Vet Clin Small Anim

34 (2004) 1027–1041

Urine culture as a test for cure:

why, when, and how?
Jody P. Lulich, DVM, PhD*,
Carl A. Osborne, DVM, PhD
Minnesota Urolith Center, College of Veterinary Medicine, University of Minnesota,
1352 Boyd Avenue, St. Paul, MN 55108, USA

Case scenario
Consider the following case scenario. A colleague in private practice
called the urology service for advice about a 9-year-old-spayed female
Golden Retriever with persistent pollakiuria and gross hematuria of 2
months’ duration. Urinalysis revealed numerous red blood cells, white
blood cells, proteinuria, and spherical structures thought to be bacterial
cocci. A diagnosis of bacterial urinary tract infection (UTI) was made,
and therapy with orally administered amoxicillin with clavulanic acid was
prescribed. After 2 weeks of therapy, the owners indicated that clinical
signs were still present but less severe. Urinalysis revealed persistence of
numerous red blood cells and white blood cells. Based on the assumption
that uropathogenic bacteria causing these abnormalities were resistant to
amoxicillin with clavulanic acid, oral administration of trimethoprim/
sulfadiazine was provided. In this clinical setting, what is the likelihood
that poor response to therapy was caused by antimicrobial resistance by
uropathogenic bacteria? Furthermore, what is the likelihood that use of
trimethoprim/sulfadiazine will be associated with eradication of pollakiu-
ria and hematuria?
In considering the answers to these questions, consider the following
observations. In two retrospective clinical studies, it was estimated that the
hospital proportional morbidity rate of UTI in dogs was 10% to 14%
[1,2]. In contrast, in another retrospective clinical study, the hospital
proportional morbidity rate for persistent or recurrent UTIs in dogs was
only 0.3% [3]. In a retrospective clinical study of 100 dogs with persistent

* Corresponding author.
E-mail address: lulic001@maroon.tc.umn.edu (J.P. Lulich).

0195-5616/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvsm.2004.03.005
1028 J.P. Lulich, C.A. Osborne / Vet Clin Small Anim 34 (2004) 1027–1041

or recurrent infections, only 30% of 374 bacterial isolates were resistant to

achievable serum concentrations of commonly prescribed oral antibiotics
(ie, trimethoprim-sulfonamides, amoxicillin, amoxicillin with clavulanic
acid, cephalexin, tetracycline) [4]. When considered in the context of the
fact that these antimicrobics usually achieve higher concentrations in urine
than in serum, 30% is likely to represent an overestimation of the true
prevalence of resistant microbes as a cause for persistent or recurrent
UTIs.
In the context of the Golden Retriever described in the clinical scenario,
which of the following two assumptions is the most likely explanation for
persistent clinical signs of lower urinary tract disease?

1. Pollakiuria, hematuria, and inflammation detected by urinalysis were

caused by uropathogenic bacteria that were resistant to amoxicillin with
clavulanic acid therapy.
2. Pollakiuria, hematuria, and inflammation detected by urinalysis were
caused by a noninfectious disease process that would not respond to
amoxicillin with clavulanic acid therapy.

In contemplating the answer to this question, consider the following.

Clinical signs persisted for weeks despite therapy with trimethoprim/sulfadi-
azine. Because of the presumption that the dog had UTI caused by resistant
bacteria, it was subsequently treated with two additional antimicrobial drugs
without success. At that point, radiography and biopsy of the urinary bladder
were performed. The results revealed an infiltrating transitional cell carcinoma
of the urinary bladder. It is apparent that treatment failure in this instance was
not a result of the use of ineffective antimicrobial drugs to treat resistant
uropathogens. Rather, it was associated with ineffective use of antimicrobial
drugs to treat a noninfectious disorder.
What is the point? In addition to bacterial infections, many diverse
noninfectious disease processes, including neoplasia and urolithiasis, result
in inflammatory lesions of the urinary tract characterized by exudation of
red blood cells, white blood cells, and protein into urine. Resultant
hematuria, pyuria, and proteinuria suggest inflammatory urinary tract
disease. As with the patient described here, diagnosis of bacterial UTI
solely on the basis of urinalysis and detection of inflammatory cells in urine
sediment results in overdiagnosis. Therefore, it is essential to distinguish
between inflammation and infection related to urinary tract disease.
Although detection of bacteria in fresh urine sediment should prompt
consideration of UTI, it should be verified by urine culture. Nonbacterial
‘‘look-alikes’’ in urine sediment are often confused with bacteria.
In retrospect, how would you modify management of the urinary tract
disorder in this female Golden Retriever? Won’t you agree that evaluation
of in vitro cultures of urine for bacterial pathogens was warranted before the
initiation of therapy?
 J.P. Lulich, C.A. Osborne / Vet Clin Small Anim 34 (2004) 1027–1041 1029

