CASE 71-6, QUESTION 6: Although T.W. tolerated TMP–SMX well during her previous treatment, on this
be an appropriate substitute for TMP–SMX in the treatment of T.W.’s infection?
Trimethoprim alone and in combination with sulfamethoxazole is active in vitro
against many of the Enterobacteriaceae associated with UTI and is an effective
alternative to TMP–SMX in the management of both acute and chronic UTI.
would be especially appropriate for T.W. because GI intolerance to TMP–SMX is
most commonly attributed to the sulfamethoxazole component, and trimethoprim is
associated with a lower incidence of side effects. Some concern exists for the
potential development of resistant organisms, but studies using trimethoprim alone
have failed to demonstrate a significant increase in bacterial resistance.
Trimethoprim is used for the treatment of acute, uncomplicated UTI in a dosage of
CASE 71-6, QUESTION 7: T.W. was treated successfully with trimethoprim for 6 weeks. Is prophylactic
antimicrobial therapy indicated? If so, how long should it be continued?
Cases of chronic UTI in adult patients may be managed by treating each recurrent
determinant of whether chronic suppressive therapy should be used, because
repeated treatment of recurrent infections eventually will result in a decreased
incidence of subsequent infections.
82 Long-term prophylactic therapy clearly
reduces the frequency of symptomatic infections in nearly all patients.
From a cost-effectiveness standpoint, women having more than one episode of
cystitis per year may benefit from antimicrobial prophylaxis.
or more episodes of cystitis per year, prophylaxis clearly is more cost-effective than
treating individual infections. Therefore, it is recommended that chronic
antimicrobial prophylaxis may be considered in any adult patient with two or more
The duration of prophylactic therapy is also determined by the frequency of
infection. Women with three or more UTIs in the 12 months before a 6-month course
of antimicrobial prophylaxis have a significantly higher recurrence rate (75%) in the
6 months after prophylaxis than women who have had only two infections in the 12
months before prophylaxis (26% recurrence rate).
82 Therefore, prophylaxis should be
continued for 6 months in patients with fewer than three UTIs per year and for at least
12 months in adult patients with three or more UTIs per year.
Before chronic antimicrobial suppressive therapy is initiated, active infections
must be completely eradicated with a full course of appropriate antibiotic therapy.
The low doses of antimicrobials used for chronic prophylaxis suppress bacterial
growth but do not eliminate active infection. Furthermore, surgically correctable
anatomic abnormalities that predispose the patient to recurrent infections (e.g.,
obstruction, stones) should be ruled out.
80 Age also should be considered when
contemplating chronic antimicrobial therapy. An asymptomatic, elderly patient taking
many other medications is usually not an ideal candidate for chronic prophylactic
treatment because of problems of non-adherence, cost, and potential drug interactions
80 Younger patients, however, are good candidates for long-term
Because T.W., a 28-year-old woman, has had at least three UTIs in the past few
months, has undergone extensive evaluation, and has just been successfully treated
with a standard course of trimethoprim, a 12-month course of antimicrobial
prophylaxis would seem reasonable. She also should be evaluated at regular
intervals for recurrent UTI and for the development of resistant organisms.
Although the foregoing discussion applies to antimicrobial prophylaxis in adults,
the use of long-term prophylaxis of recurrent UTI in children remains controversial.
One study examined risk factors for recurrent UTI and associations with
antimicrobial prophylaxis in a prospective cohort study involving nearly 75,000
children 6 years of age or younger.
83 Among the children in this study, antimicrobial
prophylaxis was not associated with decreased risk of recurrent UTI; however,
prophylaxis was associated with a 7.5 times increased risk of infection caused by
resistant bacteria. A second study examined 576 children younger than 18 years of
age with a history of one or more microbiologically proven UTIs randomly assigned
to receive either placebo or prophylaxis with TMP–SMX for 12 months.
randomly assigned to receive TMP–SMX experienced a 40% reduction in UTI
period; this benefit was independent of underlying risk factors such as history of
vesicoureteral reflux. However, other outcomes such as hospitalization, secondary
infections, or evidence of parenchymal disease on renal scans were not significantly
different between groups; the one exception was that children receiving antibiotics
were significantly more likely to experience UTI caused by an organism resistant to
84 Finally, a meta-analysis of 11 studies evaluating long-term antibiotic
prophylaxis in children found no significant benefits of antibiotic administration
85 Based on the conflicting data in the literature, current recommendations are
that long-term antimicrobial prophylaxis should not be routinely recommended for
prevention of recurrent UTI in children.
