The Veterinary Journal 203 (2015) 270277

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The Veterinary Journal

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Review

Effect of antibiotic treatment in canine and feline urinary tract

infections: A systematic review
L.R. Jessen a,*, T.M. Srensen a, C.R. Bjornvad a, S. Saxmose Nielsen b, L. Guardabassi c
a Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Dyrlaegevej 16, 1870
Frederiksberg C, Denmark
b Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Groennegaardsvej 8, 1870 Frederiksberg C,
Denmark
c Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Stigboejlen 4, 1870 Frederiksberg C,
Denmark

A R T I C L E

I N F O

Article history:
Accepted 7 December 2014
Keywords:
Urinary tract infection
Antimicrobial therapy
Canine
Feline

A B S T R A C T

Urinary tract infection (UTI) is a major reason for antibiotic prescription in small animal practice. Optimal
antibiotic treatment strategies have not been established for veterinary species, especially when considering duration of treatment, which is often considerably longer than for human patients with UTI.
The aims of this study were (1) to identify and assess evidence related to the ecacy of antibiotic treatment in canine and feline UTIs; and (2) to compare the ecacy of short (<5 days) and standard (7 days)
duration of antibiotic treatment for canine uncomplicated UTI. An electronic literature search was conducted for publications to 1 May 2014. Fourteen peer-reviewed prospective and controlled studies were
retrieved, 10 of which evaluated antibiotic treatment in dogs and four in cats.
Of the 14 studies, seven were clinical trials and ve of those were randomised controlled trials. Most
(12/14) studies were not considered to contribute sucient evidence to evaluate treatment strategies.
There were no clinical studies examining the effect of duration of the same drug. Of the short duration
regimens evaluated, the ecacy of 3 day antibiotic therapy with trimethoprim-sulphonamide (females
only) or high-dose enrooxacin in dogs with uncomplicated UTIs was supported by fair evidence, as these
treatment strategies were non-inferior to medium duration (1014 days) therapy with -lactam antimicrobials. In conclusion, there is little published evidence relating to antibiotic treatment of UTIs in dogs
and cats. Well-designed clinical trials focusing on the duration of treatment are warranted to create
evidence-based treatment protocols.
2014 Elsevier Ltd. All rights reserved.

Introduction
Urinary tract infection (UTI) is a major reason for antibiotic prescription in small animal practice. Despite UTI being a common
condition in dogs, there is great uncertainty regarding optimal treatments for the various forms of UTI. The emerging problem with
multidrug resistant bacteria has increased awareness of antibiotic
use and misuse in small animals. The International Society for Companion Animal Infectious Diseases (ISCAID) has published guidelines
to promote prudent use of antibiotics in canine and feline UTIs
(Weese et al., 2011).
Although subject to national and regional variation, the duration of antibiotic treatment for canine and feline UTIs is generally
long compared with recommended treatment regimens for human
patients with UTI (Grabe et al., 2014). The European Association of

* Corresponding author. Tel.: +45 35330952.

E-mail address: lrmj@sund.ku.dk (L.R. Jessen).
http://dx.doi.org/10.1016/j.tvjl.2014.12.004
1090-0233/ 2014 Elsevier Ltd. All rights reserved.

Urologists recommends that the duration of antibiotic therapy in

women with uncomplicated UTIs should range from 3 to 7 days,
depending on the drug used (Grabe et al., 2014). For dogs with uncomplicated UTIs, the advised duration of antibiotic therapy is 7
days (Weese et al., 2011), while a 1014 day course of antibiotics
was considered to be the standard of care prior to 2011. For complicated infections in humans, the recommended duration of
antibiotic therapy is usually 714 days, but it can be extended up
to 21 days depending on the underlying condition (Grabe et al.,
2014). In comparison, the recommended duration of antibiotic treatment in dogs and cats with complicated UTIs is up to 4 weeks (Weese
et al., 2011).
The potential benets of decreasing the duration of antibiotic
treatment are: (1) reduced antimicrobial resistance selection pressure (Singh et al., 2000; Chastre et al., 2003); (2) reduced adverse
effects; (3) increased compliance (Claxton et al., 2001); and (4)
reduced treatment costs. Although data from humans cannot be
translated directly to dogs and cats, the shorter duration of antibiotic treatment in humans does prompt us to question whether
medium to long duration treatment is justied in dogs and cats.