What are diagnostic urine cultures?

Quantitative urine culture before initiation of antimicrobial therapy is
considered to be the gold standard for diagnosis of bacterial UTIs. If the
patient is currently being treated with an antimicrobic, it should be
discontinued for approximately 3 to 5 days before diagnostic urine culture
to minimize inhibition of in vivo and in vitro bacterial growth. In addition
to facilitating differentiation of harmless bacterial contaminants from
bacterial pathogens, accurate identification of specific bacterial species
aids in selection of antimicrobial drugs. It also facilitates differentiation
of recurrent UTIs caused by relapses from recurrent UTIs caused by
reinfections. UTIs caused by relapses cannot be distinguished from re-
current UTIs caused by reinfections without comparison of pretreatment
bacterial culture results with follow-up culture results. The point to be
emphasized is that failure to perform bacterial urine cultures or failure to
interpret results of urine cultures correctly may lead not only to diagnostic
errors but to therapeutic failures as well.

What are therapeutic urine cultures?

In addition to diagnostic culture of urine before treatment of the patient
with antimicrobics, culture of urine at strategic times during antimicrobial
therapy (so-called ‘‘therapeutic urine cultures’’) is an effective method of
assessing therapy. If patients are not responding to treatment, therapeutic
cultures are essential for determining why there is a lack of response (Fig. 1).

When should therapeutic urine cultures be considered?

The need to obtain cultures during therapy depends on severity of
disease, underlying reasons for antimicrobic use, risks associated with
antimicrobic use, and health of the patient. The benefits of therapeutic urine
cultures are listed in Box 1.
For patients with a high risk of morbidity and mortality (eg, prostatitis,
pyelonephritis, immunosuppression, urinary tract obstruction), evaluation
of a urine culture and urinalysis 3 to 5 days after initiating therapy allows
verification of antibiotic effectiveness before development of irreversible
organ damage or systemic spread of disease. The same strategy should be
considered when prescribing antimicrobics with a high risk of toxicity.
Suggested times to culture urine to diagnose and monitor persistent UTIs
are listed in Box 2.
In general, we recommend culture of urine 3 to 5 days after initiation of
antimicrobic therapy because it facilitates timely assessment of in vivo
effectiveness of treatment. Initial response to therapy is considered to be
effective only if in vitro culture of properly collected urine samples does not
1030 J.P. Lulich, C.A. Osborne / Vet Clin Small Anim 34 (2004) 1027–1041

CLINICAL SIGNS PERSIST DURING ANTIMICROBIC THERAPY

Aerobic Culture Results

No Bacterial Growth Original Bacterial Isolate New Bacterial Isolate

NONBACTERIAL DISEASE SUPERINFECTION

Investigate other causes: Restore host defenses

Structural abnormalities Antimicrobic eradication of infection or
Functional abnormalities Delay/postpone antimicrobics
Behavioral changes

Antimicrobial Susceptibility Results

Bacteria are susceptible to Bacteria are NOT susceptible to

current antimicrobics current antimicrobics

INADEQUATE ANTIMICROBIC DELIVERY ANTIMICROBIC RESISTANCE

Select active drug Restore host defenses

Administer sufficient dose Mono/multidrug therapy or
Improve client compliance and patient acceptance Delay/postpone antimicrobics
Promote intestinal absorption
Minimize drug inactivation
Expose/eradicate infection nidus

Fig. 1. Algorithm for diagnosis and management of antimicrobic failure in patients with
urinary tract infection.

