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Bacterial Cystitis
Leah A. Cohn
Professor, University of Missouri – College of Veterinary Medicine
[email protected]
Urinary tract infections (UTI) are common in dogs, affecting as many as 14% of
all dogs during their lifetime. As a result of anatomy, UTI occur far more often in
females than in males. UTIs occur less often in cats. While the urinary tract is
susceptible to viral, fungal, and even parasitic infections, bacteria are responsible
for most UTI and will be the focus of this presentation. The focus of this
presentation will be on lower UTI, and more specifically bacterial cystitis.
Cystitis can result in pollakiuria, inappropriate urination or urge incontinence,
dysuria, hematuria, cloudy urine, perineal licking, perivulvar dermatitis, or a
strong urine odor. Alternatively, bacteria can colonize the bladder without
producing any clinical signs at all.
Bacterial cystitis often causes an active urine sediment with WBC, +/- RBC, +/struvite crystals, and depending on bacterial concentration, rods or cocci may be
visualized microscopically. The “dipstick” can’t be used in place of microscopic
sediment exam as the colorimetric test for WBC and bacteria are not accurate in
dogs and cats. Identification of an active sediment is hampered if urine is dilute,
or if inflammation is suppressed by conditions such as hyperadrenocorticism or
steroid therapy. Therefore, sediment alone cannot be used to rule out UTI. Urine
culture is the gold standard to diagnose or rule out UTI.
Unless transitional cell carcinoma or coagulopathy are suspected, urine for culture
should be obtained by cystocentesis. Recommendations from the International
Society for Companion Animal Infectious Diseases(ISCAID) are that urine
culture should be performed for every UTI, but the author may employ empiric
therapy for uncomplicated UTI (see below). If an empiric choice fails or if
infection recurs, culture is necessary. Urine for culture should be processed as
soon as possible, or samples refrigerated in special tubes containing preservatives
can be used if a delay of up to 72 hours is necessary. Recently, Flexicult ™ Vet
plates (Atlantic Diagnostics, FL) have become available to both culture urine and
provide limited antimicrobial susceptibility results. Commercial laboratories will
provide antimicrobial susceptibility testing based on Agar disk diffusion, or
antimicrobial dilution to determine Minimum Inhibitory Concentration (MIC) of
an antimicrobial. For unusually resistant pathogens, an expanded susceptibility
profile is often offered either automatically or by request.
As many as a third or more of all bacterial cystitis in dogs and cats is due to
infection with the E. coli, with another third of infections caused by
Staphylococcus sp, Streptococcus sp, or Enterococcus sp. For the remainder,
Proteus, Klebsiella, Pseudomonas, and a variety of other pathogens are identified.
Although usually only a single organism is identified, up to a quarter of infections
(especially complicated infections) are caused by 2 or more pathogens.
Urinary tract infections can be categorized as “Uncomplicated” or
“Complicated”. Uncomplicated infections are first time bacterial infection of the
lower urinary tract of spayed female dogs with no underlying structural or
functional urinary issues and no systemic disease. All the rest are complicated,
including infection in any cat or in male dogs.
For uncomplicated infections, a 7 day course of either amoxicillin or TMS is
suggested by ISCAID. Although excreted in the urine, they do not recommend
routine use of amoxicillin/clavulanic acid because there is no evidence of an
improved outcome by using an expanded spectrum but the risk of developing
resistant pathogens may increase. Although often effective, fluoroquinolones are
reserved for lower UTI with documented resistance to amoxicillin and TMS as
routine use may contribute to development of drug-resistant pathogens. If clinical
signs resolve within the first few days of therapy, no further evaluation is
required. If signs fail to resolve or recur, it should be treated as a complicated
infection.
Culture and susceptibility (C/S) should be conducted for all complicated UTI.
Pending culture, categorization of infection by Gram stain and morphology can
guide therapy. Again, amoxicillin or TMS are reasonable choices pending C/S.
Ideally, the antimicrobial chosen should be excreted in the urine in an active form
(eg, amoxicillin, cephalosporin’s, TMS, fluoroquinolones), which allows urine
concentrations to surpass blood concentrations. Doxycycline is a poor choice as it
is excreted through the intestines instead of the kidneys. Pathogens resistant to
commonly used antimicrobials pose unique challenges. Nitrofurantoin,
meropenem, and imipenem-cilastatin are reserved for multi-drug resistant
infections.