L.R. Jessen et al./The Veterinary Journal 203 (2015) 270277

The primary aim of this systematic review was to identify and

assess the available evidence related to the ecacy of antibiotic treatment in canine and feline UTIs. A secondary aim was to compare
the ecacy of short (<5 days) and standard (7 days) durations of
antibiotic treatment for uncomplicated canine UTIs, according to
the available evidence.
Materials and methods
Search strategy
This systematic review was conducted according to the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) criteria (Moher et al., 2009).
A literature search was conducted to identify peer-reviewed publications up to
1 May 2014 comparing in vivo antibiotic treatment in cats and dogs with naturally
occurring or induced UTIs. The primary outcome parameters of concern were short
term clinical and bacterial cure rates. Secondary outcome parameters were adverse
effects and long term clinical and bacteriological cure rates. No limitations to publication year or language, other than a requirement that the abstract should be in
English, were imposed.
The electronic databases AGRICOLA, AGRIS, CAB Abstracts, EMBASE, International Pharmaceutical Abstracts and Medline were searched using PubMed1 and
OvidSP.2 In addition, the Web of Science Core Collection was searched using Web
of Knowledge.3 The search terms used in all search engines were: ([antibiotic$ OR
antimicrobial$] AND [treatment$ OR therapy OR therapies OR therapeutic$] AND
[urinary tract OR urologic* OR UTI$ OR bladder OR cystitis OR prostatitis OR pyelonephritis] AND [infection$ OR infectious]) AND (small animal$ OR companion
animal$ OR pet$ OR dog$ OR canine$ OR bitch* OR puppy OR pup$ OR puppies OR
hound$ OR mongrel$ OR cat$ OR feline$ OR tom OR tomcat$ OR kitten$). In the
PubMed search, all $ were changed to * and in the OvidSP search an addition of (NOT
human$) was used.
The reference lists of reviews published after 2000, identied by the electronic
searches, were manually screened to identify eligible studies missed by the electronic search. Identied references were imported to reference management software
(RefWorks, RefWorks-COS), and duplicates were identied and removed.
Study selection
Screening was divided in two phases. During phase I, papers of relevance were
selected based on the following inclusion criteria: (1) original research report; (2)
published in peer reviewed journal; and (3) study relating to in vivo systemic antibiotic treatment of spontaneous or induced UTIs in dogs and/or cats reporting on
type, dose and duration of antibiotic intervention.
Studies fullling the above criteria and those in which fullment of the criteria
could not be determined from the abstract were retrieved as full texts. Papers in
languages other than English were translated into Danish by Google translate or by
a professional translator.
Studies identied in phase I were excluded from entry into this systematic review
according to the following phase II exclusion criteria: (1) case report or case series;
(2) retrospective case control study or retrospective cohort study; (3) single intervention (uncontrolled) prospective clinical studies; or (4) studies lacking both of the
primary outcome parameters (clinical and bacterial cure rates).
Data extraction
Data were extracted independently by the rst two authors using a purposedesigned extraction sheet. Reviewers were not blinded to author names, institutions
or publication titles. For short term outcomes, data were extracted from the point
in time dened as the short term evaluation in the original paper. If multiple short
term evaluations were available, data were extracted from a time point of 24 days
post-cessation of treatment. For long term outcomes, data were extracted from the
time of the second evaluation after cessation of treatment.
Level of evidence and methodological quality
The studies were graded by level of evidence (LOE) on a scale of 13 according
to the pyramid of evidence used in the RECOVER and PROVETS guidelines (Boller
and Fletcher, 2012; Goggs et al., 2014): LOE 1 for randomised controlled clinical trials
(RCTs), LOE 2 for non-randomised controlled clinical trials (NCTs) and LOE 3 for experimental controlled trials (ECT), randomised and non-randomised.
The methodological quality of the studies was evaluated by the following three
parameters: (1) risk of bias; (2) size of study groups; and (3) quality of subject enrolment. Risk of bias was evaluated using the Cochrane collaborations tool for assessing

1
2
3

See: http://www.ncbi.nlm.nih.gov/pubmed (accessed 1 May 2014).

See: http://ovidsp.uk.ovid.com (accessed 1 May 2014).
See: http://apps.webofknowledge.com (accessed 1 May 2014).

271

risk of bias (Higgins et al., 2011). The studies were categorised as having high, moderate (unclear) or low risk of selection, performance, detection, attrition, reporting
and other bias. For non-randomised studies, selection bias was assessed, taking into
account the adjustment for confounders (Reeves et al., 2008). Finally, the overall combined risk of bias was dened using a predened numerical system used in previous
veterinary systematic reviews (Olivry and Mueller, 2003; Summers et al., 2012).
Size of study groups was dened as good, moderate, small and very small according to the following criteria used in previous veterinary systematic reviews (Olivry
and Mueller, 2003; Summers et al., 2012): > 50 (good), 2050 (moderate), 1019
(small) and <10 (very small) animals per group.
The quality of subject enrolment was dened according to the following criteria: (1) good, when the health/disease status of included animals was conrmed by
clinical examination and a thorough diagnostic workup, including haematological
(complete blood count, CBC) and biochemical (BC) parameters, diagnostic imaging,
urinalysis (UA) and bacteriological culture, along with information on age and sex,
although diagnostic imaging was not considered mandatory for experimental studies;
(2) fair, when the health/disease status of included animals were conrmed by a
reasonable diagnostic workup, including UA and bacteriological culture, with or
without CBC, BC or diagnostic imaging, along with information on age and sex; and
(3) poor, when important information regarding age or sex was not reported, and
diagnostic work-up other than culture was not performed or reported.
Denition and classication of urinary tract infections
UTI was classied as uncomplicated UTI (lower UTI in otherwise healthy animals
with no underlying anatomic, functional or systemic diseases), complicated UTI (lower
UTI in animals with underlying anatomic, functional or systemic diseases and/or recurrent or persistent lower UTI), pyelonephritis (upper UTI) or induced UTI
(experimental UTI).
Presentation of qualitative results
The evidence for or against ecacy of a treatment strategy in uncomplicated/
complicated/upper UTI was graded as good, fair or insucient, according to the
following criteria modied from Summers et al. (2012) and based upon the denitions of the US Preventive Services Task Force (USPSTF).4 Evidence was graded
according to multiple (good), at least one (fair) or no (insucient) RCT(s) with a low
or low to moderate estimated overall risk of bias reported results for a dened class
of UTI. Evidence was also considered insucient if: (1) interpretation of the results
was hampered by limited power of the studies; (2) results of outcome parameters
were conicting; or (3) information regarding important outcome parameters (bacterial or clinical cure rates and/or adverse effects) was lacking. Ecacy of a treatment
was dened as superiority or non-inferiority to the comparator, whereas lack of efcacy was dened as inferiority to the comparator or no superiority to placebo/no
treatment. Evidence (good or fair) was considered to support a treatment strategy
if ecacy was demonstrated. Alternatively, evidence (good or fair) was considered
to advise against a treatment strategy if either lack of ecacy was demonstrated
or if harmful events associated with use of the treatment were considered
unacceptable.
Statistical methods
Fishers exact test and exact two-sided 95% condence intervals were calculated when possible, if not already reported in the original studies, using commercially
available statistical software (SAS 9.4, IBM). When results of clinical studies that were
not originally designed as non-inferiority studies demonstrated no signicant difference between groups, a post hoc non-inferiority calculation was applied to the
data; the one-sided 95% condence interval was calculated for the difference in cure
rates between study groups and assessed for non-inferiority with = 0.2. If the lower
limit of the one-sided 95% condence interval was above 20%, the study was considered to demonstrate non-inferiority (Jones et al., 1996). In determining the ecacy
of intervention and comparing short vs. standard duration treatment, metaanalysis was considered to be inappropriate, since the studies were heterogeneous
in terms of study designs, disease denitions, methodologies, outcome measures
and treatment interventions tested.

