specificity. The overall efficiency of
disc diffusion test–based antibiograms to accurately
distinguish between relapsing or persisting infections
and reinfections was 58%.
There was 93% categorical agreement between EtestsH
and disc diffusion tests. Differences were primarily
related to cefuroxime (5/8 [62.5%] disagreements).
The development of resistance to fluoroquinolones
and beta-lactam antibiotics was observed in the last
E coli strain isolated from cat A. An obvious change in
all MIC values (not leading to any change in NCCLS
susceptibility categories) was observed between isolates
1 and 2 from cat E.

Antibiograms Inaccurately Distinguish Different UPEC Clones
Fig 2. Results of antibiotic susceptibility testing.
PFGE
PFGE identified 9 unique E coli clones among the 17
isolates from the 5 cats with multiple diagnoses of
infection. Four of 5 of these cats (80%) experienced
a reinfection and 3/5 (60%) had at least 1 relapsing or
persisting infection (Fig 1). No more than 2 unique
clones were isolated from any particular cat. The
average Dice coefficient similarity level of unrelated
strains was low (35.9%). One of the 9 unique E coli
clones also was found in a sixth cat, which lived in the
same household as 1 of the 5 cats with multiple
diagnoses of infection.
PFGE determined that 6 E coli isolates obtained
sequentially from cat A over a period of 385 days were,
interestingly, of the same clone. Lengthy antibiotic
therapy with a fluoroquinolone (marbofloxacin) resulted
in intermittent urine sterility while the animal was
receiving antibiotic. However, postantibiotic urine
sterility was not achieved. Severe bladder wall thicken-
ing was diagnosed sonographically, but not investigated
further due to severe concurrent pulmonary illness and
subsequent euthanasia of the animal.
Cat B was diagnosed with a relapsing or persisting
infection after an intervening UTI episode caused by
a different E coli clone. The interval between the first
and third UTI diagnoses in cat B, associated with the
same E coli clone, was 354 days. This was the longest
infection-to-relapse interval recorded in this study,
although cat A was infected by the same E coli clone
over a longer total period.
Two cats that were members of the same household
(cats D and E) were found to be infected by the same
E coli clone. Cat D was diagnosed with UTI first, was
treated, and was not subsequently observed to be
infected (as assessed by clinical evaluation and urinaly-
19391676, 2006, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2006.tb02853.x by University Degli Studi Di Bari, Wiley Online Library on [28/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
247
sis). Three months after the UTI in cat D was detected,
cat E was found to be infected by the same E coli clone.
Cat E was treated and not subsequently found to be
infected until 2.5 years later, when a reinfection with
a different clone was diagnosed.
Discussion
Results of the present study indicate that antibiotic
susceptibility profiles cannot be relied upon when
distinguishing between relapsing or persisting infections
and reinfections in cats with recurrent UTI and CRF.
Changes in antibiotic susceptibility profile frequently
were detected within individual UPEC clones. Similar
results have previously been reported in a case of
monoclonal E coli pyelonephritis and urosepsis in
a human patient.16 Changes in antibiotic susceptibility
patterns also were identified in UPEC causing persistent
UTI in dogs.10 In our study, an increase in the number of
antibiotics included in the antibiogram did not lead to
better discrimination between relapses and reinfections,
emphasizing the unreliability of antibiograms for de-
termining E coli clonality. EtestsH and disc diffusion
testing yielded similar susceptibility categorization
results. A change in 1 or more MIC values identified
with EtestsH may indicate reinfection, although NCCLS
antibiogram categories predict a relapsing or persisting
infection (eg, the different clones from cat B in Fig 2).
However, MICs do not reliably distinguish between
relapsing or persisting infections and reinfections,
because E coli clones may acquire antibiotic resistance
(eg, the last isolate from cat A).
Macrorestriction analysis (ie, PFGE) indicated that
CRF-affected cats with multiple diagnoses of UTI
suffered from persistent infections or relapses

248 Freitag et al
considerably more often than is appreciated using
antibiotic sensitivity profiles. Individual E coli clones
may persist for periods of a year or more despite
apparently successful antibiotic treatment and intermit-
tently demonstrated urine sterility (data not shown). One
cat in this study was diagnosed with a relapsing or
persisting infection with one E coli clone after an
intervening infection with a different E coli clone. It
remains to be determined whether E coli clones that cause
relapsing or persisting infections primarily persist in the
external environment, the cat’s gastrointestinal tract or,
as has recently been shown in mice,17–19 in biofilms inside
epithelial cells of the urinary tract. Importantly, viable
UPEC were demonstrated in the bladder tissue of
experimentally infected mice despite appropriate antibi-
otic treatment of UTI.18 Periodic efflux of UPEC was
demonstrated and associated with evident relapse.