CASE 71-6, QUESTION 8: What drugs could be appropriately used for long-term suppressive therapy in
Although numerous drugs are used for prophylaxis, TMP–SMX may be the drug of
choice for chronic antimicrobial therapy owing to extensive experience, proven
efficacy, infrequent toxicities, and low cost.
80 TMP–SMX also has the effect of
decreasing vaginal colonization with uropathogens.
either one-half or one full tablet daily, is commonly prescribed for chronic UTI
prophylaxis and is an effective, well-tolerated, and convenient prophylactic
Successful prophylaxis, however, is significantly decreased in patients with
urologic abnormalities or renal dysfunction. Also, infections that are not eradicated
by a short-term therapeutic trial of TMP–SMX are not likely to respond to a longterm regimen.
79 Finally, enterococci may colonize introitally in patients taking
Fluoroquinolones are effective for chronic suppressive therapy but should be used
only when antimicrobial resistance or intolerance to other recommended drugs is
present. Cephalosporins also have been recommended, but they are best reserved for
patients intolerant to or failing prophylaxis with other agents.
When selecting a drug for chronic antimicrobial therapy, it is important to consider
efficacy, the likelihood that resistant organisms will develop, long-term toxicity,
convenience, and cost to the patient. The most commonly used agents are listed in
Based on the available information, T.W. could be switched to TMP–SMX.
Although she has a history of GI distress because of this drug, this may not be a
problem with the lower doses used for prophylaxis. If she is intolerant, trimethoprim
alone, nitrofurantoin, or a fluoroquinolone also should be effective.
Cranberries and probiotics have long been of interest for their potentially
beneficial effects in preventing UTI. Cranberries contain known compounds (i.e.,
flavonols, anthocyanidins, proanthocyanidin-tannins) that prevent E. coli from
adhering to uroepithelial cells in the urinary tract.
88 A wide variety of cranberry
products (e.g., juice concentrate, juice cocktail, cranberry extracts in capsules and
tablets) and different dosing regimens have been evaluated in the prophylaxis of UTI,
but the results are inconclusive overall and there are no formal recommendations
regarding cranberry products for prevention of UTI.
88–90 A recent meta-analysis found
that cranberry-containing products were effective in prevention of UTIs, with
particular benefits seen in women (51% reduction in risk of infections), women with
recurrent UTI (47% reduced risk of recurrences) and children (67% reduction in UTI
88 However, this analysis also noted that available studies are quite
heterogeneous, and the results of the meta-analysis should be interpreted with
88 Probiotics (particularly Lactobacillus strains) may prevent colonization
with pathogens associated with UTI.
91 Studies of probiotics for prophylaxis,
however, are inconclusive at this time. Lack of standardization of ingredients (i.e.
purity, dosage strengths) among available products and paucity of well-designed
clinical studies are among the reasons for lack of clear recommendations regarding
probiotics for this use. Further research is required to clarify unanswered questions
regarding the role of cranberries or probiotics in the prevention of UTI.
Urinary Tract Infection and Sexual Intercourse
QUESTION 1: On routine screening, asymptomatic bacteriuria is noted in W.W., a 30-year-old pregnant
Antimicrobial Agents Commonly Used for Chronic Prophylaxis Against
Nitrofurantoin 50–100 mg nightly Contraindicated in infant <1 month
of age. To be taken with food or
milk. May cause brown or rustyellow discoloration of urine.
Trimethoprim 100 mg nightly Not recommended in children <12
Trimethoprim 80 mg + 0.5–1 tablet nightly Or 3/week Not recommended for use in infants
sulfamethoxazole 400 mg <2 months. To be taken on an
empty stomach with a full glass of
water. Photosensitivity may occur.
Norfloxacin 200 mg/day Avoid antacids; monitor
Includes unique patient consultation information in italics.
Studies strongly support an association between sexual intercourse and UTI.
direct relationship seems to exist between the number of days with intercourse within
the previous week and the risk of developing a UTI.
1–3,27 One study found the relative
risk of infection in women with 1, 4, and 7 days of intercourse within the previous
week to be 1.4, 3.5, and 9.0, respectively, compared with women who were sexually
inactive within the previous week. Another study found that the risk of UTI was
doubled in women having intercourse more than 4 times/month compared with those
27 Studies also indicate that introital colonization by fecal
bacteria has a definite role in recurrent infections related to intercourse. The
migration of these colonizing bacteria into the bladder appears to be facilitated
during intercourse, but the exact mechanism remains unclear.
uncommon in men, transmission of an infection from the man is unlikely.