Results
A total of 2142 citations were identied by the literature search
strategy, with 167 citations fullling the phase I inclusion criteria.
Of these, 14 peer-reviewed full-length studies published in English
from 1962 to 2014 fullled the phase II criteria and entered the systematic review (Fig. 1). Ten studies reported treatment outcomes

4
See: http://www.uspreventiveservicestaskforce.org/uspstf/grades.htm (accessed 1 May 2014).

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L.R. Jessen et al./The Veterinary Journal 203 (2015) 270277

Fig. 1. Flow diagram of study selection process. Phase I excludes studies that are not an original research report, not published in a peer-reviewed journal and not examining in vivo systemic antibiotic treatment of spontaneous or induced urinary tract infections in dogs and/or cats reporting on type, dose and duration of antibiotic intervention.
Phase II excludes (a) case reports or case series, (b) retrospective case control or cohorts, (c) single intervention (uncontrolled) prospective clinical studies and (d) studies
lacking both primary outcome parameters.

in canine UTIs and four studies reported treatment outcomes in feline

UTIs.
Four canine studies (Cotard et al., 1995; Passmore et al., 2007;
Westropp et al., 2012; Clare et al., 2014) were RCTs and categorised
accordingly as LOE 1, one study (Ling and Gilmore, 1977) was an
NCT and categorised as LOE 2, and ve studies (Barsanti et al.,
1985; Senior et al., 1986; Turnwald et al., 1986; Rogers et al.,
1988; Seo et al., 2012) were experimental and classied as LOE 3
(Tables 1 and 2). For cats, one study was a RCT (Passmore et al.,
2008) and categorised as LOE 1, one study (Litster et al., 2007)
was a NCT and thus categorised as LOE 2, and two studies (Piermattei,
1962; Senior et al., 1985) were experimental and categorised as
LOE 3 (Table 3). The clinical trials were multicentre, except for
one canine RCT (Clare et al., 2014) and one canine NCT (Ling and
Gilmore, 1977).

Methodological quality
Randomisation of animals was reported in nine studies, of which
ve were classied as RCTs (Cotard et al., 1995; Passmore et al., 2007,
2008; Westropp et al., 2012; Clare et al., 2014) and four were experimental studies (Senior et al., 1985, 1986; Turnwald et al., 1986;
Rogers et al., 1988). Of those nine studies, only two (both RCTs;
Westropp et al., 2012; Clare et al., 2014) adequately described the
method of randomisation applied. Blinding of owners, personnel
and outcome assessors was applied in 4/5 RCTs and was well described in all cases. NCTs and experimental studies used open subject
allocation, except for blinding of outcome assessors in one experimental canine study (Barsanti et al., 1985). The majority of clinical
trials lost, withdrew or excluded >5% of initially included animals
from one or more outcomes (Senior et al., 1986; Cotard et al., 1995;

L.R. Jessen et al./The Veterinary Journal 203 (2015) 270277

273

Table 1
Summary of controlled clinical studies reporting systemic antimicrobial treatment outcomes in canine urinary tract infectiona.
Study

Level of evidence, study

design and methodological
quality

Study population and urine

collection method

Antimicrobial intervention
and comparator

Evaluation time and cure

rates

Clare et al.,
2014

LOE 1.
Blinded RCT.
Low to moderate estimated
overall risk of bias.
Small to moderate number
of well-characterised dogs
in each group

Adult female intact and

neutered dogs with
spontaneous
uncomplicated UTIs.
Sampling by cystocentesis
or voiding

Tx: TMP-SMX 15 mg/kg

twice daily PO for 3 days
followed by placebo, twice
daily PO for 7 days.
C: Cephalexin 20 mg/kg,
twice daily PO for 10 days

ST (4 days PT):
Tx: Bacterial: 59%, clinical:
85%;
C: Bacterial: 36%, clinical:
72%;
LT (>30 days PT):
Tx: Bacterial: 44%, clinical
50%;
C: Bacterial: 20%, clinical:
65%

Cotard et al.,
1995

LOE 1.
Multicentre open RCT.
Moderate to high estimated
overall risk of bias.
Unknown number of wellcharacterised dogs in each
group

