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Urinary Tract Infections

Dr. Lamya Alnaim, PharmD


Introduction
UTIs represent a wide variety of
syndromes including urethritis,
cystitis, prostatitis, and
pyelonephritis.
One of the most commonly occurring
infections.
Introduction
Young women are particularly
susceptible, 40% of all women will
suffer at least one UTI at some
point.
Infection in men occurs less
frequently until the age of 50,
when incidence in men and women is
similar.
Definition
It is the presence of
microorganisms in the urinary tract
that cannot be accounted for by
contamination.
The organisms have the potential to
invade the tissues of the UT and
adjacent structures.
Definition
A UTI can manifest as several
syndromes associated with an
inflammatory response to microbial
invasion that range from
asymptomatic bacteriuria to
pyelonephritis.
Classification
According to anatomic site of
involvement:
Lower tract infection: cystitis,
urethritis, prostatitis
Upper tract infection:
pyelonephritis, involving the kidneys
Classification
According to Degree
1-Uncomplicated
Occur in individuals who lack
structural or functional
abnormalities in the UT that
interfere with the normal flow of
urine.
Mostly in healthy females of
childbearing age
Classification
According to Degree
2-Complicated
predisposing lesion of the UT such as
congenital abnormality or distortion
of the UT, a stone a catheter,
prostatic hypertrophy, obstruction,
or neurological deficit
All can interfere with the normal
flow of urine and urinary tract
defenses.
Recurrent UTIs
Multiple symptomatic infections with
asymptomatic periods
Reinfection: caused by a different
organism than originally isolated and
account for the majority of
recurrent UTIs.
Relapse: repeated infections with
the same initial organism and
usually indicate a persistent
infectious source.
Other Definitions
Asymptomatic bacteriuria
Common among the elderly
Bacteiruria > 105 bacteria/ml of
urine without symptoms
Symptomatic abacteriuria:
Symptoms of frequency and dysuria
in the absence of significant
bacteriuria
Other Definitions
Significant bacteriuria
More than 105 bacteria /ml (CFU)
of urine in clean catch specimen
1/3 of symptomatic women have
CFU counts below this level
A bacterial count of 100 CFU/ml
has a high positive predictive value
of cystitis in symptomatic women
Other Definitions

Count less than 105 may represent


true infection in certain situations
Concurrent antibacterial drug
administration
Rapid urine flow
Low urine PH
Upper tract obstruction
Etiology
The microorganism that cause UTIs
usually originate from the bowel flora
of the host
Uncomplicated UTI:
E.coli accounts for 85%
S.saprophyticus 5-15%
K.pneumoniae, protues sp,
Pseudomonas, and Enterococcus 5-
10%
S.epidermidis if isolated should be
considered a contamination
Etiology
Complicated UTIs
More varied and generally more
resistant
E.coli 50%
K.pneumoniae, protues sp,
Pseudomonas, Enterococcus,
Enterobactor sp
Etiology
Complicated UTIs
Enterococcus fecalis 2nd most
frequently isolated organism in
hospitalized patients
S.aureus infection is more commonly
a result of bacteremia producing
metastatic abscesses in the kidney
Candida sp is common cause of UTI
in critically ill and chronically
catheterized patients
Etiology
The majority of UTIs are caused
by a single organism
In patients with stones , indwelling
catheter, or chronic renal
abscesses multiple organisms may
be isolated
Although this may be due to
contamination and a repeat
evaluation should be done.
Predisposing factors
Abnormalities in the UT that
interfere with natural defenses
1-Obstruction can inhibit urine flow,
disrupting the natural flushing and
voiding effect in removing bacteria
from the bladder and resulting in
incomplete emptying
Predisposing factors
Abnormalities in the UT that
interfere with natural defenses.
2-Condition that result in residual
urine volumes e.g. prostatic
hypertrophy, urethral stricture,
calculi, tumors, and drug such as
anticholinergic agents, neurological
malfunctions associated with stroke,
diabetes, and spinal cord injuries.
Predisposing factors
Abnormalities in the UT that
interfere with natural defenses.
3-Other risk factors include: urinary
catheter, mechanical
instrumentation, pregnancy, and the
use of spermicidies and diaphragms
Clinical presentations
Lower tract infection:
Include dysuria, urgency,
frequency, nocturia, suprapubic
heaviness, and hematuria in women.