Occasionally, bacteria harbored under the foreskin of an uncircumcised man may be
transmitted to his partner through intercourse.
CASE 71-7, QUESTION 2: Was it rational to treat W.W.’s repeated infections with a single dose of an
Postcoital antibiotic prophylaxis is useful when recurrent UTI results from sexual
intercourse. Theoretically, a single dose of an antimicrobial agent produces
bactericidal activity in the urine before bacteria have a chance to multiply, and the
infection is averted. Patients should be instructed to empty their bladder just after
intercourse and before taking the medication to minimize the number of bacteria
present in the bladder and to reduce dilution of the drug in the urine. Because most
drugs effective for UTI are rapidly excreted by the kidney and quickly reach high
urinary concentrations, this regimen is reasonable and decreases the incidence of
93 However, this practice is not recommended in patients with
structural abnormalities of the urinary tract or decreased renal function. Symptomatic
infection must be completely treated before beginning prophylaxis.
Depending on the frequency of intercourse, postcoital prophylaxis may result in
less antibiotic use compared with continuous prophylaxis. TMP–SMX or
nitrofurantoin is the most commonly recommended agent; however, other agents such
as fluoroquinolones and cephalexin may be used.
Urinary Tract Infection and Pregnancy
CASE 71-7, QUESTION 3: Because W.W. is asymptomatic at this time, should treatment be withheld
W.W. should be treated because acute symptomatic lower UTI or pyelonephritis
may develop in pregnant women with untreated bacteriuria. In addition, a UTI during
pregnancy has been suggested to be associated with increased rates of preterm labor,
premature delivery, and lower birth-weight infants.
27 A cause-and-effect relationship
between UTI and maternal or infant risk has not been definitely established; in fact, a
recent retrospective cohort study in nearly 86,000 mothers with or without UTI
during pregnancy found no adverse pregnancy outcomes.
with an appropriate antimicrobial agent is currently recommended for all pregnant
patients with significant bacteriuria.
Nitrofurantoin is often recommended during pregnancy because teratogenic effects
have not been observed clinically.
In vitro and retrospective investigations,
however, suggest a slight mutagenic potential.
98 During lactation, nitrofurantoin
could cause hemolytic anemia in a G6PD-deficient nursing infant; however, only
small amounts have been detected in breast milk.
contraindicated in pregnancy because of the arthropathy observed in immature
The penicillins and cephalosporins are safe for use during pregnancy. These drugs,
along with the others listed in Tables 71-3 and 71-5, cross the placental barrier; thus,
the risk of toxicity or teratogenicity to the fetus must always be considered before
deciding to treat a pregnant patient with a UTI.
In this case, a cephalosporin or sulfisoxazole could be safely prescribed for
treatment of W.W. Although sulfisoxazole is felt to be safe in the first trimester of
pregnancy, trimethoprim and trimethoprim/sulfamethoxazole should be avoided
because of the folate antagonist actions of trimethoprim and concerns regarding
neural tube and cardiovascular defects potentially associated with maternal folate
deficiency during the first trimester. Sulfisoxazole should not be used after 32 weeks
of gestation because of concerns regarding neonatal hyperbilirubinemia, jaundice,
and kernicterus. W.W. was correct in discontinuing her nitrofurantoin before
pregnancy because of the risk to the fetus, although small, tends to offset the
advantage of antimicrobial prophylaxis. W.W. must receive proper follow-up care.
CASE 71-7, QUESTION 4: For how long should W.W. be treated?
Few studies have compared single-dose and 3-day therapy with conventional 7-
day therapy in pregnant patients. Available trials suggest, however, that cure rates of
single-dose therapy were lower than 7- to 10-day therapy.
trials have shown that single-dose therapy effectively eradicates bacteriuria in
pregnancy, these studies were conducted in a small number of patients. Therefore,
similar to other populations, it is recommended that pregnant patients receive either a
3-day regimen or a 7- to 10-day regimen rather than single-dose therapy.
Irrespective of the duration of therapy, appropriate follow-up of patients is
crucial. Clinicians must document elimination of pathogens 1 to 2 weeks after therapy
and follow the patient monthly for the remainder of gestation. If bacteriuria recurs,
therapy should be given for relapse or reinfection and the patient evaluated
radiologically for structural abnormalities.
screening. Should she be treated with an antimicrobial agent?