Box 1. Benefits of therapeutic urine cultures

1. Timely test of antimicrobic efficacy
2. Verification of proper antimicrobic administration
3. Early detection of bacterial resistance to antimicrobics
4. Timely detection of persistent infections
5. Provision of justification for early discontinuation of potentially
toxic antimicrobics
 J.P. Lulich, C.A. Osborne / Vet Clin Small Anim 34 (2004) 1027–1041 1031

Box 2. Suggested times to culture urine to diagnose

and monitor persistent urinary tract infections
I. Diagnostic
Before administration of therapy
II. Therapeutic
3 to 5 days after initiating therapy
Any time clinical signs or laboratory abnormalities recur
during therapy
Before discontinuing therapy
III. Surveillance
7 to 14 days after stopping therapy
1 to 2 months after stopping therapy
3 to 6 months after stopping therapy
Any time clinical signs recur

result in growth of bacteria. Even though there may be viable bacterial

pathogens in surrounding tissues, the urine containing an appropriate
concentration of antimicrobic should be sterile. Treatment is ineffective and
relapse occurs if the bacterial colony count has only been reduced (eg, from
105 to 102). Therefore, one cannot rely on examination of urine sediment to
detect elimination of bacteria by therapy, because persistence of reduced
numbers of bacteria may fall below the limit of detection by light
microscopic evaluation of urine sediment. Although urine contains no
viable microbes, hematuria, pyuria, and proteinuria associated with
compensatory inflammation are likely to be detected by urinalysis 3 to 5
days after initiating effective antimicrobial therapy. These inflammatory-
associated abnormalities may be of lesser magnitude compared with
pretreatment findings, however. Anytime clinical signs persist after a suitable
period of antimicrobic therapy, therapeutic urine cultures should also be
repeated.
For complicated UTIs, consider evaluation of a urine culture and urinalysis
3 to 5 days (or sooner if necessary) before scheduled discontinuation of
therapy, especially if prophylactic antibiotics are to be subsequently used to
prevent frequent reinfection. Therapy may be discontinued if urine is sterile
and urine sediment is normal. If culture results indicate persistent infection,
however, re-evaluation of therapy is essential. In this situation, initiation of
prophylactic low-dose antimicrobial therapy is contraindicated.

How should urine samples be collected for bacterial culture?

We prefer to collect urine samples for bacterial culture by cystocentesis to
avoid iatrogenic UTI and to eliminate problems of differentiating contam-
inants from pathogens. Detection of bacteria, even in low numbers, in urine
1032 J.P. Lulich, C.A. Osborne / Vet Clin Small Anim 34 (2004) 1027–1041

aseptically collected by cystocentesis is indicative of UTI. False-positive

results may occur if the needle penetrates a loop of intestine during
cystocentesis or if the sample is contaminated during transfer to culture
media, however. For this reason, quantitative urine culture is routinely
recommended, even for samples collected by cystocentesis. In addition, urine
culture results should be interpreted in the context of other clinical findings.

How should urine samples be preserved before culture?

Because urine may be a good culture medium at room temperature
(bacterial counts may double every 20–45 minutes), it should be cultured
within 15 to 30 minutes from the time of collection. Another indication for
culture of fresh urine samples is that destruction of some fastidious bacteria
may occur within an hour of collection. If culture of freshly collected urine
samples is not possible for any reason, samples should be kept in a sealed
sterile container and immediately refrigerated after collection. Refrigerated
samples may be stored for 6 to 12 hours without significant additional
growth of bacteria; nevertheless, it is emphasized that fastidious organisms
may be killed in the urine environment if refrigeration storage time is
prolonged. Freezing urine samples may also destroy bacteria.

How do therapeutic cultures help to detect and manage antimicrobic failures?