No systemic symptoms
Upper tract infection:
Flank pain, costovertebral
tenderness, abdominal pain, fever,
nausea, vomiting and malaise.
Clinical presentations
Elderly patients:
Frequently do experience specific
urinary symptoms
Altered mental status, change sin
eating habits, or GI symptoms
Patients with catheters
Will have no lower tract symptoms
Just flank pain and fever
Laboratory findings
Symptoms alone are unreliable for
diagnosis
Examination of the urine is the
cornerstone of diagnosis
Collection of urine:
Mid stream clean catch method is
preferred method
Laboratory findings
Collection of urine:
Catheterization for patient who are
uncooperative or unable to void, but
introduction of bacteria in the
bladder occurs at 1-2%
Suprapubic aspiration bypasses the
contaminating organism in the
urethra, safe and painless.
Diagnosis:
Based on isolation of significant
numbers of bacteria from a urine
specimen
Microscopic examination
is performed by preparing a gram
stain that indicates the morphology
of the organism and help direct
the selection of an appropriate AB.
Diagnosis:
Microscopic examination
The presence of one organism per
oil-immersion field in an un
centrifuged sample correlates with
100,000 bacteria/ml
Diagnosis:
Pyuria: WBC > 10 WBC/mm3
it only signifies the presence of
inflammation
Sterile pyuria is associated with
urinary tuberculosis, chlamydial,
and fungal infections
Diagnosis:

Hematuria, non-specific, may indicate


other disorders such as calculi or
tumor
Protenuria is found in the presence of
infection
Diagnosis
Biochemical tests
1-dipstick test for nitrite: bacteria
in the urine reduce nitrate nitrite
false negatives are common and
caused by
gm+ve or pseudomonas that do not
reduce
low urinary PH
frequent voiding and dilute urine
Diagnosis
Biochemical tests
2- leukocyte esterase dipstick test
rapid screening test for detecting
the presence of pyuria
LE is found in neutrophills
Specific for detecting more than 10
WBC/mm3
Diagnosis
Quantitative urine culture
Based on properly collected urine
Urine is normally sterile
Determines the number of bacteria
present in a urine sample
1/3 of symptomatic women have
bacteria < 105
Diagnosis
Quantitative urine culture
one organism per oil immersion field
correlates with 100,000 CFU/ml by
culture
Susceptibility
determine bacterial susceptibility to
different antimicrobials
Treatment
Desired outcome
Prevent or treat systemic
consequences of infection
Eradicate the invading organism
Prevent reoccurrence of infection
Treatment
Non-specific therapies
1-fluid hydration:
rapid dilution of bacteria and
removal of infection through
increased voiding
2-cranberry juice
increase the antibacterial activity
of urine
Treatment
Non-specific therapies
3-urinary analgesics
phenazopyridine
has little clinical role in infection
because symptoms respond rapidly
to anitmicrobial therapy
Acute uncomplicated cystitis
Most common form of UTI?
Occur in women of childbearing age
Can be explained by
sexual activity
anatomy (short urethra)
delay in micturation
use of diaphragm and spermicidal
Causes
Mostly cause E.coli
Other causes : S.saprophyticus.
K.pneumonia, Proteus mirabilis
Acute uncomplicated cystitis
Management:
Urinanalysis including microscopic
examination, cell count, and LE
test
C&S add little to the choice of
therapy empiric therapy
Regarding the use of laboratory tests to diagnose
urinary tract infections, which of the following
statements is correct?
A. In a patient with suspected cystitis, urine dipstick
results should be confirmed with a urinalysis
B. The urine should always be cultured in outpatients with
acute cystitis
C. Urine dipstick results usually provide the laboratory
information needed to manage young otherwise healthy
patients with acute cystitis
D. The use of urine dipsticks should be avoided; urinalysis
is the test of choice.