Adult to old intact and

neutered male and female
dogs with spontaneous
UTIs.
Sampling by cystocentesis
or catheter

ST (07 days PT):

Tx: Bacterial: 96%, clinical:
83%;
C: Bacterial: 85%, clinical:
70%

Passmore et al.,
2007

LOE 1.
Multicentre blinded RCT.
Low to moderate estimated
overall risk of bias.
Good number of fairly wellcharacterised dogs in each
group

Young to old intact and

neutered male and female
dogs with spontaneous
UTIs.
Sampling by cystocentesis,
catheter or voiding

Tx: Marbooxacin 4 mg/kg,

once every 4 days SC for 1
or 9 days, 2 mg/kg, once
daily PO for 10 or 28 days
depending on UTI class.
C: ACA 12.5 mg/kg, twice
daily PO for 528 days
depending on UTI class
Tx: Cefovecin single dose
8 mg/kg SC followed by
placebo, twice daily PO for
14 days.
C: Single dose placebo SC
then Cephalexin 15 mg/kg,
twice daily PO for 14 days

Westropp et al.,
2012

LOE 1.
Multicentre blinded RCT.
Low to moderate estimated
overall risk of bias.
Moderate number of wellcharacterised dogs in each
group

Adult neutered female and

male dogs with
spontaneous
uncomplicated UTIs.
Sampling by cystocentesis

Tx: Enrooxacin 1820 mg/

kg, once daily PO for 3 days.
C: ACA 13.7525 mg/kg,
twice daily PO for 14 days

Ling and
Gilmore,
1977

LOE 2.
Open NCT.
Moderate to high estimated
overall risk of bias.
Good number of poorly
characterised dogs in each
group

Male and female dogs with

spontaneous UTIs.
Sampling by cystocentesis,
catheter or voiding

Tx: Penicillin G 110,000

165,000 U/kg divided in
34 daily doses PO for 10
14 days.
C: Ampicillin 77110 mg/kg
divided in 34 daily doses
PO for 1014 days

ST (59 days PT):

Tx: Bacterial: 77%, clinical:
89%;
C: Bacterial: 81%, clinical:
88%;
LT (18 days PT):
Tx: Bacterial 69%, clinical:
88%
ST (414 days PT), bacterial:
Tx: 64%,
C1: 76%

ST (7 days PT):
Tx: Bacterial: 88%, clinical:
82%;
C: Bacterial: 57% (53% of
susceptible strains),
clinical: 70%

Statistical comparison
(P value, 95% CI)b
ST: NS difference in
bacterial cure (P = 0.44),
clinical cure (P = 0.44) or
resolution of clinical signs
on day 3 (P = 1.00); noninferior to cephalexin in
bacterial cure [0.11, 0.52]c,d
and clinical cure [0.14,
0.39]c,d ( = 0.20); LT: NS
difference in bacterial
(P = 0.40) or clinical cure
(P = 0.50). Non-inferior to
cephalexin in bacterial cure
[0.10, 0.54]c,d ( = 0.20)
Reports the use of
likelihood ratio, 2, Fishers
exact test, Students t test,
but no group size, statistical
signicance, NS or P values
reported

Cefovecin: Signicantly
higher bacterial cure than
cephalexin, P = 0.0001 [0.14,
0.46]d; Signicantly higher
overall cure, P = 0.001 [0.11,
0.45]d; non-inferior to
Cephalexin in clinical cure
[0.02, 0.25]c ( = 0.15,
Newcombe Method 10)
Enrooxacin: Non-inferior
to ACA in bacterial cure
[0.20, 0.12]c,d and clinical
cure [0.12, 0.14]c,d
( = 0.20)

NS difference between
groups (P = 0.11) e

ACA, amoxicillin-clavulanic acid; TMP-SMX, trimethoprim-sulphamethoxazole; UTI, urinary tract infection; SC, subcutaneous; PO, perorally; PT, post-cessation of treatment; LOE, level of evidence; NS, not signicant; RCT, randomised controlled clinical trial; NCT, non-randomised controlled clinical trial; Tx, treatment; C, comparator; LT,
long term; ST, short term.
a The complete summary table of canine studies can be found in Tables S1.
b
Unless otherwise indicated, Fishers exact test was used.
c 90% CI, 90% condence interval [lower limit, upper limit].
d
Calculated by the authors of this systematic review.
e Cure rate is calculated as the proportion of bacterial isolates eradicated post-treatment, not the proportion of cured dogs.

Litster et al., 2007; Passmore et al., 2007, 2008; Westropp et al., 2012;
Clare et al., 2014). One of these studies (Clare et al., 2014) applied
an intention to treat analysis. One of the experimental studies (Senior
et al., 1985) had a 5% loss, and the remaining experimental studies
did not report any losses. The numerical scoring system and risk
of bias assessment of individual studies are shown in Tables S3 and
S4 and the methodological quality of individual studies is reported in Tables 13.
Primary and secondary outcomes
Short term clinical cure rates were reported in 4/10 studies in
dogs (Cotard et al., 1995; Passmore et al., 2007; Westropp et al., 2012;
Clare et al., 2014), but not in any of the studies in cats. All 14 studies

reported short term bacteriological cure rates with short term evaluation times ranging from 0 to 14 days post-treatment cessation
in dogs and 28 days post-treatment cessation in cats. The bacteriological cure rate was dened as the proportion of individuals with
negative post-treatment cultures in all but one study (Ling and
Gilmore, 1977), where the bacteriological cure rate referred to the
proportion of isolates eradicated post-treatment. Denition of positive and negative cultures varied between studies, as did collection
methods and sampling times (see Tables S1 and S2).
Long term clinical cure rates were reported in 2/10 studies
in dogs (Westropp et al., 2012; Clare et al., 2014) and in none of
the studies in cats. Long term bacteriological cure rates were reported in 4/10 canine studies (Turnwald et al., 1986; Rogers et al.,
1988; Westropp et al., 2012; Clare et al., 2014), with long term