Failure to respond to antimicrobic drug therapy results from a variety of
causes. Potential causes for poor response to antimicrobic therapy are listed
in Box 3.
Empirically switching the antimicrobic or adding additional antimicro-
bics based on the presumption that a resistant uropathogen is present may
be efficient but is often ineffective. To minimize expense and iatrogenic
morbidity associated with ineffective antimicrobial therapy, appropriate
diagnostic tests to determine the cause of failure should be performed first.
In this context, we recommend evaluation of urine culture and antimicrobic
susceptibility results before altering antimicrobial therapy (see Fig. 1).
Although the following sections of this article focus on therapeutic failures
related to ineffective use of antimicrobial drugs and use of ineffective
antimicrobial drugs, recall that establishment of infections is related to
impaired host defense mechanisms in addition to virulence of bacterial
pathogens. In a retrospective study, underlying disorders capable of
breaching normal host defenses were identified in 71% of dogs with
persistent and recurrent UTIs [4]. When underlying causes were corrected,
control of infection improved in almost half of the dogs. These findings
indicate that identification and correction of underlying defects in host
defenses also represent an important strategy for success.
 J.P. Lulich, C.A. Osborne / Vet Clin Small Anim 34 (2004) 1027–1041 1033

Box 3. Potential causes for poor response to antimicrobic

therapy
1. Administration of antimicrobics to correct noninfectious
disorders causing signs similar to those associated with
urinary tract infection (UTI)
2. Inadequate antimicrobic delivery
Poor client compliance
Unable to administer drug
Unwilling to adhere to dosage schedules
Premature withdrawal of drug as clinical signs subside
Discontinuation of drug because of expense
Poor patient acceptance
Unwilling to swallow drug
Vomiting after drug administration
Unable to tolerate side effects of drugs
Ineffective drug
Expired drug
Inactivated drug
Ineffective dose
Diuresis reducing urine drug concentration
Impaired drug transport
Decreased intestinal absorption
Altered perfusion of infected tissue
Microbes sequestered in inaccessible site
Decreased glomerular filtration reducing urinary
excretion
3. Microbes resistant to antimicrobic
Intrinsic resistance
Acquired resistance
4. Superinfection
Failure or inability to recognize and eliminate or control
predisposing cause for UTIIatrogenic reinfection caused by
catheters or surgical techniques

Culture Result ¼ No Bacterial Growth

Negative therapeutic culture results during antibiotic administration are

consistent with successful eradication of infection. Therefore, persistence of
clinical signs should prompt further evaluation of the patient (eg, transrectal
palpation of the urethra, radiographic and ultrasonographic imaging,
cystoscopy) for concomitant nonbacterial disorders as causes for a UTI.
1034 J.P. Lulich, C.A. Osborne / Vet Clin Small Anim 34 (2004) 1027–1041

As illustrated in the case scenario at the beginning of this discussion, dysuria

and hematuria associated with lower urinary tract neoplasia should not be
expected to resolve in association with antimicrobial therapy [5].
False-negative cultures can result from iatrogenic bactericidal events
during collection, storage, or transport of urine samples to diagnostic
facilities. Therefore, appropriate sample handling should be maintained
when samples are shipped for processing.

Culture Result ¼ Isolation of the Same Bacterial Species Susceptible

to the Currently Administered Antimicrobic

Culture results that remain unchanged (ie, the same bacteria exhibiting in
vitro susceptibility to the current antimicrobic drug) during appropriate
antimicrobic therapy indicate that antimicrobics are not reaching the site of
infection. Incomplete or infrequent administration of antimicrobics and
unwillingness of patients to accept medications are common causes for
inadequate tissue delivery of apparently effective medicine. In a study
conducted in conjunction with the American Animal Hospital Association,
only 48% of pet owners were compliant in administering heartworm
preventative [6]. We can expect a similar lack in compliance during
administration of antimicrobic drugs, especially as clinical signs wane. To
improve client compliance, consider medications that are easy to administer
and readily accepted by patients and administration regimens that can be
easily incorporated into owners’ schedules.
In some situations, antimicrobic administration is sufficient but intestinal
absorption is impaired. For example, tetracyclines have been recommended
as an effective treatment for Pseudomonas UTI with a reasonable assurance
of success [7]. To facilitate oral administration, some owners package
medication in appetizing malleable foods, such as cheese. However, when
human patients were administered demeclocycline with 110 g of cottage
cheese, serum concentrations were 60% to 80% lower than when demeclo-
cycline was administered without food [8]. Tetracyclines, not including
doxycycline and minocycline, form relatively insoluble chelates with divalent
and trivalent metals, such as calcium, aluminum, magnesium, and iron.
Antacids containing aluminum, magnesium, and calcium also adversely
affect absorption of tetracyclines and possibly other antimicrobics as well.
Therefore, in addition to evaluating whether or not medications are being
administered at the prescribed dosage and time intervals, the method of oral
administration should be considered as well.
Some diseases may also increase the risk of poor therapeutic response by
impairing adequate delivery of otherwise effective antimicrobics to sites of
infection. For example, eradication of bacteria embedded inside uroliths or
bacteria walled off within abscesses is dependent on passive diffusion of an
adequate quantity of antimicrobic into site(s) of infection. Because these
 J.P. Lulich, C.A. Osborne / Vet Clin Small Anim 34 (2004) 1027–1041 1035