The treatment of patients with asymptomatic bacteriuria depends on the clinical
setting in which it is found. Asymptomatic bacteriuria occurs in a heterogeneous
group of patients with different prognoses and risks. Therefore, recommendations for
treatment of asymptomatic patients with significant bacteriuria (two consecutive
voided urine specimens showing ≥10
5 bacteria/mL of urine in women, or a single
clean-catch voided specimen in men) are based on specific age, sex, and clinical
28 These recommendations consider the risk for development of
acute UTI and subsequent long-term complications. Generally, patients who benefit
most from antibiotic treatment are those with urinary tract structural abnormalities,
immunosuppressive therapy, and procedures requiring urinary tract instrumentation
1–3,13 Short-course regimens (i.e., single-dose or 3-day) are usually
recommended when treatment is desired,
3 although longer regimens have also been
Urinary tract infections in infants and preschool children (predominantly girls)
occasionally are associated with renal tissue damage,
although the incidence of renal damage has been estimated as low as 0.4% in
children with previously normal renal function, and the overall risk of UTIs in this
99 Asymptomatic bacteriuria of childhood is also
important because it may be a manifestation of an anatomic or mechanical defect in
the urinary tract. Therefore, it should be evaluated fully. Because most cases of renal
scarring as a result of bacteriuria occur within the first 5 years of life, it is
controversial whether treatment should be limited to infants and preschool children
or whether all children should be treated regardless of age. Screening for bacteriuria
in children and treating those with positive cultures, regardless of their clinical
presentation, seems reasonable and is frequently recommended.
although still controversial, seems prudent because any renal damage resulting from
asymptomatic bacteriuria generally occurs during childhood. Should the decision be
made to treat, principles of therapy are similar to those for symptomatic infections.
Pregnant Patients, the Elderly, and Other Adult
Without urinary tract obstruction, UTI in adults rarely lead to progressive renal
5 Therefore, asymptomatic bacteriuria does not require treatment in most
adult patients who have no evidence of mechanical obstruction or renal insufficiency.
As previously discussed, antimicrobial therapy is appropriate during pregnancy
because as many as 40% of pregnant women with asymptomatic bacteriuria later
develop symptomatic UTI, particularly pyelonephritis.
confirmed associations between acute pyelonephritis during pregnancy with
increased rates of preterm labor, premature delivery, and lower birth-weight
27 The treatment of asymptomatic bacteriuria in pregnancy is therefore
justified to decrease the risk of associated complications.
Bacteriuria in the elderly is common; it is estimated that 20% of all women and
10% of all men aged 65 years and older have bacteriuria.
in this population often leads to symptomatic infection, clinical studies have
consistently documented no beneficial outcomes in treated patients compared with
15 Consequently, therapy is not recommended for the
asymptomatic older patient because the expense, side effects, and potential
complications of drug therapy appear to outweigh the benefits.
experiencing symptomatic infections should be treated as usual.
The treatment of asymptomatic bacteriuria in women with diabetes does not reduce
complications and is not currently recommended.
stain of the urine. What is a reasonable assessment of R.D.’s clinical presentation?
Acute urethral syndrome is defined as symptoms consistent with lower UTI but
with no organisms evident on Gram stain or culture. The lack of detectable pathogens
may mean that the urine specimen is sterile or that the concentration of the organisms
in the urine sample is low. Patients with these symptoms still may have a UTI even
though the voided urine is sterile or contains less than 10
causative organisms and the pathogenesis of infection in these cases are the same as
for lower UTI. Other organisms that can cause urethritis in this setting, especially in
the presence of pyuria, are Chlamydia trachomatis, Neisseria gonorrhoeae, and
100 Conversely, in patients with acute urethral syndrome
without pyuria, noninfectious causes of urethritis are common and should be sought.
Because R.D. is symptomatic, has 10 to 15 WBC/LPF in her urine, and no bacteria
on Gram stain, infection with C. trachomatis or some other more atypical pathogen is
Interstitial cystitis, also known as painful bladder syndrome or bladder pain
syndrome, is a chronic clinical syndrome characterized by bladder or pelvic pain and
101 Although the exact cause of interstitial cystitis is not
known, it is apparently not an infection-related disorder and does not respond to
antibiotic therapy. The clinical presentation of interstitial cystitis is very similar to
that of symptomatic abacteriuria, but absence of pyuria is a key difference. Interstitial
cystitis should be suspected in patients with clinical findings suggestive of lower UTI
but who do not manifest pyuria and who have not responded to previous empiric
antibiotic therapy; no antibiotics should be administered without further diagnostic
CASE 71-9, QUESTION 2: Should R.D. be treated with antibiotics?