Most frustrating are those complicated UTIs that are categorized as recurrent (3 or
more UTI in 12 months), relapsed (re-infection with the same pathogen within 6
months of apparently successful treatment), or refractory (persistent infection with
the same pathogen despite in vitro susceptibility) UTI. Super-infections refer to
recognition of an additional species of bacteria during treatment for a recognized
UTI. All these warrant a search for predisposing conditions via blood tests,
imaging studies, or other means. Whenever possible, factors that complicated UTI
should be addressed. For example, cystoliths may be removed, diabetes mellitus
or hyperadrenocorticism can be controlled, and structural anatomic defects may
be amenable to surgical correction. Obviously some complicating factors are
intrinsic to the patient (eg, sex or species), and others are simply not correctable
(eg, permanent paralysis).
Refractory, recurrent, and relapsed infections without a correctable underlying
pathology are a real problem with no easy solutions. Often times, resistant
infections require antimicrobials that are expensive, toxic, or must be given by a
parenteral route. These decisions can only be made in light of C/S testing.
Additionally, drug absorption, excretion, inactivation, comorbidities, and
individual animal factors (eg, renal function) must be considered. A 4 week
course is often prescribed for complicated UTI but evidence on optimum duration
is absent. Since infections don’t always respond as predicted (see refractory
infections and super-infections), re-culture the urine about a week into treatment.
Even if culture during treatment is negative, culture should be repeated 7 days
after antimicrobial completion. Biofilms, aggregates of microbes encased in
polymeric material on a solid surface (including bladder epithelia, stones, or
catheters), are formed by some urinary pathogens and serve to protect the
microbes from antibiotics. Various strategies have been suggested to “break up”
biofilms, but the best way to do so is not yet determined.
In humans, the term “asymptomatic bacteriuria”, or ABS, refers to 2 consecutive
urine cultures containing > 100,000 CFU/ml bacteria in a patient lacking urinary
symptom. Subclinical bacteriuria can also be found in dogs or cats – urinary
bacteria without signs of UTI. If urine sediment is active (eg, many WBC) or if
the animal is immune suppressed and therefore more susceptible to ascending
infection, treatment is indicated. However, if these conditions are not met,
treatment may not be necessary, even in the face of a multidrug resistant
organism. Often, and Enterococci is present in such subclinical bacteriuria cases.
Enterococci may respond readily to first line antimicrobials, but they are often
resistant to many drugs. All Enterococci are considered resistant to all
cephalosporins, and have limited susceptibility to fluoroquinolones. When present
as part of a dual infection, they will often not grow on initial culture and only
become apparent once the other pathogen is suppressed by antibiotics.
A variety of other treatment and preventative strategies have been suggested for
complicated UTI, but there is little scientific evidence to support any of these
options.
 Fosfomycin (Monaural) is an antimicrobial with proven efficacy against
human uropathogenic E. coli. It comes as a 3-gram, one dose packet to treat
simple UTI in women, and is often affective against MDR pathogens.
Clinical isolates from cats and dogs were quite susceptible in vitro. Although
no dose has been published for this drug, the author has used 1/3 of a packet
for three days in a row in dogs with reasonable success.
 Prophylactic antibiotic use has not been studied in veterinary medicine.
Routine use of antibiotics to prevent frequent recurrence of UTI may or may
not work, and may increase the likelihood that infections that do develop will
contain more drug resistant pathogens. If used, it is typical to choose
amoxicillin or a cephalosporin given as a single dose after the last night-time
voiding. For drugs like typically given BID or TID, the usual dose is given
but only once at night. Alternatively, the antibiotic may be given as per
standard dosing guidelines 1 week out of 4 per month. Urine should be
routinely cultured, and if re-infection occurs a treatment protocol instituted.