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L.R. Jessen et al./The Veterinary Journal 203 (2015) 270277

Table 2
Summary of controlled experimental studies reporting systemic antimicrobial treatment outcomes in canine urinary tract infectiona.
Study

Level of evidence, study

design and methodological
quality

Study population and urine

collection method

Antimicrobial intervention
and comparator

Evaluation time and cure

rates

Barsanti et al.,
1985

LOE 3.
Blinded ECT.
Moderate estimated overall
risk of bias.
Very small number of wellcharacterised experimental
dogs in each group
LOE 3.
Open ECT.
Moderate to high estimated
overall risk of bias.
Very small number of wellcharacterised experimental
dogs in each group

Healthy adult male and

female dogs with induced
lower UTIs.
Sampling by cystocentesis

Tx: Cefadroxil 22 mg/kg,

twice daily PO for 21 days.
C: No treatment

ST (4 days PT), bacterial:

Tx: 86%,
C: 86%

None reported. NS
difference between
Cefadroxil and control
(P = 1.0). High self-cure in
controls

Healthy male and female

dogs with induced lower
UTIs.
Sampling by cystocentesis

Tx1: Amikacin single dose

of 20 mg/kg SC
Tx2: TMS single dose of
30 mg/kg PO.
Tx3: Amikacin 10 mg/kg,
twice daily SC for 3 days.
Tx4: TMS 15 mg/kg, twice
daily PO for 3 days.
C: No treatment

ST (2 days PT), bacterial:

Tx1: 25% (f 50%, m 0%),
Tx2: 25% (f 50%, m 0%),
Tx3: 25% (f 50%, m 0%),
Tx4: 75% (f 100%, m 50%),
C: 0%;
LT (1214 days PT),
bacterial:
Tx1: 25% (f 50%, m 0%),
Tx2: 0%,
Tx3: 12.5% (f 25%, m 0%),
Tx4: 50% (f 100%, m 0%),
C: 0%

LOE 3.
Blinded randomised ECT.
Moderate estimated overall
risk of bias.
Small number of wellcharacterised experimental
dogs in each group
LOE 3.
Open ECT.
Moderate estimated overall
risk of bias.
Very small number of wellcharacterised experimental
dogs in each group
LOE 3.
Open randomised ECT.
Moderate to high estimated
overall risk of bias.
Small number of poorly
characterised experimental
female dogs in each group

Healthy male and female

dogs with induced lower
UTIs.
Sampling by cystocentesis

Tx: ACA 11 mg/kg, twice

daily PO for 10 days.
C: Placebo tablet PO twice
daily 10 days

ST (3 days PT), bacterial:

Tx: 8090%,
C: 0%

Healthy adult male dogs

with induced lower UTIs.
Sampling by catheter

Tx: ACA 12.5 mg/kg, twice

daily PO for 18 days.
C: No treatment

ST (0 days PT), bacterial:

Tx: 80%,
C: 20%

Single dose: NS differences

between therapy and
control or between male
and female responses
(P > 0.05); 3 day therapy:
signicant difference
between responses of
female dogs treated with
TMS and controls (m and f),
P = 0.03 [0.26, 1.00]c, and
between responses of male
and female dogs treated
with TMS, P = 0.03 [0.26,
1.00]d
ACA: Signicantly higher
bacterial cure than placebo,
P = 0.05 [0.11, 0.99]d.
Bacterial counts were
signicantly lower in ACA
group 3 days PT (Students t
test, P = 0.01)
NS difference between
groups (P = 0.206)d

Healthy female dogs with

induced lower UTIs.
Sampling by cystocentesis

Tx1: TMS single dose of

60 mg/kg PO.
Tx2: TMS single dose of
90 mg/kg PO.
C: TMS 15 mg/kg, twice
daily PO for 21 days

ST (5 days PT), bacterial:

Tx1: 0%,
Tx2: 0%,
C: 100%;
LT (24 days PT), bacterial:
Tx1: 50%,
Tx2: 17%

Rogers et al.,
1988

Senior
et al.,1985

Seo et al., 2012

Turnwald et al.,
1986

Statistical comparison
(P value, 95% CI)b

An overall difference
existed in the ranked data
with respect to all groups
(F = 41.47; P < 0.0001); 21
day TMS: signicantly
higher bacterial cure than
both single dose regimens,
P = 0.002 [0.47, 1.00]d

ACA, amoxicillin-clavulanic acid; TMS, trimethoprim-sulphadiazine; UTI, urinary tract infection; f, female; m, male; SC, subcutaneous; PO, perorally; PT, post-cessation of
treatment; LOE, level of evidence; NS, not signicant; ECT, experimental controlled trial; Tx1-4, treatment; C, comparator; LT, long term; ST, short term.
a The complete summary table of canine studies can be found in Tables S1.
b
Unless otherwise indicated, Fishers exact test was used.
c
90% CI, 90% condence interval [lower limit, upper limit].
d Calculated by the authors of this systematic review.