UTI in cats frequently occurs without any clinical
signs and without abnormalities on urine sediment
evaluation and CBC.2,20,21 Only 2/18 of the infections in
this study were associated with clinical signs. In the
absence of clinical signs, early recognition of UTI may
be achieved by regular urine cultures as part of the
assessment of the health status of CRF cats.22 To
prevent possible sequelae associated with UTI, antibi-
otic treatment of any clinically silent UTI currently is
recommended.21 Conversely, silent UTI or asymptom-
atic bacteriuria (ABU) is not always treated in humans,
particularly not in elderly patients.23 Although ABU
may lead to the development of symptomatic UTI,
morbidity and mortality do not decline with antibiotic
therapy of ABU.24 On the contrary, antibiotic treatment
may be harmful, due to the occurrence of adverse effects
or emergence of antibiotic resistance. Similar studies are
needed to understand the etiopathogenesis of feline
asymptomatic UTI and to show whether antibiotic
therapy is beneficial.
The development of resistance to fluoroquinolones
after several 3- to 6-week marbofloxacin treatment
periods was observed in 1 isolate that caused persistent
or relapsing UTI over a period of 14 months. Failure
to resolve the persistent or relapsing infection and
subsequent development of fluoroquinolone resistance
by mutation may have been caused by subtherapeutic
antibiotic levels at the site of infection due to poor tissue
perfusion; deep-seated, possibly intracellular infection;
the presence of partial fluoroquinolone resistance; or
poor owner compliance. The fluoroquinolone-resistant
isolate also showed concurrent development of in vitro
resistance to beta-lactam antibiotics (amicillin, cefurox-
ime, and cephalothin). This finding was surprising
because the animal was not known to have been treated
with beta-lactam antibiotics. Postcollection development
of resistance is not likely to have occurred, because
contact between this E coli clone and beta-lactam
antibiotics or transmissible genetic elements was
avoided. Antibiograms and PFGE were run in duplicate
from separate subcultures of the original isolate.
Identical results were obtained each time. Hence, we
suspect that this E coli clone acquired resistance to 2
distinct classes of antibiotic in vivo.
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PFGE identified 2 cats (members of 1 household) that
both were infected with the same UPEC clone at some
stage during a 3-month period. This finding is in
agreement with recent studies25,26 that reported that
humans and cats living in a close relationship to each
other can share indistinguishable UPEC isolates. Spread
of UPEC between individuals also has been demon-
strated in mice populations.18 After the likely trans-
mission of UPEC clones between individuals, UPEC
may overcome host defenses and cause UTI using
specific uropathogenicity factors.27 It is also possible
that the sheer abundance of a particular UPEC clone in
host and environment may increase the probability of
UTI developing.28
In the presence of concurrent disease, treatment of
UTI may be particularly rewarding, but can be
challenging. Long-term antibiotic treatment often is
indicated.20 When UPEC persists despite long-term
therapy with apparently appropriate antibiotics, in vivo
antibiotic resistance of UPEC should be considered. In
this study, PFGE was successfully applied to discrimi-
nate UPEC causing relapsing or persisting UTI from
UPEC causing reinfection. The application of PFGE in
a clinical setting may allow alteration of treatment
protocols quickly, thus enhancing overall treatment
success.
Footnotes
a
EtestsH, AB Biodisk, Solna, Sweden
b
Barber Penny J, Rawlings JM, Markwell PJ, et al. Incidence and
prevalence of bacterial urinary tract infections in cats with chronic
renal failure. 17th Annual American College of Veterinary
Internal Medicine Forum, Chicago, IL; 1999:101
c
XbaI, Roche, Mannheim, Germany
d
PFGE agarose, Bio-Rad, CA
e
CHEF-Mapper, Bio-Rad, CA
f
Antimicrobial discs, Oxoid Ltd, Hampshire, UK
Acknowledgments
We thank Kim Souttar, VN, BSc, for her involvement
in the clinical work. Alex Grinberg, IVABS, Massey
University, kindly helped with statistical analysis. Lynn
Rogers, Medlab Central Laboratory, Palmerston North,
kindly helped with EtestsH. This project was supported
by a grant from the Clinical Studies Fund of the
European College of Veterinary Internal Medicine
(ECVIM-CA).
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