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TREATING UNCOMPLICATED
URINARY TRACT INFECTIONS
IN A DRUG RESISTANT ERA

Lisa M. Taylor, Pharm.D. Candidate



Introduction
Among common infections managed in the
outpatient setting, few conditions have treatment
guidelines, antibiotic selection strategies, or diag-
nostic protocols that have changed or evolved as
rapidly as those for urinary tract infections (UTIs).1
Changing resistance patterns observed with com-
mon urinary pathogens have altered the empirical
approach to antibiotic selection for UTIs.1 In the
past, decisions regarding antimicrobial therapy
have been made on patient characteristics and the
most likely pathogens. The emergence of drug-
resistant E. coli strains has complicated the man-
agement of infections including UTIs. Recently,
there have been significant increases in the resis-
tance to trimethoprim-sulfamethoxazole (TMP-
SMX) among outpatient E. coli isolates.2 As a re-
sult, uncomplicated community-acquired UTIs,
which have traditionally been easily treatable, are
now therapeutic challenges. This article will review
the problem of antimicrobial resistance in acute un-
complicated UTI, focusing on TMP-SMX resis-
tance, and outline recommendations for empirical
treatment of uncomplicated UTI in a period of
evolving antimicrobial resistance.

Epidemiology
Symptomatic UTIs are among the most


common bacterial infections. Urinary tract infec-
tions are the leading cause of gram-negative bac-
teremia in patients of all ages, and are associated
with a high risk of morbidity and mortality, espe-
cially in the elderly.1 It is estimated that UTIs result
in nearly 8 million office visits each year in the
United States, with an additional 1 million visits to
emergency departments. 13 However, assessing the
accurate incidence of UTI is difficult, because UTIs
are not reportable diseases in the United States.3
Although accurate diagnosis depends on both the
presence of symptoms and a positive urine culture,
uncomplicated UTIs in the outpatient setting are
usually diagnosed without the benefit of a culture
making it difficult to determine its exact fre-
3
quency.
Symptomatic UTIs are very common
among sexually active women and far more com-
mon among women than men. An estimated 1 in 3
women will have at least 1 UTI by 24 years of age
and 40% to 50% of women will experience at least
1 UTI during their lifetime.3 As both sexes age, the
incidence of bacteriuria increases from less than
5% in young adult women and less than 0.1% in
young adult men to at least 20% of women and
10% of men older than age 65.2

Microbiology
The microbial etiology of urinary tract in-
fections is well-established and has been reasona-
bly consistent for several decades.4 E. coli remains
the predominant uropathogen isolated in acute
community-acquired uncomplicated infections, fol-
lowed by Staphylococcus saprophyticus with Kleb-
siella, Proteus, Enterococcus, and Pseudomonas
species seen less commonly.1,4 The etiology of UTI
is also affected by underlying host factors such as


m
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Table 1. Percent incidence of urinary tract pathogens in uncomplicated and complicated UTIs2
Pathogen Uncomplicated Complicated
Escherichia coli 70-95 40-55
Klebsiella spp 2-6 10-17
Enterobacter spp 0-2 5-10
Proteus mirabilis 2-4 5-10
Pseudomonas aeruginosa 0-1 2-10
Enterococcus spp 2-5 1-20
Staphylococcus saprophyticus 5-20
UTIs urinary tract infections


age, diabetes, spinal cord injury, or catherization.4
Consequently, complicated UTI has a more diverse
etiology than uncomplicated UTI.4 The incidence
of urinary pathogens in uncomplicated versus com-
plicated UTIs is shown in Table 1.