A double-blind, placebo-controlled study evaluated the use of doxycycline 100 mg
twice a day (BID) in patients with UTI and low bacterial counts. Clinical cure of
bacteriuria and pyuria was significantly greater in the doxycycline-treated group, but
doxycycline did not reduce symptoms in patients without pyuria.
other gram-negative bacteria, and C. trachomatis are the usual causes of acute
urethral syndrome, an antibiotic such as doxycycline with activity against Chlamydia
is a reasonable initial treatment for patients such as R.D. presenting with urinary tract
symptoms (without bacteriuria) and with pyuria. All tetracyclines and sulfonamides,
with or without trimethoprim, also are likely to be effective in such patients, but
doxycycline has been best studied to date. Of the fluoroquinolones, newer agents,
such as levofloxacin, offer promise as alternatives to doxycycline but have not been
100 Azithromycin as a single dose also has a major role in
treating chlamydial infections (see Chapter 72, Sexually Transmitted Diseases).
Prolonged therapy of 2 to 4 weeks in duration and treatment of sexual partners may
be required to prevent reinfection through intercourse. Prolonged therapy is
appropriate if the patient has a history consistent with Chlamydia urethritis; a sexual
partner with recent urethritis; a recent new sexual partner; a gradual, rather than
abrupt, onset of symptoms that has occurred during a period of days (as in R.D.); and
no hematuria. Patients without such a history can be treated with a short course of
antibiotics as any other patient with a lower UTI.
HOSPITAL-ACQUIRED ACUTE URINARY TRACT
QUESTION 1: P.M., an alert, 70-year-old woman with chest pain, was hospitalized to rule out acute
burning on urination and bladder pain. TMP–SMX double-strength, one tablet BID was ordered after
microscopic examination of the urine indicated a UTI. Was this empiric therapy appropriate?
Hospital-acquired (or nosocomial) UTIs occur in about one-half million patients
per year and most are associated with the use of indwelling bladder catheters.
Approximately 10% to 30% of catheterized patients exhibit infection.
Complications of catheter-associated UTI are significant. Nosocomial UTIs are the
source of up to 15% of all nosocomial bloodstream infections, occurring in about 4%
; the associated mortality rate is approximately 15%.
Nosocomial UTI also prolongs hospitalization by an average of 2.5 days and costs an
23 Prevention is the best way to manage nosocomial UTI, but
antibiotic treatment is usually initiated in hospitalized patients who exhibit UTI
The susceptibility of hospital-acquired pathogens to antimicrobial agents differs
from community-acquired bacteria, and these susceptibilities frequently vary from
one hospital to another. Therefore, the microbiology department of a particular
hospital should be consulted to determine current trends in the antibiotic
susceptibility of bacteria acquired in that setting. In general, E. coli is still the
predominant urinary tract pathogen. An increased proportion of infections is caused,
Repeated courses of antibiotic therapy, anatomic defects of the urinary tract, old
age, increased length of hospital stay, and repeated hospital admissions are
associated with a higher incidence of infection with antibiotic-resistant
102 Pseudomonas, Proteus, Providencia, Morganella, Klebsiella,
Enterobacter, Citrobacter, and Serratia are particularly difficult to eradicate because
they usually are less susceptible to commonly used antimicrobial agents.
P.M. is elderly, hospitalized, and has been repeatedly exposed to potentially
resistant organisms during her previous hospitalizations. Oral fluoroquinolones are
most commonly used as empiric therapy in this setting because of their greater
activity against potentially resistant pathogens compared to TMP–SMX; however,
TMP–SMX is an acceptable empirical therapy in P.M. as long as her clinical and
laboratory data are appropriately monitored.
103 Cultures of P.M.’s urine should
be performed and, once C&S test results are known, therapy promptly changed
according to susceptibility reports. To achieve the most cost-effective therapy, oral
agents should be administered to all patients capable of taking medications by mouth
unless the isolated pathogens are resistant to oral medications, or underlying GI
dysfunction makes adequate absorption of oral antibiotics questionable.
recommended duration of antibiotic therapy for patients such as P.M., who present
with mild-to-moderate symptoms, is 5 to 7 days; patients who do not respond
promptly to treatment may be treated for a total of 10 to 14 days.
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