evaluation points ranging from 12 to >30 days post-treatment cessation, and in 1/4 feline studies (Piermattei, 1962), with a long term
evaluation point of 2539 days post-treatment cessation.
With the exception of one NCT in dogs (Ling and Gilmore, 1977),
adverse effects were reported in all clinical trials. Of the experimental studies, only two reported adverse events (Senior et al., 1985,
1986). The rigor of the adverse event reporting varied greatly
between studies. No studies were similar to an extent that allowed
for meaningful pooling of their outcome data. Cure rates are reported in Tables 13 and all outcomes, along with materials and
methods of individual studies, are presented in Tables S1 and S2.

et al., 2014). Based on the outcome of those two studies, there was
fair evidence to support the conclusion that short duration (3 day)
antimicrobial therapy with trimethoprim-sulphonamide (Clare et al.,
2014) and enrooxacin (Westropp et al., 2012), respectively, were
not inferior to 1014 days antimicrobial therapy with cephalexin
and amoxicillin/clavulanic acid, respectively, in the treatment of uncomplicated UTIs in female (Clare et al., 2014) and neutered female/
male (Westropp et al., 2012) dogs. Both studies demonstrated noninferiority within a 20% margin. The qualitative assessment of
individual studies is reported in Tables S5 and S6.
Discussion

Qualitative results
Two randomised clinical studies with low to moderate estimated overall risk of bias contributed to the evidence of antibiotic
treatment in uncomplicated UTIs in dogs by reporting outcomes specically for uncomplicated UTIs in dogs (Westropp et al., 2012; Clare

The primary aim of this systematic review was to identify and

assess the available evidence related to the effect of antibiotic treatment of canine and feline UTIs. By including three levels of evidence,
we identied 14 studies, of which only ve were categorised as LOE
1 and the remaining were open clinical trials or experimental studies.

L.R. Jessen et al./The Veterinary Journal 203 (2015) 270277

275

Table 3
Summary of controlled clinical and experimental studies reporting systemic antimicrobial treatment outcomes in feline urinary tract infectiona.
Study

Level of evidence, study

design and methodological
quality

Study population and urine

collection method

Antimicrobial intervention
and comparator

Evaluation time and cure

rates

Statistical comparison
(P value, 95% CI)b

Passmore et al.,
2008

LOE 1.
Multicentre, blinded RCT.
Low to moderate estimated
overall risk of bias.
Moderate to good number
of fairly well-characterised
cats in each group

Young to old intact and

neutered male and female
cats with spontaneous UTIs.
Sampling by cystocentesis,
catheter or voiding

ST (7 days PT), bacterial:

Tx: 76%,
C: 75% (77.8% of susceptible
strains)

Cefovecin: Non-inferior to
cephalexin in bacterial cure
[0.14, 0.18]c ( = 0.15,
Newcombe Method 10)

Litster et al.,
2007

LOE 2.
Multicentre, open NCT.
High estimated overall risk
of bias.
Moderate number of fairly
well-characterised cats in
each group

Young to old male and

female cats with
spontaneous UTIs.
Sampling by cystocentesis
or catheter

ST (38 days PT), bacterial:

Tx: 100%,
C1: 87%,
C2: 89%

Piermattei,
1962

LOE 3.
Open ECT.
Moderate to high estimated
overall risk of bias.
Very small number of
poorly characterised
experimental cats in each
group

Young to old male and

female cats with induced
lower UTIs. Sampling by
catheter

Tx: Cefovecin single dose

8 mg/kg SC followed by
placebo, twice daily PO for
14 days.
C: Single dose placebo SC
followed by cephalexin
15 mg/kg, twice daily PO for
14 days
Tx: Pradooxacin 0.2 mL/kg
of 2.5% suspension, once
daily PO for 1130 days.
C1: Doxycycline LD of 5 mg/
kg followed by two doses of
2.5 mg/kg, twice daily,
followed by 2.5 mg/kg, once
daily PO for 1439 days in
total.
C2: ACA 62.5 mg per cat,
twice daily PO for 1146
days
Tx1: DHS 44 mg/kg, once
daily IM for 413 days.
Tx2: Nitrofurantoin 10 mg
per cat, three times daily PO
for 418 days.
C: No treatment

Senior et al.,
1985

LOE 3.
Blinded randomised ECT.
Moderate estimated overall
risk of bias.
Small number of wellcharacterised experimental
cats in each group

Healthy male and female

cats with induced lower
UTIs. Sampling by
cystocentesis

Tx: ACA approximately

11 mg/kg, twice daily PO for
10 days.
C: Placebo tables, twice
daily PO for 10 days

ST (3 days PT), bacterial:

Tx: 7580%,
C: 50%

Pradooxacin: Therapy
length signicantly shorter
than other two groups
(ANOVA, P < 0.05); NS
difference in proportions of
bacterial cure compared to
other groups (2, P value
not reported); non-inferior
in bacterial cure to ACA
[0.11, 0.32]c,d and to
doxycycline [0.10, 0.36]c,d
( = 0.20)
Overall occurrence of sterile
cultures in Nitrofurantoin
group signicantly higher
than other two groups
(Students t test, P value not
reported); ST and LT
bacterial cure NS difference
in proportions between
groups (P > 0.08)d; high LT
self-cure in controls
Signicantly lower
bacteriological count in ACA
group compared with
placebo on days 7 and 14 of
treatment (Students t test,
P < 0.001). Proportion of
culture positive
signicantly lower in ACA
compared with placebo on
days 7 and 14 of treatment
(P < 0.001); NS difference in
proportions of ST bacterial
cure (P = 0.52)d; high selfcure in controls

