NEW SOLUTIONS FOR OLD PROBLEMS
| CURRENT TREATMENT STRATEGIES FOR URGE INCONTINENCE AND THE OVERACTIVE BLADDER —Richard
T. Kershen, MD, Assistant Professor, University of Vermont College of Medicine, Division of Urology and Director of Female
Urology, Neurourology and Voiding Dysfunction, Fletcher Allen Health Care, Burlington
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| General considerations: overactive bladder (OAB) not diagnosis, but constellation of symptoms; symptom complex of urinary
frequency (8 visits to bathroom daily), nocturia (2 visits to bathroom at night), and urgency (key component of OAB);
urge incontinence may or may not be present; ≈50% of women with OAB also have urge incontinence; 30% of these women
also have stress incontinence; prevalence—≈20 million women in United States suffer from OAB symptoms; ≈30% of
women >65 yr of age suffer from OAB; potentially serious health effects—poor hygiene, recurrent urinary tract infections
(UTIs), skin breakdown, recurrent yeast infections, and fractures; embarrassment leads to social isolation and depression;
avoidance of sexual contact and intimacy; limitation of physical activities; major reason for nursing home placement in
elderly; >$1 billion spent annually on disposable pads in United States; barriers to treatment—patient feels condition part
of aging, not severe or frequent enough to treat, too embarrassed to discuss, or treatments not effective; two thirds of patients
symptomatic for 2 yr before seeking treatment; ≈30% of patients mentioning problem to provider receive no assessment or
treatment of problem; effective treatments available, eliminating necessity for disposable pads
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| Causes: majority of patients with urge incontinence suffer from uninhibited bladder contractions (called “wet” OAB); patient
can have uninhibited bladder contractions and remain dry because of strong external sphincter muscles; “key in the
door” symptom (physiologic phenomenon) causes bladder contraction; OAB spectrum of pathophysiology; considered
motor, muscle, and nervous system disease; urgency and frequency sensory phenomena; new treatments currently in development
targeted only at symptom of urgency; causes—unknown; aging, microischemia of bladder, neurologic illness,
bladder outlet obstruction, and stress incontinence
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| Evaluation: rule out reversible causes; identify other treatable conditions; pathologic factors—UTI, intravesical foreign
bodies, urethral stone, bladder tumor, and inflammatory conditions (eg, interstitial cystitis); rule out metabolic factors;
identify related conditions, eg, stress incontinence, pelvic organ prolapse, large cystocele, bladder obstruction, neurologic
disease; review voiding patterns and symptoms (eg, frequency, nocturia); get general history, especially genitourinary
symptoms; review medications, eg, diuretics; perform mental status examination if appropriate; voiding diary—
essential; provides clue to severity of problem; physical examination—look for signs of previous surgeries (eg, hysterectomy,
bladder suspension); rule out retention; speaker does half-blade speculum examination to assess for urogenital
atrophy, urethral caruncle, maceration, prolapse, and urethral diverticulum; assess for fecal impaction (pushes up on
bladder and affects voiding function); perform focused neurologic examination to assess for changes in pelvic floor musculature
and lower extremities; laboratory tests—urinalysis to rule out diabetes and evidence of hematuria; blood work
as appropriate; when to refer to urologist—symptoms do not respond to initial treatment; mixed incontinence suspected;
evidence of hematuria without infection; signs or symptoms suggestive of poor bladder emptying; evidence of
unexplained neurologic or metabolic disease; pelvic prolapse
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| Treatment: goals—get patient to total dryness, relieve primary symptoms of OAB, restore patient’s quality of life; continuously
reevaluate patient’s response to therapy using voiding diary; medication dose adjustments may be required to
reach treatment goals; behavior modification—first-line therapy for all patients; timed voiding—instruct patient to delay
voiding by inhibiting urge (squeezing of pelvic floor muscles), to void according to schedule, and to increase interval
between voids; bladder capacity should expand over time; ≈50% reduction of incontinent episodes in ≈75% of women;
Kegel exercises or electrical stimulation effective in retraining bladder; data show behavior modification therapy in combination
with pharmacologic therapy more efficacious than either modality alone
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| Antimuscarinic agents: only drugs approved for treatment of OAB; block muscarinic receptors (5 types in body); inhibit