locations lack an intrinsic blood supply to ensure delivery of an adequate

quantity of antimicrobic, however, bacterial cure is unpredictable. There-
fore, in these situations, surgical drainage or eradication of the nidus of
infection remains an important component of successful treatment.
Recognition of recurrent UTIs associated with bacterial infections
inaccessible to antimicrobics that otherwise would eradicate them warrants
further consideration. Although viable bacteria remain sequestered in sites
inaccessible to bactericidal concentrations of antimicrobics, cultures of
samples obtained by cystocentesis during antimicrobic administration are
likely to be negative if the drug is eliminated in a high concentration in
urine. Urine cultures are likely to be positive after an interruption in
antimicrobic therapy, however. Consequently, these types of infections are
commonly diagnosed as relapses of a persisting uropathogen.
Inadequate antimicrobic delivery may also be associated with adminis-
tration of outdated or inactivated medications. We have experienced
situations where poor response to treatment of bacterial UTI may have
been associated with owners who removed tablets containing amoxicillin
with clavulanic acid from their protective foil covering weeks in advance to
facilitate administration. Clavulanic acid is susceptible to inactivation once
exposed to moisture. Similarly, inappropriately prescribing or administering
doses lower than recommended may reduce antimicrobic effectiveness,
especially in polyuric patients.

Culture Result ¼ Isolation of the Same Bacterial Species That Is

Not Susceptible to the Currently Administered
Antimicrobic

Emerging antimicrobial resistance should be suspected when results of

therapeutic cultures reveal persistence of the original organism that is no
longer susceptible to antimicrobics that were previously effective. Resistant
bacteria flourish during ineffective antibiotic use because they have
a selective advantage over the remaining susceptible bacterial population.
Therefore, once resistance is detected, current antimicrobic therapy should
be discontinued. Selection of replacement antimicrobics should be based on
susceptibility results. To ensure that a sufficient concentration of drug is
maintained at the site of infection, administer medications at the higher end
of the dosage range (particularly when administering concentration-de-
pendent antimicrobics, such as fluoroquinolones) and with increased
frequency (particularly when administering time-dependent antimicrobics,
such as potentiated penicillins).
Simultaneous administration of two or more antimicrobial agents is
based on the premise that antibacterial killing activity is enhanced, thereby
minimizing the development of antimicrobic resistance. Only a few
1036 J.P. Lulich, C.A. Osborne / Vet Clin Small Anim 34 (2004) 1027–1041