ST (24 days PT), bacterial:

Tx1: 67%,
Tx2: 83%,
C: 17%;
LT (2543 days PT),
bacterial:
Tx1: 83%,
Tx2: 100%,
C: 83%

ACA, amoxicillin-clavulanic acid; DHS, dihydrostreptomycin; UTI, urinary tract infection; SC, subcutaneous; IM, intramuscular; PO, perorally; LD, loading dose; PT, postcessation of treatment; ANOVA, analysis of variance; LOE, level of evidence; NS, not signicant; ECT, experimental controlled trial; RCT, randomised controlled clinical trial;
NCT, non-randomised controlled clinical trial; Tx1-2, treatment; C1-2, comparators; LT, long term; ST, short term.
a
The complete summary table of feline studies can be found in Tables S2.
b Unless otherwise indicated, Fishers exact test was used.
c 90% CI, 90% condence interval [lower limit, upper limit].
d
Calculated by the authors of this systematic review.

Based on the criteria outlined in the Materials and methods, the

results derived from 12/14 studies, all published before 2012, were
considered to provide insucient evidence to analyse the evaluated treatment strategies, either because of the nature or quality
of the study design, lack of a dened classication of UTI, or because
results from different UTIs were combined.
In 2012 and 2014, two methodologically sound RCTs were published, both evaluating short duration antibiotic treatment of one
drug against a standard duration treatment of a different drug in
dogs with uncomplicated UTIs. The evidence from those studies is
discussed in the section on short duration therapy below. With regard
to complicated and upper UTIs in dogs, this systematic review did
not identify sucient evidence concerning specic treatments, nor
did it identify sucient evidence with regard to antibiotic treatments for uncomplicated and complicated UTIs in cats.

Of the drugs recommended through the ISCAID Guidelines for

rst-line treatment of lower UTIs, only trimethoprim-sulphonamide
was evaluated and only in dogs, and there were no studies examining the effect of the other rst line agent, amoxicillin. The
remaining drugs belonged to the group of drugs being considered
either as second line drugs, second line drugs with restricted use
in lower UTIs (uoroquinolones, third generation cephalosporins)
or drugs that, for various reasons, are not recommended for routine
use in UTIs (Weese et al., 2011).
The secondary aim of this systematic review was to assess
whether short duration treatment (<5 days) was as effective as standard treatment (7 days). Five studies evaluated the effect of various
short vs. standard duration treatment regimens in canine UTIs. Although the results could not be combined in a meta-analysis due
to high reporting heterogeneity, an attempt was made to provide

276

L.R. Jessen et al./The Veterinary Journal 203 (2015) 270277

a qualitative assessment. The study by Clare et al. (2014) evaluated a 3 day course of trimethoprim-sulphonamide vs. 10 day
treatment with cephalexin. The study was designed as a superiority study, but there was no signicant difference in treatment
outcomes, a consequence of the relatively small number of animals
included.
According to our criteria, ecacy was dened as superiority or
non-inferiority of a treatment compared with the comparison group.
We performed a post-hoc non-inferiority calculation on the results
of the study by Clare et al. (2014) and were able to conclude that
the short duration treatment described was non-inferior to standard treatment well within a 20% margin of difference. This study
is particularly relevant, as it is the rst clinical RCT assessing the
effect of a recommended rst line drug. Short term clinical and bacteriological cure rates of trimethoprim-sulphonamide were good to
acceptable, but the long term clinical and bacteriological cure rates
were relatively low. However, as this was also the case for the comparison group, it might reect the population of animals rather than
the duration of treatment.
Two studies evaluated the effect of short duration treatment with
uoroquinolones. The study by Cotard et al. (1995) evaluated singledose marbooxacin against 5 day treatment of amoxicillin/clavulanic
acid. Diagnoses were classied as uncomplicated UTI, complicated UTI, prostatitis or pyelonephritis. However, when reporting the
results, the outcomes were pooled, so they were unable to contribute sucient evidence for individual UTI classications. The study
by Westropp et al. (2012) yielded fair evidence for the treatment
of uncomplicated UTIs in dogs with a 3 day course of high dose
(20 mg/kg) enrooxacin, as this treatment showed non-inferiority
within a margin of 20% to the comparison group (a 14 day course
of amoxicillin/clavulanic acid). However, enrooxacin is not recommended as a rst line agent in uncomplicated UTIs (Weese et al.,
2011) and, in some Scandinavian countries, the authorities have
banned the use of enrooxacin in companion animals unless justied by culture and susceptibility testing. Nevertheless, the results
reported by Westropp et al. (2012) are very relevant for dogs with
more resistant infections, since short duration high dose
uoroquinolone therapy is believed to be less likely to promote development of multidrug-resistant bacteria, such as extendedspectrum -lactamase (ESBL)-producing Enterobacteriaceae (Trott
et al., 2004; Daniels et al., 2014).
It is important to note that the studies by Clare et al. (2014) and
Westropp et al. (2012) did not specically examine the effect of duration of antibiotic therapy, as they both compared short duration
of one drug vs. standard duration of a different drug. Although they
provide valuable comparisons of specic treatment regimens, they
do not help to establish optimal treatment duration for any of the
drugs tested. Both studies used a medium duration -lactam as comparator. Although -lactams were used as comparators in all the
clinical studies, representing the standard of care for canine and feline
UTIs, the optimal duration of therapy of this class of drug has never
been established.
Two small experimental studies evaluated the effect of short duration therapy of trimethoprim-sulphonamide. The effect of a singledose of trimethoprim-sulphonamide was evaluated at 30, 60 and
90 mg/kg (Turnwald et al., 1986; Rogers et al., 1988). All single dose
treatment regimens were ineffective, since infection either persisted or relapsed in most individuals. Although experimental studies
do not provide sucient evidence, these studies supported the hypothesis that a single dose treatment with trimethoprimsulphonamide is inadequate in the treatment of uncomplicated UTIs.
This agrees with the duration of trimethoprim-sulphonamide treatment (3 or 5 days) recommended for uncomplicated UTIs in women
(Grabe et al., 2014).
The ecacy of treatment is not the only factor to consider when
composing antibiotic use guidelines and it is beyond the scope of