Acute uncomplicated cystitis
Management:
1- Single dose therapy
65-100% cure rate with SMX-
TMP, amoxicillin
advantages of single does:
less expensive
better compliance
low side effects
low potential for development of
resistance
Acute uncomplicated cystitis
1- Single Dose Therapy
Not all agents are effective as single
dose
2 DS TMP/SMX is most effective
Flouroquniolones: 800 mg norfloxacin,
125 mg ciprofloxacin, 200 ofloxacin
B-lactam are less effective due to
increasing resistance and because they
are eliminated rapidly and do not
achieve high urine concentrations
Acute uncomplicated cystitis
2-Three day course
single dose Tx was blamed for high rate
of recurrence within six weeks
this may be due to failure to eradicate
gm-ve bacteria from the rectum
TMP/SMX or fluoroquinilones is superior
to single dose
Amoxicillian, nitrofurantion, and
sulfonamides are not appropriate due to
increasing resistance of E.coli
Acute uncomplicated cystitis
Management:
Short course therapy is not
appropriate for
Patient with previous infection with
a resistant bacteria
Male patients
Complicated UTI
Acute uncomplicated cystitis
Management:
If symptoms do not respond or they
reoccur, a urine culture should be
obtained and conventional therapy
started
Fluoroqunilones should not be used unless
patient cannot tolerate TMP/SMX
Theyre a high frequency of resistance
due to recent antibiotic use
Acute uncomplicated cystitis
Management:
3-Seven-day course
in pregnant women
diabetic women
women who have had symptoms for
more than one week and are at
higher risk for pyelonephritis
Symptomatic abacteriuria
Acute urethral syndrome
In females, present with dysuria
and pyuria
Urine culture reveals < 105 bacteria
/ml
Accounts for half the complaints
of dysuria in women
Most likely infected with a small
number of bacteria
Symptomatic abacteriuria
Causes:
E.coli, S. saprophyticus, or
chalmydia
Other causes:
Most patients will require short
course therapy as above
Symptomatic abacteriuria
Chlamydial treatment
1g of azithromycin or doxycycline
100 mg bid for 7 days
Concomitant treatment of sexual
partner is required to cure this
infection and prevent recurrence
Asymptomatic bacteriuria
Patients with no urinary symptoms
Have two consecutive urine
cultures with > 105
The majority are elderly and
female
Asymptomatic bacteriuria
Aggressive treatment does not
affect infection, complications or
mortality
Also present in pregnant women
Relapse and reinfection are
common and chronicity occurs
which is difficult to eradicate
Asymptomatic bacteriuria
Management
Groups who benefit from treatment:
pregnant women
patient with renal transplant
Patient who will undergo urinary
procedure
Asymptomatic bacteriuria
Management
Depend on age and whether they
are pregnant
In children: conventional treatment
because of greater risk for renal
damage
In non-pregnant female:
controversial
Asymptomatic bacteriuria
Management
In elderly: two groups
Persistent bacteriuria:
Intermittent bacteriuria
Mostly seen as a benign disease
and does not warrant treatment
Two cultures should be obtained to
confirm the presence of bacteria
Asymptomatic bacteriuria
Management
Ambulatory treatment is effective
in removing bacteria for 6 months
Only 50% remained free of
bacteria for 1 year
Hospitalized patients: therapy in
non-efficacious
Case 1
A 24-year-old woman comes to the clinic to
discuss recent laboratory results. She went to
a local walk-in clinic asking to be screened for
a urinary tract infection. She comes to the
clinic to review them with
you. She is asymptomatic and has no past
medical history. She is married and has a 3-
year-old boy. Her physical exam is
unremarkable. A urinalysis showed 1+
leukocyte esterase; a urine culture revealed
>100000 CFU of Escherichia coli.
Case 1
Which of the following management strategies is
the most appropriate for this patient?
A. Explain that even though the urine culture was
positive she does not need treatment
B. Start oral ciprofloxacin for three days
C. Repeat a urine dipstick, and if the presence of
pyuria is confirmed start treatment
D. Start oral ampicillin for seven days
Case 1
The IDSA guidelines recommend screening for
and treatment of asymptomatic bacteriuria in
only three circumstances: pregnancy, before
invasive urologic procedures that are
associated with mucosal bleeding, and in women
who are found to have catheter-acquired
bacteriuria that persists 48 hours after the
catheter is removed
Complicated UTI
Accurate urine culture and
susceptibility is necessary to target
the pathogen
Treatment duration at least 10-14
days
Acute pyelonephritis
Perform uniranalysis, gram stain,
C&S
Severely ill patients
Should be hospitalized and treated
with IV Abs
Use broad spectrum directed at
bacteremia or sepsis
Acute pyelonephritis
Empiric therapy:
3rd generation cephalosporin with
antipseudomanl activity as
ceftazidime, cefoperazone
Ampicillian + gentamicin
TMP/SMX OR Quionoles
B-lactamase inhibitor combination:
ampicillian/Sulbactam,
ticarcillin/clavunate,
Aztreonam or imipenem
Acute pyelonephritis
If the patient has been hospitalized
for > 6 months:
Consider P.aeruginosa and
enterococci, and multiple organisms
Empiric therapy:
Ticarcillin/clavunate,
Piperacillin/tazobactam
Aztreonam or imipenem
In combination with AG
Acute pyelonephritis
Management
Fluoroquinolones
major advantages is their oral
formulation.