Emerging Resistance Patterns
Historically, empiric therapy has proven
clinically successful for UTIs. Until recently, high
cure rates could be expected because a predictable
group of urinary pathogens have manifested a low
degree of resistance to most antibiotics selected on
an empiric basis.1 However, a number of recent
studies have highlighted evolving changes in an-
timicrobial resistance patterns to E. coli. Penicil-
lin-based antibiotics were once a mainstay of UTI
treatment, but current resistance rates among E. coli
(approaching 40% in many regions) have limited
their effectiveness.' Nonetheless, nitrofurantoin and
the fluoroquinolones have retained in vitro activity
against most E. coli isolates that cause uncompli-
cated UTIs.
The most substantial change in resistance
prevalence has occurred with TMP-SMX. Resis-
tance to TMP-SMX among uropathogens in the
community was relatively infrequent in the United
States during the early 1990s.5 McCarty and col-
leagues6 conducted a multicenter trial of low-dose
ciprofloxacin compared with standard-dose oflox-
acin and TMP-SMX for the treatment of acute un-
complicated UTIs in women. They reported only a
7% prevalence of TMP-SMX resistance among the
E. coli isolates.
The rates of resistance did not increase to
levels that may compromise clinical effectiveness
until the mid-1990s. Gupta and colleagues7 con-
ducted a cross-sectional survey of urine isolates


from a sample of outpatient women in western
Washington State who had an uncomplicated UTI
over a five-year period (1992-1996). They found
that the prevalence of TMP-SMX resistance among
E. coli isolates was 9% in 1992, but had increased
to 18% by 1996, the last year of the study.
More recently, Gupta and colleagues8 used
a national laboratory database to assess the rates of
resistance among uropathogens that were recovered
from female outpatients both nationally and within
9 geographic regions in the United States. Almost
all E. coli isolates that were recovered from female
outpatients were susceptible to nitrofurantoin and to
the fluoroquinolones that were tested. In contrast,
33%-40% of E. coli isolates were resistant to am-
picillin and 16%-18% were resistant to TMP-SMX.
There was significant variation in resistance to
TMP-SMZ in relation to geographic region, rang-
ing from a high of 22% in the western United States
to a low of 10% in the Northeast (p<.001).
Burnam and colleagues9 conducted a retro-
spective review of outpatients with E. coli UTIs
during the first 6 months of 1998 to determine the
rate of TMP-SMX resistance. The study was con-
ducted within the Denver public health care system
and was followed by a prospective phase to confirm
the rate of TMP-SMX resistance. The rates of resis-
tance were similar in both phases (24% vs. 23% in
the retrospective and prospective phases, respec-
tively). A summary of the in vitro susceptibility of
E. coli from several United States studies of UTIs is
shown in Table 2.

Clinical Outcomes and TMP-SMX Resistance
Resistance rates in the United States vary
from region to region, and knowledge of local re-
sistance rates are important factors when determin-


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Table 2. In vitro susceptibility of Escherichia coli in the U.S.
Isolates TMP-SMX Nitrofurantoin Fluoroquinolones
Year Study Site Study Sample (#) (%) (%) (%)

1990s6 U.S. OP women, 545 93 N/A 100.0t
18-93 yo
19955 WA State OP women, 499 89 99.4 99.8
university
1996 WA State OP HMO women, 580 82 99.8 99.8
18-50 yo
19989 Denver OP women, 811 76-77 92.0 97
17-42 yo
19988 U.S. OP women, 63,196 82 99.0 99
15-50 yo
TMP-SMX trimethoprim-sulfamethoxazole, U.S. United States, OP outpatient, WA Washington, HMO=health maintenance organization
*Retrospective phase n 681, prospective phase n=130. ciprofloxacin and ofloxacin. ciprofloxacin. levofloxacin