antimicrobic combinations have been evaluated for treating UTIs in dogs

and cats, however. For example, in dogs, greater than 94% of Staphylococcus
intermedius infections demonstrated in vitro susceptibility to the synergistic
effects of amoxicillin with clavulanic acid, whereas only 20% were susceptible
to ampicillin without clavulanic acid [9]. Compared with other bacterial
species, Pseudomonas spp demonstrate a high frequency of resistance to
many antimicrobics in dogs [4] and human beings [10]. Because of the ability
of bacteria to adapt rapidly by a variety of pathways to avoid antimicrobic
killing, synergistic antimicrobic combinations have been recommended in
human beings [11]. Although antipseudomonal penicillins (ticarcillin and
piperacillin) and aminoglycosides have been historically prescribed, sub-
stitutions of newer antimicrobics (ie, third-generation cephalosporins or
fluoroquinolones for antipseudomonal penicillins or aminoglycosides) may
be as effective. In human beings, efficacy of combination antipseudomonal
therapy has been reflected in improved survival rates in patients with
septicemia and neutropenia [12]. Based on these findings, we assume that
appropriate combination therapy for similar situations would effectively
eradicate resistant bacteria and reduce emergence of resistant urinary tract
pathogens in dogs and cats. Nevertheless, there are also potential negative
aspects of combining two or more antimicrobics. In addition to increased
cost, there is increased risk of toxicity. Also, antagonism of antibacterial
effectiveness may result when bacteriostatic and bactericidal agents are given
concurrently. Although antagonism of one antimicrobic by another has been
a frequent observation in vitro, documented clinical examples of this
phenomenon in veterinary medicine are unknown to us.
In a study evaluating antimicrobic susceptibility profiles in dogs over a 15-
year period (1984–1998), resistance to specific antimicrobic classes directly
correlated with apparent use of that antimicrobial drug. With the in-
troduction of fluoroquinolones, resistant staphylococcal isolates increased
from 0% to 12%. During the same period, penicillin-type antibiotics were
prescribed less frequently and correlated with a decline in staphylococcal
isolates resistant to penicillin-type antibiotics. Results of two studies
evaluating bacteria isolated from skin of dogs also suggest that reductions
in resistance to particular antimicrobics paralleled decreased use of those
specific antibiotic classes [13,14]. These data and other information support
the premise that driving forces for emerging antimicrobial resistance are
repeated exposure of bacteria to antimicrobics (ie, selection pressure) and
access of bacteria to a large antimicrobic-resistant gene pool [15]. On the
basis of these observations, discontinuing antimicrobic therapy to determine
if persistent bacteria will become less resistant or be replaced by commensal
bacteria that are more susceptible to routine antimicrobials is sometimes
a rational therapeutic choice.
One question remains: ‘‘When is antimicrobic withdrawal safe for the
patent?’’ There are no clear guidelines on safety for discontinuing
antimicrobic therapy as a component of the therapeutic strategy for
 J.P. Lulich, C.A. Osborne / Vet Clin Small Anim 34 (2004) 1027–1041 1037

management of resistant bacterial UTIs in dogs and cats. These decisions

must be made on a case-by-case basis, balancing potential risks and
potential benefits in conjunction with appropriate monitoring. When
considering withholding antimicrobic therapy, we attempt to predict the
patient’s ability to tolerate infection without further harm. Potential
sequelae to bacterial UTIs are listed in Box 4.
For example, although infections of the urinary bladder may cause
hematuria and dysuria, they are unlikely to cause systemic illness and are
typically associated with a low risk of mortality. Therefore, we are more
likely to consider discontinuing antimicrobic therapy for resistant infections
localized to the urinary bladder than resistant infections localized to the
kidneys. In a study of persistent and recurrent UTIs in dogs, more than half
were asymptomatic. In that same study, hematuria was absent in 53% and
pyuria was absent in 29% [4]. These findings indicate that when therapy of
some dogs with polyresistant bacterial UTI is withdrawn, these dogs are
unlikely to experience undue discomfort.
We discontinued therapy of several dogs and cats when uropathogens
developed resistance to antimicrobial therapy. Although these patients had
persistent significant bacteriuria, they were asymptomatic (so-called ‘‘asymp-
tomatic bacteriuria’’). In some patients, the bacteria became less resistant to
antimicrobics after several months. In other patients, quantitative cultures
revealed that the original uropathogens were replaced by different bacteria
that were less resistant. Some of these patients have remained asymptomatic
for several years without treatment. When one patient developed dysuria,
treatment with an antimicrobial drug was associated with rapid resolution of