Use as empiric therapy in this
setting may be limited because of
resistance rates.
Acute pyelonephritis
Management
ceftazidime, cefepime, piperacillin,
piperacillin/tazobactam, and
aztreonam.
They have reliable activity against
many nosocomially acquired gram-
negative rods, including P
aeruginosa.
Acute pyelonephritis
Management
Carbapenems, imipenem-cilastatin and
meropenem.
have extremely broad-spectrum coverage
and should be reserved for only the most
severe forms of nosocomial infections,
such as multiresistant pathogens, sepsis
syndrome, overwhelming intra-abdominal
infections, or septic shock
Acute pyelonephritis
Effective therapy should stabilize
patient within 12-24 hrs
Bacterial load should reduce in 48
hrs
If the patient fails to respond in 3-4
days further investigation is
necessary to
Exclude bacterial resistance
Exclude obstruction
Or other disease process
Acute pyelonephritis
Oral therapy can be started when
the patient is febrile for 24 hrs
Oral therapy should be continued
for 2 wks
Follow-up urine cultures should be
obtained 2 wks after end of
therapy
Acute pyelonephritis
Mild cases:
can be treated orally as
outpatients for at least 2 w ks
Gram ve bacilli: TMP/SMX or
fluoroquiolones
Gram +ve: cocci: consider
enterococcus fecalis, DOC
Ampicillin
Case 2
22 year-old woman without any significant past
medical history presents to the emergency room
with 2 days of worsening fever, urinary
frequency, back pain, nausea and vomiting. She
is not able to keep food or liquids down. On
physical examination she is febrile and
tachycardic. The abdominal exam is normal
except for the presence of moderate
costovertebral angle tenderness. A blood
pregnancy test is negative. A urinalysis is
obtained and reveals >50 PMN per high power
field and 10-25 red blood cells. Blood cultures
are sent to the lab.
Case 2
Which of the following management strategies is
the most appropriate for this patient?
A. Order an ultrasound to confirm your clinical
impression, and start intravenous antibiotics if
needed
B. Admit the patient for administration of
intravenous antibiotics, and obtain imaging studies
only if the patient does not improve after a few
days
C. Start intravenous antibiotics, and order abdominal
CT scan to rule out complicated pyelonephritis
D. Discharge the patient home on an oral
fluoroquinolone
Infection in males
Infection in males are considered
complicated
Occur in presence of functional or
structural abnormalities that
disrupt the normal defense
mechanism of urinary tract.
Infection in males
The most common causes are
Instrumentation
Catheterization
Renal and urinary stones
In the elderly the most common
cause is bladder outlet obstruction
due prostatic hypertrophy.
Infection in males
Treatment
Urine culture is needed because
causative organism is not easily
predictable
A urine culture with>100 CFU/ml is
best sign of infection
If Gm ve is TMP/SMX or FQ
Duration therapy should be 10-14
days
Infection in males
Treatment
Parental therapy may be required in
Severely ill patients
The presence of acute prostatitis
(may need 6-12 weeks)
Patient who cannot tolerate oral
MEDs
Repeat a follow up culture 4-6 weeks
after treatment
Case 3
A 53 year-old man with history of benign
prostatic hypertrophy comes to the emergency
room complaining of burning with urination and
increased urinary frequency. He is afebrile,
denies back pain, nausea or vomiting. His past
medical history is also significant for
hypertension and diabetes. He takes
hydrochlorothiazide, enalapril, aspirin, metformin
and terazosin. On physical examination his
prostate is enlarged, but is not tender. Urine
dipstick shows 3+ leukocyte esterase.