ing initial antibiotic therapy.2 Potential confusion
arises when the reported resistance levels are re-
lated to the blood concentration of antibiotic and
not the urine concentration.1 As a rule, antibiotics
used for UTIs are concentrated in the urine and
have higher urine levels than blood levels.1 There-
fore, isolates that are reported resistant to an antibi-
otic by laboratory testing actually may be eradi-
cated by the antibiotic in the in vivo environment.
The outcomes associated with treating a
UTI by using an agent to which the pathogen is re-
sistant have not been studied extensively.5 How-
ever, at least two treatment trials have examined
bacteriologic outcomes of acute uncomplicated UTI
among women with uropathogens resistant to the
study drugs.5 Masterton and Bochslero1 conducted a
randomized trial comparing a high-dose formula-
tion of amoxicillin-clavulanate and 7-day therapy
with TMP-SMX for women with uncomplicated
UTIs in the United Kingdom. Of 135 women ran-
domly assigned to TMP-SMX, 12% had an uropa-
thogen resistant to the drug. Bacterial eradication at
day 14 was achieved in 50% of women (7 of 14)
with an uropathogen resistant to TMP-SMX, com-
pared with 86% (106 of 123) of all women in the
TMP-SMX group.
More recently, McCarty and colleagues6
found that the bacterial eradication rate was 50% (5
of 10) and the clinical cure rate was 60% (6 of 10)
among women with an uropathogen resistant to
TMP-SMX who had been randomly assigned to
TMP-SMX treatment. Although these studies are
limited by small sample sizes and therefore are not
definitive, it seems that the failure rate in the setting


of TMP-SMX resistance is greater than that for
cases of uncomplicated UTIs caused by susceptible
strains, which is documented in the literature as ap-
proximately 5%.5
On the basis of these data, the effect of
TMP-SMX resistance on clinical outcomes can be
estimated depending on the level of resistance in
the community.5 In a setting with no TMP-SMX
resistance, bacterial eradication and clinical cure
rates with a 3-day course of TMP-SMX are ex-
pected to approach 93% and 95%, respectively.11
Assuming a 50% bacterial eradication rate and a
60% clinical cure rate among women treated with
TMP-SMX in the setting of a TMP-SMX resistant
pathogen, the expected effect of a resistance preva-
lence of 10% in a population of 100 women is rela-
tively small.5 However, the cure rates would be
lower than those expected with a 3-day regimen of
a fluoroquinolones among fluoroquinolones-
susceptible cases of UTI.11 At 20% TMP-SMX re-
sistance, the expected cure rates are even lower. Ta-
ble 3 summarizes the estimated impact of TMP-
SMX resistance on bacterial eradication rate and
clinical success rate.

Current Treatment Options
The antimicrobial agents used to treat un-
complicated community-acquired UTIs include the
B-lactams, TMP-SMX, nitrofurantoin, fosfomycin,
and the fluoroquinolones.5 All of these agents
achieve high urinary concentrations, usually greatly
exceeding the expected serum levels.5 The amin-
openicillins, ampicillin and amoxicillin, and most
cephalosporins are rapidly excreted in the urine and


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Table 3. Impact of TMP-SMX resistance on microbiological and clinical outcomes in patients with uncomplicated UTI5*
TMP-SMX Resistance Rate Expected Bacterial Eradication Rate Expected Clinical Success Rate
(%) (%) (%)
0 93 95
10 89 92
20 84 88
30 80 85
Adapted from reference 5. TMP-SMX = trimethoprim-sulfamethoxazole.


attain high urinary concentrations.5 However, be-
cause of increasing in vitro resistance the B-lactams
are no longer recommended for empirical UTI ther-
apy.11 In certain settings, such as pregnancy or
when enterococci is suspected, ampicillin and
amoxicillin may still be an appropriate choice for
acute UTI.11
Trimethoprim with or without SMX, has
been the mainstay of therapy for UTI for the past
20 years. The combination of TMP and SMX is
synergistic against a variety of organisms, includ-
ing aerobic gram-negative rods such as E. coli.5 Af-
ter a single oral dose of one double-strength tablet
(TMP, 160 mg; SMX, 800 mg), the peak urine con-
centrations are approximately 35 times higher for
TMP and 3 to 4 times higher for SMX than serum
concentrations.5
Nitrofurantoin is one of the oldest urinary
anti-infective agents in use. It appears to be associ-
ated with lower cure rates (85%) than other first-
line agents (90-95%).12 The macrocrystalline for-
mulation requires frequent dosing every six hours.5
A modified monohydrate-macrocrystal form delays
gastric uptake and allows twice-daily dosing.5 Both
the macrocystalline formulation and the twice daily
formulation are prescribed for 7 days.12 Nitrofu-
rantoin is 90% really excreted with a very high
urine concentration making it an effective urinary
antimicrobial agent.5 However, it does not achieve
high serum concentrations and is therefore not rec-
ommended for the treatment of acute pyelonephri-
tis.12
Fosfomycin tromethamine is a phosphonic
acid bactericidal agent with activity against many
common uropathogens, including E. coli, Citrobac-
ter spp, Enterobacter spp, Klebsiella spp, Serratia
spp, and Enterococcus spp.12 It achieves very high
concentrations in the urine and persists in the urine