this systematic review to make treatment recommendations. Adherence to the ISCAID Guidelines or, if available, local guidelines,
is strongly recommended. The ISCAID Guidelines advise that
amoxicillin or trimethoprim-sulphonamide should be used as rstline antibiotics for lower UTIs, unless local patterns of resistance
make empiric use of these drugs inappropriate, and that the use
of enrooxacin to treat lower UTIs should be restricted to more resistant infections (Weese et al., 2011). The optimal duration of
antibiotic treatment for the various forms of UTI is still to be
established.
In a recent systematic review on antibiotic ecacy in canine deep
and supercial pyoderma, which included 17 clinical trials (mainly
RCTs), the authors did not nd a correlation between publication
year and methodological quality (Summers et al., 2012). Based on
the very few clinical trials included in the present systematic review,
we found that the methodological quality of the RCTs performed
in recent years was largely improved compared with the RCT published in the 1990s (Cotard et al., 1995). In general, the level of detail
provided regarding study design details increased with publication year. The most recent RCT (Clare et al., 2014) was conducted
according to the CONSORT criteria and, as the only study that applied
an attrition owchart and an intention to treat analysis, it set new
standards for the quality of study design in future veterinary clinical trials.
Systematic reviews aiming to evaluate effect of treatment are
often based on RCTs only, as they present the highest level of evidence. Introducing lower levels of evidence could inuence the
quality of this systematic review. We included experimental evidence in this systematic review, since 50% of the available studies
included experimentally induced UTIs. Experimental UTI studies have
the advantage of being performed in a target species. However, as
with all experimental conditions, we do not know how well they
can be generalised to eld conditions. Induced UTIs can have inherent problems with either exaggerated inammation or rapid selfhealing; this was the case in some studies included in this systematic
review (Piermattei, 1962; Barsanti et al., 1985; Senior et al., 1985;
Seo et al., 2012). Thus, data based on experimental evidence alone
are insucient to assess the potential effects of treatment under
eld conditions. However, experimental data should still be considered for its ability to create hypotheses for future clinical research.
We did not pose any limitations to publication year, which led
to the inclusion of older studies. Antibiotic susceptibility is a dynamic
process and is subject to changes over time. Susceptibility patterns from the 1970s probably do not reect current circumstances,
just as the susceptibility pattern in one region might not reect the
pattern in other regions. Not all drugs tested in the included studies
are of clear relevance for the treatment of UTIs. In particular, drugs
tested in some of the older studies (dihydrostreptomycin, amikacin,
penicillin, ampicillin) are not generally recommended for UTIs. Nitrofurantoin is an older drug that is of interest due to anecdotal
evidence of its ecacy against ESBL producing pathogens. It is considered an option for the treatment of lower UTIs caused by multidrug resistant pathogens (Weese et al., 2011). However, the
concentration tested in the included study (Piermattei, 1962) was
lower (10 mg/cat) than the recommended dose (4.45.0 mg/kg),
thereby limiting the relevance of the data.
Conclusions
There is surprisingly little published evidence concerning antibiotic treatment of UTIs in dogs and cats. Most (12/14) studies in
this systematic review, all published before 2012, were not considered to contribute sucient evidence on the evaluated treatment
strategies. The question of whether short duration therapy is as effective as standard duration treatment of a given drug remains
unanswered, since no clinical study examined the effect of

L.R. Jessen et al./The Veterinary Journal 203 (2015) 270277

duration of the same drug. Of specic short duration regimens, the

ecacy of 3 day antibiotic therapy with either trimethoprimsulphonamide (females only) or high-dose enrooxacin in dogs with
uncomplicated UTIs, was supported by fair evidence, as these regimens were non-inferior to medium duration (1014 days) therapy
with -lactams. Well-designed and adequately powered clinical trials
are warranted to create evidence-based treatment protocols for
canine and feline UTIs. Study designs should include adequate reporting of randomisation, blinding, and attrition owcharts.
Outcomes should be specically reported for uncomplicated or complicated UTIs, since treatment recommendations differ between
types. Studies specically examining the effect of treatment duration are warranted to establish optimal treatment durations and to
ll the current evidence gap.
Conict of interest statement
None of the authors has any nancial or personal relationships
that could inappropriately inuence or bias the content of the paper.
Acknowledgements
This work was supported by the University of Copenhagen Research Centre for Control of Antibiotic Resistance (UC-Care5). The
authors wish to acknowledge Prof. Torben Martinussen, Department of Public Health, University of Copenhagen, for assisting with
the non-inferiority calculations in this systematic review.
Appendix: Supplementary material
Supplementary data to this article can be found online at
doi:10.1016/j.tvjl.2014.12.004.
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