Box 4. Potential sequelae to bacterial urinary tract infection

Lower urinary tract dysfunction
Dysuria, pollakiuria
Urge to incontinence
Damage to the detrusor muscle
Damage to the urethra
Prostatitis (acute or chronic)
Infertility
Struvite urolithiasis and its sequelae (especially urinary
obstruction)
Renal dysfunction (acute and chronic)
Pyelonephritis
Renal failure
Septicemia (especially in patients with concomitant obstruction
to urine flow)
Anemia of chronic infection
1038 J.P. Lulich, C.A. Osborne / Vet Clin Small Anim 34 (2004) 1027–1041

clinical signs and elimination of the initial uropathogens (Proteus spp and
Escherichia coli) from urine. Significant numbers of Streptococcus spp were
cultured from urine collected on the seventh day of therapy (so-called
‘‘superinfection’’), however. These findings are not unique to dogs and cats.
In a prospective study of 50 older women randomized to receive therapy or no
therapy for asymptomatic UTI, there was no difference in morbidity or
mortality between the two groups over 12 months [16]. The group receiving
antibiotics had significantly greater adverse drug reactions and development
of resistant reinfections, however.
If a patient is unresponsive to antimicrobic therapy and if diagnostic urine
cultures were not obtained before therapy, isolation of resistant bacteria in
subsequent cultures may indicate empiric selection of an ineffective antimi-
crobial drug. Some bacteria have intrinsic antimicrobic-resistant mechanisms
that are inherent to the species. For example, Pseudomonas spp are in-
trinsically resistant to most b-lactam antibiotics because they are sufficiently
hydrophobic and these drugs do not diffuse through the outer bacterial
membrane. This situation could be avoided by initial selection of an
antimicrobic on the basis of in vitro susceptibility testing:

Culture Results ¼ New Bacterial Species

Cultures of urine during antimicrobial therapy that reveal eradication of

microbes identified by diagnostic cultures but growth of new uropathologic
bacteria indicate that previous antimicrobic therapy was effective against the
initial pathogen. In this situation, it is apparent that the antimicrobial drug
predisposed the patient to infection with a resistant uropathogen (ie,
superinfection). Superinfections are defined as infections with an additional
organism during the course of antimicrobial treatment. They are most likely
to occur in association with indwelling urethral catheters or as sequelae to
urinary diversion techniques in which the urinary tract communicates with
the intestinal tract. They also occur when proximal portions of the urethra,
urinary bladder, or kidneys communicate directly with the exterior (eg,
antepubic urethrostomy, tube cystostomy, percutaneous nephropyelos-
tomy). Unless the breach in host defenses can be identified and corrected,
recurrent infections are imminent even with effective antimicrobic drugs to
treat the current infection. Because ongoing antimicrobic therapy is selecting
for resistant strains, it should be discontinued. To minimize drug-induced
superinfections, appropriate therapy should be directed toward eliminating
or controlling abnormalities in host defenses.

How to interpret urine cultures to diagnose and manage recurrent infections

Recurrence of clinical or laboratory signs of UTI after withdrawal of
therapy may be classified as bacterial relapse or reinfection. After successful
 J.P. Lulich, C.A. Osborne / Vet Clin Small Anim 34 (2004) 1027–1041 1039