for more than 24 hours.5 Fosfomycin is indicated
for the treatment of acute uncomplicated cystitis
and is administered in 1 single dose of 3 g.12
The first fluoroquinolones widely used for
the treatment of UTIs were norfloxacin,
ciprofloxacin, ofloxacin, and levofloxacin.5 All of
these fluoroquinolones have excellent
bioavailability and achieve high urinary
concentrations.5 Henry and colleagues13 recently
conducted a multicenter, prospective, randomized
study to compare the efficacy and safety profile of
once-daily extended-release ciprofloxacin 500 mg
with conventional ciprofloxacin 250 mg BID, each
administered orally for 3 days in uncomplicated
UTI. They concluded that the extended-release
ciprofloxacin (Cipro XR) 500 mg given once daily
for 3 days was as effective and well tolerated as
conventional ciprofloxacin 250 mg given twice
daily for 3 days. The pharmacokinetic
characteristics of selected antimicrobial agents used
in the treatment of uncomplicated UTI are shown in
Table 4.

Evidence Based Treatment Recommendation
Recently, the Infectious Diseases Society of
America (IDSA) developed evidence-based
practice guidelines for antimicrobial treatment of
acute uncomplicated cystitis and acute
pyelonephritis in women. These guidelines are
based in part on the rate of resistance to TMP-SMX
in the geographic region of each individual
practitioner.1 The guidelines recommend TMP-
SMX for 3 days as the current standard of therapy
if the TMP-SMX resistance rate in the community
is <20%.11 In communities known to have a higher
prevalence of resistance (>20%) to TMP-SMX, the
IDSA recommends the use of a fluoroquinolone for
3 days or another alternative. Other alternatives


-
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Table 4. Pharmacokinetic characteristics of agents used to treat community-acquired urinary tract infections5
Oral Dose Serum Cmax Urine Cmax Half-life
(mg) (mcg/mL) (mcg/mL) (h)
Amoxicillin 250 3.5-5.0 305-865 0.7-1.4
500 5.5-11.0 772
Cephalexin 250 9 830 0.5-1.2
500 15-18 1100

TMP-SMX 160/80 1-2/40-60 75/190 8-15/7-12
Nitrofurantoin 100 <2 50-150 0.3
Fosfomycin 3000 26 1053-4415 5.7
Ciprofloxacin 250 0.8-1.9 >200 3-5
500 1.6-2.9 350
Levofloxacin 500 5.7 521-771 6-8


Strimethoprim-sulfamethoxazole.


include 7-day treatment with nitrofurantoin or
single-dose treatment with fosfomycin. Empiric
treatment with 8-lactam antimicrobials is not
recommended. Table 5 summarizes the recommen-
dations from the IDSA guidelines.
More recently, a primary care consensus re-
port was published regarding UTI risk stratifica-
tion, clinical evaluation, and evidence-based antibi-
otic therapy.1 There recommendations differ from
those developed by the IDSA in that they recom-
mend fluoroquinolones as the drug of choice for
uncomplicated UTI in women.1