detrusor overactivity; increase bladder capacity; decrease urinary frequency and prevent urgency, urge incontinence, and
nocturia; should not be used in patients with narrow-angle glaucoma; dry mouth most common side effect; other side effects
include blurred vision, constipation, and central nervous system (CNS) effects, eg, somnolence, diminished cognitive function
if agent crosses blood-brain barrier (use caution in elderly); decision whether medication clinically effective based
on relief of symptoms, tolerability, and likelihood patient will continue to take medication; ideal agent not yet developed
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| Oxybutynin (Ditropan): available for >20 yr; extremely safe; some selectivity for M3 receptor; some local anesthetic and direct
muscle relaxant effects on bladder; data show ≈70% of patients on immediate-release oxybutynin stop taking it by 3 mo
because of high incidence of side effects; extended-release oxybutynin (Ditropan XL)—works by slow-release polymer
system; avoids first-pass metabolism; primarily released in lower gastrointestinal tract; reduces active metabolite (responsible
for most side effects); once-daily dosing; available in several dosages; dose escalation possible without major side effects;
transdermal oxybutynin—patch changed twice weekly; avoids first-pass hepatic metabolism; less active metabolite; lowest
incidence of dry mouth; few CNS side effects; rash in ≈20% of patients
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| Tolterodine (Detrol): first medication developed specifically for OAB; nonselective for muscarinic receptors; more selective
for bladder than salivary glands; limited CNS penetration; available in immediate-release and extended-release
forms; metabolized in liver; Ditropan XL vs Detrol LA trial results—equivalent efficacy; no difference in urge incontinence
episodes; more Ditropan XL subjects reported total dryness, but more reported dry mouth
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| Darifenacin (Enablex): only completely M3 muscarinic-selective antagonist; M3 receptor responsible for detrusor contractility;
once-daily dosing; can be taken with food; metabolized by liver; rapid onset of action; relieves symptoms of urgency
and frequency; no significant efficacy difference between 7.5 mg- and 15-mg dosage (≈70% reduction in
incontinence episodes with 7.5-mg dose vs ≈80% reduction with 15-mg dose); similarly efficacious in reducing nocturia;
side-effect profile significantly worse with 15-mg dose; higher risk for constipation with 15-mg dose because M3 receptor
involved in bowel contractility; unknown whether M3 selectivity is advantage; more M2 receptors in bladder; selecting
M3 blocking may cause loss of efficacy in certain patient populations
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| Solifenacin (VesiCare): nonselective receptor agent; once-daily dosing; 5 mg or 10 mg similarly efficacious in reducing
urgency; highest in vitro affinity for bladder (compared to salivary gland) of all agents; 14% incidence of dry mouth with
5-mg dose (≈20% to 25% with other agents)
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| Trospium (Sanctura): structure is quaternary amine, compared to tertiary amine; does not cross blood-brain barrier; good
choice for patient if CNS effects of concern; twice-daily dosing; must be taken on empty stomach; available in Europe for
20 yr; effective in reducing symptoms of OAB; tolerability for dry mouth and constipation comparable to other agents
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| Choosing antimuscarinic agent: equivalent efficacy among all agents; may differ in affinity for muscarinic receptor;
currently, no agent totally bladder-selective; cost and ease of use important factors in deciding on agent to use; if cost
issue—Ditropan immediate-release cheapest; if dry mouth issue—Solifenacin or Oxytrol patch; if medication interaction
issue—trospium does not pass through cytochrome P450 enzyme system; does not cross blood-brain barrier; could
be good choice for elderly patient; patient with refractory symptoms—Ditropan XL; consider combination therapy; if
patient unresponsive to Detrol, consider adding Oxytrol patch; data show patients stop taking medication because of lack
of efficacy, adverse side effects, symptom resolution, and cost; medications not perfect long-term solution
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| Refractory OAB: botulinum toxin type A (Botox)—most potent neurotoxin known; inhibits release of acetylcholine from
nerve terminals; causes functional denervation lasting up to 6 mo; cure or improvement in nearly 80% of patients; most patients
need repeat injection in 6 mo; not currently approved for bladder problems; expensive and not always covered by insurance;
sacral neuromodulation (Interstim)—Food and Drug Administration (FDA) approved; electrical stimulation of