Case 3
A 53 year-old man with history of benign
prostatic hypertrophy comes to the emergency
room complaining of burning with urination and
increased urinary frequency. He is afebrile,
denies back pain, nausea or vomiting. His past
medical history is also significant for
hypertension and diabetes. He takes
hydrochlorothiazide, enalapril, aspirin, metformin
and terazosin. On physical examination his
prostate is enlarged, but is not tender. Urine
dipstick shows 3+ leukocyte esterase.
Case 3
Which of the following interventions is the most
appropriate for this patient?
A. Start ciprofloxacin, and order urine culture
B. Start Levofloxacin, and order urine culture only
of the patient fails to improve after five days of
symptoms.
C. Start nitrofurantoin empirically
D. Admit the patient for intravenous
piperacillin/tazobactam
Recurrent infection
Reinfections:
80% 0f recurrent infection
Infection by an organism different
from the initial infection
Mostly occurs in females where
reinfection rate is 20%
Factors contributing to infection:
1-sexual intercourse
2-diaphram and spermicidal use
3- postmenopausal women
Recurrent infection
Divided into two groups:
1-Those with less than 2 or 3
episodes per year
Each episode should be treated as
a separate infection
Short course therapy is
appropriate
Can be self administered
Recurrent infection
Divided into two groups:
2-Those with more than 3 episodes
per year
Long-term prophylaxis may be
needed
Patient should be treated
conventionally before prophylaxis is
started
Recurrent infection
Regimen:
TMP/SMX SS tables OD
TMP 100 mg OD
Fluroqunilone
Nitrofurantion 50-100 mg OD
Continued for 6 months
Urine cultures followed monthly
If symptomatic episodes develop
they should be treated with a full
course
Recurrent infection
Infection related to sexual activity:
Voiding after intercourse
Single-dose prophylactic with
TMP/SMX taken after intercourse
In postmenopausal women
Recurrent episodes related to
decreased estrogen and changes in
bacterial flora
TX: topical estrogen cream
Relapses
Persistence of the infection with
the same organism after therapy
Usually indicate structural
abnormality, renal involvement, or
chronic bacterial prostatitis
Relapses
In women:
If relapse after short course treat
with 2 week course
In-patient who relapse after 2 wk
course continue for another 2-4
wks
If relapse after 6 wks of therapy,
urologic evaluation and any
obstruction corrected
May need therapy for 6 months
Relapses
In males
Relapse usually indicate bacterial
prostaitis
TMP/SMX and fluroquniolones
appear to be highly effective for
relapses
Case 4
A 26-year-old woman comes to the clinic
complaining of recurrent cystitis. Over the
previous year she has had 5 episodes of cystitis
that were treated with antibiotics. The
symptoms improved rapidly after each course of
therapy. The episodes have happened once every
two to three months for the last year. Her past
medical history is otherwise unremarkable. She
uses oral contraceptives for contraception. She
has had two urine cultures done during the
previous year that showed pansusceptible
Escherichia coli. The patient asks for ways to
prevent these infections from coming back.
Case 4
Based on the history and test results, which of the
following interventions is indicated on this patient?
A. Ask the patient to report the onset of infection as
soon as possible, and start treatment if a urine
dipstick is positive
B. Offer antibiotic prophylaxis
C. Change her contraception to spermicides and
diaphragms
D. Obtain abdominal ultrasound to look for a secondary
cause of recurrent UTIs
E. Perform an immunologic evaluation to rule out an
underlying immune deficiency
Pregnancy
Predisposing factors:
Dilation of the renal pelvis and
ureters
Decrease urethral peristalsis
Reduced bladder tone
All lead to urine stasis and reduced
defenses against reflex of bacteria
to the kidney
Hormonal changes predispose to
infection
Pregnancy
Asymptomatic bacteriuria Occur in
4-7%
20-40% will develop acute
pyelonephritis
Routine screening for bacteriuria
should be performed at the initial
prenatal visit and at 28 wks
Pregnancy
Significant bacteriuria should be
treated regardless of symptoms
Organism is the same for
uncomplicated UTI
Therapy should be for 7 days
Pregnancy
Regimen
Sulfonamide (not in 3rd trimester)
amxoicillin
augmentin
cephalexin
nitrofurantion
Not TCN, fluoroquinoloes
Follow up urine culture 1-2 wk
after completing therapy, then
monthly until gestation
Catheterized patients
Most common cause of hospital aquired
UTI
diagnosis is difficult,
patients often have some degree of pyuria
Virtually all patients with catheters for 1 to
2 wks exhibit bacteriuria, making
differentiation of infection from colonization
difficult.
often lack symptoms
Occur in 5% of patients
Catheterized patients
Etiology
often polymicrobial.