 Methenamine is given orally and transformed in the urinary bladder, provided
an acidic urine pH, into formaldehyde. Because of the necessary bladder pH,
it will not be effective against urease-producing microbes (eg, Proteus,
Staphylococcus, Ureaplasma). The drug is often given with a urinary
acidifier to force urine pH< 6.0, a situation contraindicated in animals with
renal failure or other causes for metabolic acidosis. While not suitable to treat
UTI, this therapy may minimize frequency of recurrence.
 While many vets are familiar with the use of probiotics in treating diarrhea,
there is a theoretical role for their use in minimizing recurrent UTI. Since the
pathogens responsible for lower UTI generally originate in the GI tract, the
theory is that replacing pathogenic bacteria with “healthy” bacteria will
reduce the risk of urinary infection. While not proven, this is a safe treatment
with only minimal to moderate costs. There are also vaginal suppository
probiotics if the owner is willing and able to place them, daily initially.
 Topical instillation of antimicrobials/antiseptics has not been adequately
evaluated, but there may be a place in animals with biofilm forming
infections, UTIs recur frequently and an underlying cause cannot be
corrected, or when there is easy access to the bladder as in animals with
cystostomy catheters in place. Tricide (Molecular Therapeutics, Athens, GA)
is a topical chelating agent that can be combined with neomycin or
fluoroquinolone for installation into the bladder. It has been used by repeated
installation, initially daily then reducing frequency, in some dogs with
urinary biofilms and MDR resistant infections.
 Cranberry extract/concentrates/ juice has bacteriostatic properties in humans.
While unproven, these are safe and inexpensive nutriceuiticals. One
commonly used preparation is Crananidin® (Nutrimax Labs; dose per
package directions)
 D-mannose has been recommended for E. coli infections on the basis that
uropathogenic E. coli possess adhesion fimbriae that non-uropathogenic E.
coli do not, and D-mannose blocks adhesion in vitro (other uropathogens do
not have the same fimbriae). Available as a powder or capsule, efficacy
studies of this nutricutical in dogs or cats are lacking.
 The root of Coleus forskholii (forskalin) is available as an herbal supplement
and may increase cause cytoskeletal contraction and expunge colonizing E.
coli. Although no published evidence supports its use in pets, anecdotal
reports of 385 mg PO q 8h in dogs >20 kg or 190 mg <20 kg, or 50 mg/cat q
8h have been safe and may be helpful.
 In humans, purposeful infections with avirulent organisms known to cause
asymptomatic UTI have been induced to treat symptomatic UTI. In healthy
dogs, this has not produced long-term colonization but the situation may be
different in dogs with chronic UTI.
Antimicrobial options for UTI in dogs and cats (adapted from ISCAID
recommendations)
Amikacin
Amoxicillin
Amoxicillin/clavulanate
Cephalexin
Cefpodoxime
Ceftiofur
Chloramphenicol
Enrofloxacin
Dogs: 15–30 mg/kg
IV /SC q24h; 10-14
mg/kg cats
11–15 mg/kg PO q8h
12.5–25 mg/kg PO
q8h
12–25 mg/kg PO
q12h
5 to 10 mg/kg q24h
PO
2 mg/kg q12-24h SC
Dogs: 40–50 mg/kg
PO q8h; 12.5-20
mg/kg cats
10–20 mg/kg q24h
(dogs); 5 mg/kg cats
Imipenem-cilastatin
5 mg/kg IV/IM q6-8h
Marbofloxacin
2.7–5.5mg/kg PO
q24h
Meropenem
8.5 mg/kg SC or IV q
Reserved for infections with MDR and
with documented susceptibility in vitro.
Avoid if renal compromise present.
First line choice
Not necessarily a better empiric choice
than amoxicillin
Not necessarily a better empiric choice
than amoxicillin. Enterococci are resistant
Not necessarily a better empiric choice
than amoxicillin. Enterococci are resistant
Not necessarily a better empiric choice
than amoxicillin. Enterococci are resistant
Not excreted in the urine intact. Reserved
for MDR infections. Minimize human
contact with drug.