antimicrobic therapy, timely follow-up evaluations (so-called ‘‘surveillance

cultures’’) are indicated to detect recurrent infections at a subclinical state
(see Box 2). Relapses (persistent infections) are defined as recurrences caused
by the same species and serologic strain of bacteria, usually within several
weeks of cessation of therapy. Recovering the same organism from pre-
viously sterile urine is presumptive evidence that antimicrobial therapy failed
to eradicate the infection completely. Deep-seated infections or a lapse in
compliance is a common cause for bacterial relapses. For example, infections
of the canine prostate gland are a common cause for recurrent infections. In
this situation, relapses seem to be related to poor penetration of antimicro-
bial drugs into prostatic secretions. Reinfections may also be associated with
persistent abnormalities in prostatic defenses against bacterial infections.
Another cause of relapsing bacterial UTI may be linked to the recent
observation that uropathogenic E coli in mice can invade uroepithelial cells
and encase themselves in protective polysaccharide-rich pods that evade
immune stimulation and antimicrobic killing [17,18]. To eradicate relapsing
infections, consider treatment for a longer period (3–6 weeks) with
appropriate antimicrobics capable of greater tissue penetration (lipid-soluble
agents with low protein binding). To ensure that a sufficient concentration of
drug is maintained at the site of infection, administer medications at the
higher end of the dosage range (particularly when administering concentra-
tion-dependent antimicrobics, such as fluoroquinolones) and with increased
frequency (particularly when administering time-dependent antimicrobics,
such as potentiated penicillins). Reculturing urine during therapy and after
therapy is essential to monitor therapeutic efficacy.
Reinfections are defined as recurrent infections caused by a different
pathogen(s). If tissues of the urinary tract have had time to heal from
infection, reinfections often occur at a longer interval after cessation of
therapy than do relapses. Detection of frequent reinfections after antimi-
crobial therapy is an indication to evaluate the patient for predisposing
causes capable of breaching normal host defenses. Reinfections should be
managed by choosing antimicrobial agents on the basis of antimicrobial
susceptibility tests. Elimination of bacterial pathogens associated with
reinfections may require therapy of shorter duration (10–14 days) than
recurrences associated with relapses (3–6 weeks). Infrequent recurrences
(two or three times per year) may be treated as single episodes (ie, short
course of a suitable antimicrobial agent).
In some patients with recurrent reinfections, elimination of predisposing
causes may be impossible. In such cases, it may be helpful to provide low-
dose (preventative) antibacterial therapy for an indefinite period (6 months
or more) with drugs primarily eliminated in urine. Reduced dosages
(approximately 33% to 50% of the daily therapeutic dose) of drugs excreted
in high concentration in urine may be used provided there has been
complete eradication of bacterial pathogens by therapeutic dosages of
appropriate drugs first. Logically, preventative antimicrobial therapy would
1040 J.P. Lulich, C.A. Osborne / Vet Clin Small Anim 34 (2004) 1027–1041

be inappropriate for management of patients with recurrent bacterial UTI

caused by relapses (reinfection with the same organism), because the
organism has never been eliminated.
Even though this preventative dosage regimen may not result in
bactericidal concentrations of antimicrobials throughout the day, low
concentrations of some drugs apparently interfere with development of
fimbriae by some uropathogens. This, in turn, interferes with the ability of
potential pathogens to adhere to uroepithelial cells. It is best to give one
daily preventative dose of the antibiotic at a time when the drug is likely to
be retained in the urinary tract for several hours (ie, before bedtime).
During preventative therapy, urine samples collected by cystocentesis
(not by catheterization or voiding) should be recultured approximately once
each month. If bacteria are identified, a ‘‘breakthrough’’ infection may have
occurred. The patient should be treated again with therapeutic dosages of an
antimicrobial drug selected on the basis of susceptibility tests. Once the
infection has been eradicated and the associated inflammatory response
subsides (usually 2–4 weeks), preventative therapy may be resumed.
After 6 to 9 months of consecutive negative urine cultures, therapy may
be discontinued on a trial basis to determine if a reinfection will occur. If
abnormalities in host defenses have healed, UTI may not recur. If UTI
develops within a short period, the procedures outlined previously should be
repeated.
Long-term use of antimicrobial agents is not without risk of adverse
effects. For example, sulfadiazine-trimethoprim combinations have been
associated with keratoconjunctivitis sicca, folate deficiency anemia, and
immune complex reactions. The potential for long-term low-dose antimi-
crobic therapy to contribute to bacterial resistance in commensal bacteria in
dogs and cats is unknown but appears likely.

Summary
Quantitative urine cultures and antimicrobial susceptibility profiles pro-
vide an accurate method of diagnosing bacterial infection and monitoring
therapy. Diagnostic urine cultures are performed prior to initiation of
antimicrobic therapy and are essential to avoid treating noninfectious
disorders with antimicrobial drugs. Therapeutic urine cultures are obtained
during antimicrobic therapy and are used to verify antimicrobic efficacy and
to help determine reasons for antimicrobic failure. Surveillance urine
cultures are preformed shortly after completion of successful antimicrobic
therapy. Surveillance cultures are used to detect recurrent infections at
a subclinical state and are essential to differentiate relapses from reinfections.

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