Causative agents include P aeruginosa and
nosocomial gm ve rods, with more
resistant susceptibility profiles;
enterococci; and Candida species.
Diagnosed with > 100 CFU/ml of urine
from catheter
Urinalysis and urine cultures should
always be obtained.
Catheterized patients
Management
1-Asymptomatic,
Remove the catheter
Do not treat unless
immunosuppresed patient
Patient at risk of endocarditis
Patient who will undergo urinary
tract instrumentation
Catheterized patients
Management
2-Symptomatic
Remove the catheter and treat as
complicated UTI
Vancomycin-Resistant
Enterococci
VRE are often isolated from urine
cultures of patients who have been
hospitalized for a prolonged period.
Most commonly, a urinary catheter is
present.
If the organism is E.faecalis, then
penicillin/ampicillin susceptibility is
frequently maintained, and ampicillin is
the treatment of choice.
VRE
However, most VRE are E. faecium
that are also resistant to ampicillin
(VARE) and to multiple other
antimicrobials.
Many VARE are susceptible to
nitrofurantoin, and it can be used
as long as the patient has a CrCL
>60 mL/min
VRE
Chloramphenicol or novobiocin, with or
without other drugs, have been used.
Two newer antibiotics,
quinupristin/dalfopristin and linezolid,
have been marketed for gram-positive
infections and have activity against
VARE.
VRE- Quinupristin/dalfopristin
The 1st injectable streptogramin antibiotic.
It inhibit protein synthesis and has bactericidal
effect with the exception of VARE.
spectrum is mostly gm+ve and includes
Staphylococcus species (both methicillin-
susceptible and methicillin-resistant
Staphylococcus aureus), E faecium, and VARE.
It is not active against other enterococci
including E faecalis.
VRE- Quinupristin/dalfopristin
toxicities
chemical phlebitis (especially when
infused via a peripheral line)
myalgias and arthralgias (particularly
in patients with hepatic insufficiency).
It is a potent, noncompetitive inhibitor
of cytochrome P-450 3A4.
significantly increase plasma levels of
cyclosporine and long-acting
benzodiazepines
VRE- Linezolid
The first oxazolidinone antibiotic.
available as parenteral and oral formulations.
It inhibits protein synthesis.
It displays a bacteriostatic effect, except with
Streptococcus pneumoniae.
Its spectrum is broad against gm+ve and
includes M-susceptible and MR S aureus,
coagulase-negative staphylococci, and many
enterococci (including E faecalis, E faecium,).
VRE- Linezolid
Toxicity
Thrombocytopenia that most commonly
occurs after prolonged therapy (more
than 17 days).
Given that linezolid has broader spectrum
against the enterococci and is available
as an oral formulation, it may be
preferred over quinupristin/dalfopristin in
the treatment of VARE UTIs.
Fungal Infection
Many patients with a long-term
catheter will have colonization of
their bladder with Candida species
or, rarely, other fungi.
Fungal Infection
Usually funguria in the absence of
pyuria should not be treated, and
the catheter should be removed.
Funguria should be treated in
renal transplant recipients
those undergoing an elective urologic
procedure.
Fungal Infection
Diagnosis
pyuria (> 20 WBC/hpf)
> 105 fungal organisms / ml of
urine.
Patients may or may not have
systemic findings, such as fever
and leukocytosis.
Fungal Infection
Treatment
The catheter should be removed,
since this will result in cure in some
patients.
If C.albicans infection, then oral
fluconazole, 100 mg/d, should be
prescribed for a 2- to 5-days
IV fluconazole should be reserved for
patients without the ability to take
oral medications or in those with ileus
or bowel obstruction.
Fungal Infection
Treatment
Non-albicans Candida species, including
C.parapsilosis, C.glabrata, and C.krusei,
are becoming more common.
The Tx should be either low-dose IV
amphotericin B (0.1 mg/kg/d) or
continuous amphotericin B bladder
irrigation.
Both regimens are effective when given
for 2 to 5 days.