S3 nerve root via implantable neurostimulator; able to modulate afferent and efferent activity from bladder to inhibit overactivity;
minimally invasive implantation; ≈50% effective for patients with refractory urge incontinence (≈30% of patients improve);
>50% reduction in voiding in 75% of patients with OAB; reimbursed by Medicare; bladder augmentation
(ileocystoplasty)—last-line therapy for OAB; invasive; potential complications; increases bladder capacity with patch
graft of small intestine; interrupts detrusor overactivity; 90% efficacy; may result in impaired emptying and need for intermittent
catheterization; auto-augmentation—creation of large bladder diverticulum lined by mucosa; good option for
high-risk patient; ≈50% improvement in symptoms for patients failing other treatments
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| RECURRENT URINARY TRACT INFECTIONS —Khalil Ghanem, MD, Assistant Professor, Johns Hopkins University
School of Medicine, Baltimore
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| Definitions: reinfection—caused by same or different organism >2 wk after previous treatment; most cases reinfection;
relapse—caused by same organism; generally occurs <2 wk after treatment; suggests persistent focus of infection or inappropriate
choice of antibiotic; relapse vs reinfection—difficult to distinguish if patient presents <2 wk after treatment
of UTI; relapse suggested if patient never symptomatically improved on antibiotics; reinfection suggested with interim
culture documenting clearance after initial therapy; many UTIs recurring within 2 wk with same organism likely caused
by reinfection; pathophysiology—organisms from rectal flora; periurethral and distal urethral colonization leads to organism
moving into bladder, causing cystitis
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| Host risk factors: familial tendency significant risk factor; anatomic defects, ie, vesicoureteral reflux (VUR; occurs more
commonly in children than adults) and short anourethral distance; sexual intercourse significant risk factor; use of diaphragms
and spermicidal agents shown to increase risk (some condoms coated with spermicide); history of UTI at early
age; recent antimicrobial use and drug-resistant infection; pregnancy significant risk factor; factors not found to be
associated—postcoital voiding, douching, hot tubs, wiping pattern, body mass index, and pantyhose; postmenopausal
women—hypoestrogenism most common risk factor; likely if woman reports discomfort, vaginal dryness, pain with intercourse,
and vaginal mucosa appears dry; functional abnormalities of bladder, especially in women who have had hysterectomies;
patient having UTIs throughout life at significant risk; topical estrogens shown to reduce UTIs (work by
increasing lactobacilli and decreasing pH in vagina); oral estrogen therapy not shown effective in reducing UTIs; pregnant
women—most common complication of pregnancy; ≈2% of pregnant women develop UTIs; older age, higher parity,
past UTIs, diabetes, glucose intolerance, and sickle cell disease or trait, especially in pregnancy, can increase risk;
patient who presents with recurrent UTIs but no risk factors warrants urologic evaluation; pathogens—Escherichia coli
major causative pathogen; with evidence of structural abnormalities, consider Proteus, Pseudomonas, Klebsiella, Enterobacter
, and Staphylococcus saprophyticus (rare); most cases of Staphylococcus come from blood; rule out bacteremia;
when to obtain cultures—before instituting long-term suppressive therapy, recurrent UTI <2 wk after treatment
of previous episode, or recurrent UTI during long-term suppressive therapy; urologic evaluation—excretory urography
and cystoscopy not shown useful in management of recurrent UTIs; most women do not need urologic evaluation, except
if no clear risk factors for recurrences or suspicion that anatomic defect present
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| Antimicrobial therapy: know antimicrobial susceptibility patterns in community; blood organisms generally more resistant
than urinary organisms; data from 7-yr study show resistance to fluoroquinolones increased rapidly, suggesting that
fluoroquinolones being overprescribed; trimethoprim–sulfamethoxazole (TMP–SMZ; Bactrim) reasonable alternative;
fluoroquinolones as first-line agents for treatment of UTI not recommended; risk factors for Bactrim resistance—
diabetes mellitus, recent hospitalization, recent antibiotic use or recent Bactrim use; avoid use of Bactrim empirically in
community where prevalence of bacterial resistance >20%; principles of therapy—apply to single episode of UTI and
to acute recurrent episode; single-dose regimen less effective than 3- to 5-day regimen; 3-day regimen especially effective
when using fluoroquinolones, TMP, or Bactrim; 3-day course of β-lactams or nitrofurantoin less effective than 5-day
course