Reserved for infections not susceptible to
first line choices and with documented
susceptibility in vitro
Reserved for infections with MDR and
with documented susceptibility in vitro
Reserved for infections not susceptible to
first line choices and with documented
susceptibility in vitro
Reserved for infections with MDR and
Methenamine hippurate
Methenamine mandelate
Nitrofurantoin
12 to q 8 hr
Dogs: 500 mg PO q12
h, 250 mg cats
Dogs: 10-20 mg/kg
q8hr
4.5-5 mg/kg PO q8 h
Orbifloxacin
2.5-7.5 mg/kg PO 24
h
Trimethoprim-sulfadiazine
15 mg/kg PO q12 h
with documented susceptibility in vitro
Prophylactic and not therapeutic. Must
keep urine pH <6. GI upset common.
Often causes stomach upset. Reserved for
infections not susceptible to first line
choices and with documented
susceptibility in vitro
Reserved for infections not susceptible to
first line choices and with documented
susceptibility in vitro
First line choice. Monitor for adverse
reactions and hypersensitivity
Selected References
Weese JS, Blondeau JM, Boothe D, Breitschwerdt EB, et al. Antimicrobial Use
Guidelines for Treatment of Urinary Tract Disease in Dogs and Cats:
Antimicrobial Guidelines Working Group of the International Society for
Companion Animal Infectious Diseases Veterinary Medicine International.
2011, doi:10.4061/2011/263768
Hubka P, Boothe DM. In Vitro susceptibility of canine and feline Escherichia coli
to fosfomycin. Vet Microbiol 149:277-282, 2011.
Seguin MA, Vaden SL, Altier C, et al. Persistent uri-nary tract infections and
reinfections in 100 dogs (1989-1999). J Vet Intern Med. 2003;17:622-631.
Bishop BL, Duncan MJ, Song J, et al. Cyclic AMP-regulated exocytosis of
Escherichia coli from infected bladder epithelial cells. Nature Medicine
13:625-630, 2007.
Healthy Dogs with Positive Titers – Now What?
Leah A. Cohn, DVM, PhD, DACVIM (SAIM)
Professor, University of Missouri - College of Veterinary Medicine
Serologic titers detect antibodies or antigen in fluid samples, and these tests
have long held an important place in disease diagnosis. In addition to a role in
diagnosis, wehave routinely employed such tests to screen cats for retroviral infections
or dogs for heartworm infection for decades. In recent years, there has been an
increased use of serologic titers in healthy dogs as a screening mechanism for potential
pathogens (e.g., Ehrlichia, Lyme, Anaplasma), or as part of a panel of tests applied to an
animal with disease even when the disease doesn’t fit the clinical picture typical of the
pathogen being screened (e.g., R. rickettsii testing is part of most tick panels even if
Rocky Mountain Spotted Fever is not a clinically relevant differential diagnosis). These
screening tests come in a variety of formats and use a variety of technologies; some are
“mailed out” and other run as “cage side” tests; some are qualitative, others
quantitative. Veterinarians are faced with the choice to screen or not to screen, and if
they do screen, they will face questions as to how to handle a positive test in a healthy
pet. To respond to those questions, they must understand something of the test itself
(e.g., antigen vs. antibody, sensitivity and specificity), the pathogen prevalence in the
region (which, in turn, effects predictive value), the pathogen behavior (e.g., is there an
effective immunologic response, or is there a chronic carrier state?), and the disease
caused by the pathogen (e.g., is the disease simple or difficult to treat?)
Antigen vs. antibody matters to interpretation. Tests that detect antigen (e.g.,
most serologic heartworm tests, FeLV tests in cats), can prove that a pathogen is
present in the sample. When these tests are negative, they cannot prove that a
pathogen is absent. For example, cats with heartworm infection usually have very low
worm burdens (1 or 2 worms is typical), and the antigen test specifically detects antigen
in female worms. If a cat with heartworms has only one male worm, the antigen test will
always be negative.
As opposed to antigen tests, antibody tests detect the host’s response to
antigenencountered at some point in the past. Antibody formation takes some time.