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| Antimicrobial prophylaxis: ensure patient has modified potential exacerbating factors; treat if evidence of hypoestrogenism;
consider prophylaxis with 3 recurrent UTIs in 1 yr and discomfort; ensure patient does not have active infection (increases risk
for resistance); intermittent self-treatment—prescription given with instructions to start medications at start of symptoms;
instruct patient to call clinician if no improvement after 48 hr; postcoital prophylaxis—effective if UTI temporally related to
sexual activity; limits amount of antibiotics patient takes and does not increase resistance; continuous prophylaxis—treat for
6 mo, then stop; if UTIs recur, treat for 2 yr; data suggest continuous prophylaxis with TMP and TMP–SMZ safe up to 5 yr;
risk for recurrent UTI back to baseline once prophylaxis discontinued; single-strength tablet of Bactrim contains 80 mg of
TMP and 400 mg of SMZ; TMP available as single pill without sulfonamide for patient with sulfonamide allergy; effective
against gram-negative organisms; recommended—TMP 100 mg daily (speaker usually prescribes 200 mg bid); nitrofurantoin
50 mg daily; cephalexin 125 mg daily; fluoroquinolones not recommended if other options available; same regimens used
for postcoital prophylaxis; cranberry juice—limited data suggest 300 mL daily may be helpful in preventing UTIs; contains
antiadherence compounds; orange, pineapple, and mango juice shown to decrease pH in urine, but not shown effective in preventing
recurrent UTIs
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Educational Objectives
| The goal of this program is to educate the listener about the evaluation and treatment of urge incontinence, overactive bladder,
and recurrent urinary tract infections. After hearing and assimilating this program, the clinician will be better able to:
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 | 1. List the symptoms of overactive bladder (OAB) and discuss the impact of OAB on a patient’s quality of life.
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| 2. Identify the causes of OAB.
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| 3. Evaluate the patient complaining of OAB and determine the appropriate antimuscarinic agent for the patient with
OAB.
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| 4. Determine whether recurrent urinary tract infection (UTI) is due to reinfection or relapse, and list risk factors associated
with recurrent UTIs.
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| 5. Choose the appropriate treatment regimen for a patient having recurrent UTIs.
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Discussed on This Program
Botulinum toxin type A [Botox, Botox Cosmetic]
Cephalexin [Biocef, Keflex]
Darifenacin HBr (Enablex)
Nitrofurantoin [Furadantin]
Nitrofurantoin macrocrystals [Macrobid, Macrodantin]
Oxybutynin chloride [Ditropan, Ditropan XL, Osytrol]
Solifenacin succinate [VESIcare]
Tolterodine tartrate [Detrol, Detrol LA]
Trimethoprim (TMP) [Proloprim, Primsol, Trimpex]
Trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMZ) [Bactrim, Bactrim DS, Bactrim IV, Bactrim Pediatric,
Cotrim, Cotrim D.S., Cotrim Pediatric, Septra, Septra DS, Septra IV, Sulfatrim]
Trospium chloride [Sanctura]
Suggested Reading
Albert X et al: Antibiotics for preventing recurrent urinary tract infection in non-pregnant women. Cochrane Database
Syst Rev 3:CD001209, 2004; Cardozo L et al: Special considerations in premenopausal and postmenopausal women with
symptoms of overactive bladder. Urology 60(5 Suppl):64, 2002; Chu FM et al: Extended-release formulations of oxybutynin
and tolterodine exhibit similar central nervous system tolerability profiles: a subsanalysis of data from the OPERA
trial. Am J Obstet Gynecol 192(6):1849, 2005; Hooton TM: Infect Dis Clin North Am 17(2):303, 2003; Eskandar OS et
al: Treatment of overactive bladder (OBA) with anti-cholinergic drugs and the risk of glaucoma. J Obstet Gynaecol
25(5):419, 2005; Kershen RT et al: Preview of new drugs for overactive bladder and incontinence: darifenacin, solifenacin,
trospium, and duloxetine. Curr Urol Rep 5(5):359, 2004; Warran JW et al: Guidelines for antimicrobial treatment of
uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Infectious Diseases Society of America (IDSA).
Clin Infect Dis 29(4):745, 1999.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Dr. Kershen was recorded at Women’s Health Issues: Perception, Prevention & Practice, sponsored by the University
of Vermont College of Medicine, held September 12-14, 2005, in Burlington, Vermont. Dr. Ghanem was recorded
at Infectious Diseases Update, sponsored by the Department of Medicine at Johns Hopkins Bayview Medical
Center, held on September 8-9, 2005, in Baltimore. The Audio-Digest Foundation thanks the speakers and the sponsors
for their cooperation in the production of this program.
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