This means that titers may be absent during acute infection/illness, which is the reason
that convalescent titers (to demonstrate seroconversion or a 4-fold increase in titer) are
often required to confirm acute disease such as leptospirosis or RMSF. On the other
hand, antibodies may persist long after an infection has resolved, or at least after any
threat of illness due to infection has resolved. For example, dogs infected with E.
ewingii may remain well or develop acute illness, but chronic illness is not reported. Yet,
chronic infection can lead to chronically increased antibody titers even though the risk
of illness is past. Antibodies can be cross-reactive, meaning that a positive test result
may be due to exposure/infection not with the pathogen of interest, but with a related,
cross-reactive organism (pathogenic or not). As an example, the pathogen that causes
RMSF is cross-reactive with many other Spotted Fever Group organisms, most of which
are not pathogenic; this leads to frequent “false positive” tests. Additionally, certain
antibodies may be found after vaccination as well as after natural infection. On
occasion, diagnostic tests are designed to “work around” this problem, as is the case
with C6 peptide assays for Lyme disease that are positive only after natural exposure to
Borrelia burgdorferiand not after vaccination.
An additional set of limitations for serologic tests pertains to the likelihood that
a given test accurately reflects pathogen/disease presence or absence. Any test, no
matter how good, is subject to both false positive and false negative results. These are
reflected in the diagnostic sensitivity and specificity of the test. Diagnostic sensitivity
refers to the proportion of tests run on infected animals that are positive, while
diagnostic specificity refers to the proportion of tests run on uninfected animals that are
negative. It is apparent then that to “rule out” a diagnosis, a test with a high sensitivity
is desired, while to “rule in” a diagnosis, a test with a high specificity is desired.
Generally for screening exams, a test with high sensitivity is preferred over one with
high specificity. Even more important to the clinician than a given test’s sensitivity and
specificity are the test’s positive and negative predictive values. The positive predictive
value is the probability that an animal that tests positive actually has the infection in
question, while the negative predictive value is the probability that an animal that tests
negative is free of infection. While positive predictive value certainly is related to the
sensitivity and specificity of the diagnostic assay, it is also related to the prevalence of
disease in the population of animals tested. This means that a positive test result in a
population with a low prevalence of disease, even when the test is very sensitive and
specific, has a greater chance of being a false-positive than when the same test is
applied to a population with a high disease prevalence. As an example, if a diagnostic
test has a sensitivity of 95% and a specificity of 90%, the positive predictive value of that
test in a population with a 50% pathogen prevalence would be 90%. This means that 1
out of 10 positive tests would be a false positive. On the other hand, for that very same
test applied to a population with a 5% prevalence of pathogen, the positive predictive
value would be 33%, meaning that 2 out of 3 positive tests might be false positives.
Finally, understanding the disease that might result from the pathogen exposure
identified on a screening test impacts reaction to a positive screening test. If the
pathogen frequently results in chronic disease, it makes sense to intervene before
disease is manifest. This is very true for pathogens such as heartworm infection – a
positive screen should prompt treatment. On the other hand, if the pathogen seldom
results in chronic disease, a more “watch and wait” approach may be the responsible
approach. As an example, E. ewingii causes acute illness, but as far as we know there are
no chronic disease consequences.
There will always be both pro’s and con’s to screening healthy dogs for
infection. These are summarized here:
Screening Pro’s
• May allow treatment before disease occurs
• Provides regional prevalence information
• May provide sentinel information for both human and animal infections
• Informs ectoparasite control practices
• May reduce pathogen reservoir for some infections
• Alerts to non-tested pathogens carried by the same vectors
Screening Con’s
• False +’s in low prevalence areas are a real issue
• May lead to unneeded treatment
• Infection may never become clinical
• Past infection may be resolved
• Adverse effects; costs; resistance to drugs
• Treatment may not “cure” and doesn’t prevent re-infection
• Role of dogs for human infection debatable for some pathogens
So with all this information, what is the optimum response to a positive result
on a screening test in an apparently healthy dog? There is no single answer, but instead
all the factors discussed, as well as the owner’s wishes, must be considered. General
guidelines are presented here:
Positive Heartworm Screen
1) Evaluate for microfilaria
2) Consider confirmatory re-test
3) Obtain chest radiographs, CBC, chemistry profile, and UA for disease staging
and pre-treatment health evaluation. Consider echocardiogram if murmur
or cardiomegaly present.
4) Initiate treatment per American Heartworm Society Guidelines using
melarsomine (http://www.heartwormsociety.org/veterinaryresources/canine-guidelines.html#8)
5) Initiate heartworm prophylaxis
6) Retest in 6-12 months
7)
Positive Ehrlichia Screen
1) Know the test; sSome tests screen only for E. canis, others for E. canis AND E.
ewingii OR E. chaffeensis.
2) Discuss ectoparasite control with the pet owner. You know have proof their pet
was not only bitten by a tick, but that tick transmitted a pathogen.
3) Perform a CBC to look for morulae, thrombocytopenia, anemia, or
hyperglobulinemia. If these are identified, antibiotic treatment is indicated.
4) Perform a UA to look for proteinuria. If identified, perform UPC and blood
pressure, and consider further evaluation and antibiotic treatment.
5) If CBC and UA are normal, discuss these three options with the owner and let
them be part of the decision. The options are:
a. Watch and wait (my preferred option for my own dogs)
i. Educate the owner about the signs of disease
ii. Repeat CBC and UA in one year
b. Investigate further
i. Perform more specific serologic tests to ID species of Ehrlichia
ii. Perform PCR, realizing that a negative test does NOT rule out
infection
c. Treat with antibiotics
i. Realize there are issues of cost, convenience, and adverse
effects associated with tetracycline use
ii. Realize that antibiotics may not eliminate the pathogen entirely
iii.
Positive Lyme Screen
1) Know the test. Some tests may be positive after vaccination, others only with
natural infection (i.e., the C6 peptide test by IDEXX will not be positive after
vaccination, but Osp- based tests will be positive after vaccination).
2) Discuss ectoparasite control with the pet owner. You know have proof their pet
was not only bitten by a tick, but that tick transmitted a pathogen.
6) Perform urinalysisto look for proteinuria. If identified, perform UPC and blood
pressure, and consider further evaluation and antibiotic treatment.
3) Perform Quantitative C6 peptide test.
a. If C6 antibody is <30 U/ml in the healthy dog, discuss options with
owner and let them be part of the decision. The options are:
i. Watch and wait (my preferred option for my own dogs)
1. Educate the owner about the signs of disease
2. Repeat UA in one year
ii. Treat with antibiotics
1. Realize there are issues of cost, convenience, and
adverse effects associated with use of any antibiotic
2. Repeat C6 peptide in 6 months to confirm reduced titer
resulting from treatment
b. If C6 antibody is >30 U/ml in the healthy dog, initiate antibiotic therapy
1. Repeat UA in one year
2. Repeat C6 peptide in 6 months to confirm reduced titer
resulting from treatment
4) Discuss pros and cons of Lyme vaccine going forward
Positive Anaplasma Screen
1) Know the test. Some cross react between A. phagocytophilum and A. platys,
others don’t.
2) Discuss ectoparasite control with the pet owner. You know have proof their pet
was not only bitten by a tick, but that tick transmitted a pathogen.
3) Perform a CBC to look for morulae, thrombocytopeniaor hyperglobulinemia. If
these are identified, antibiotic treatment is indicated.
4) Perform a UA to look for proteinuria. If identified, perform UPC and blood
pressure, and consider further evaluation and antibiotic treatment.
5) If CBC and UA are normal, discuss the three options with the owner and let
them be part of the decision. The options are:
a. Watch and wait (my preferred option)
i. Educate the owner about the signs of disease
ii. Repeat CBC and UA in one year
b. Treat with antibiotics
i. Realize there are issues of cost, convenience, and adverse
effects associated with tetracycline use
ii. Realize that antibiotics may not eliminate the pathogen entirely
Positive RMSF titer (generally not a screen for healthy dogs, but often part of tick panel
applied to dogs with suspected tick-transmitted infection)
1) Discuss ectoparasite control with the pet owner. You know have proof their pet
was not only bitten by a tick, but that tick transmitted a pathogen.
2) Consider if this dog might actually have RMSF
a. Is this an ACUTE disease? (dogs with RMSF are better or dead in 2-3
weeks)
b. Is this vasculitis?
c. Is the dog febrile?
If the answers are NO, the dog likely has either had past infection, or was infected with a
different spotted fever group organism!