Conclusion
Evolving changes in drug resistance have
dramatically altered the approach to empiric
therapy of UTI.2 Although beta-lactams, sulfa-
based antibiotics, and fluoroquinolones each have
their place in the treatment of UTI, their roles are
rapidly changing, with fluoroquinolones emerging
as initial drugs of choice for uncomplicated UTI.2
Antibiotic agents, especially TMP-SMX, which has
been a mainstay of therapy cannot be considered
the treatment of choice in areas in which E. coli
resistance to TMP-SMX surpasses 20%.1 However,
rates of resistance of E. coli to TMP-SMX vary
significantly according to geographic region,
ranging from a high of 22% in the western United
States to a low of 10% in the Northeast. Therefore,
TMP-SMX remains a reasonable first-line choice


for empirical therapy in the northern and eastern
states, although it may no longer be appropriate in
western and southwestern states.8

References
1. Primary Care Consensus Reports. Urinary tract infec-
tion: risk stratification, clinical evaluation, and evi-
dence-based antibiotic therapy-year 2003 update. At-
lanta (GA): American Health Consultants; 2003.
2. Hospital Medicine Consensus Reports. Complicated uri-
nary tract infection: risk stratification, clinical evalua-
tion, and evidence-based antibiotic therapy-year 2003
update. Atlanta (GA): American Health Consultants;
2003.
3. Brown P, Foxman B. Epidemiology of urinary tract in-
fections: transmission and risk factors, incidence, and
costs. Infect Dis Clin North Am 2003 Jun;17(2):227-41.
4. Ronald A. The etiology of urinary tract infection: tradi-
tional and emerging pathogens. Am J Med 2002 Jul; 113
Suppl 1A:14S-19S.
5. Gupta K, Hooton TM, Stamm WE. Increasing antim-
icrobial resistance and the management of uncompli-
cated community-acquired urinary tract infections. Ann
Intern Med 2001;135:41-50.
6. McCarty JM, Richard G, Huck W, Tucker RM, Tosiello
RL, Shan M, et al. A randomized trial of short-course
ciprofloxacin, ofloxacin, or trimethoprim/
sulfamethoxazole for the treatment of acute urinary tract
infection in women. Am J Med 1999; 106:292-299.
7. Gupta K, Scholes D, Stamm WE. Increasing prevalence
of antimicrobial resistance among uropathogens causing
acute uncomplicated cystitis in women. JAMA
1999;281:736-738.
8. Gupta K, Sahm DF, Mayfield D, Stamm WE. Antim-
icrobial resistance among uropathogens that cause com-


p-


Cmaxpeak concentration, TMP-SMX
*Either formulation ofnitrofurantoin.


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Volume 19, Issue 2 November 2003







Table 5. IDSA guidelines for acute uncomplicated urinary tract infections"
Resistance Rate Antimicrobial Agent Dosage (mg) Frequency Duration (days)
TMP-SMX resistance <20% TMP-SMX 160/800 BID 3
TMP 200 BID 3
TMP-SMX resistance >20% Ciprofloxacin 250 BID 3
Ciprofloxacin extended-release* 500 QD 3
Norfloxacin 400 BID 3
Ofloxacin 200 BID 3
Levofloxacin 250 QD 3
Nitrofurantoin 100 BID 7
Amoxicillin-clavulanic acid 250 QID 7
Fosfomycin 3000 1 dose 1
Amoxicillin 500 TID 7-10


IDSA=Infectious Disease Society of America, TMP-SMX = trimethoprim-sulfamethoxazole, BID twice daily, QD=once daily, TID
Drug of choice for uncomplicated UTI by the Primary Care Consensus Reports. Only for known enterococcus infection.


munity-acquired urinary tract infections in women: a
nationwide analysis. Clin Infect Dis 2001;33:89-94.
9. Burman WJ, Breese PE, Murray BE, Singh KV, Batal
HA, MacKenzie TD, et al. Conventional and molecular
epidemiology of trimethoprim-sulfamethoxazole resis-
tance among urinary Escherichia coli isolates. Am J
Med 2003;115:358-364.
10. Masterton RG, Bochsler JA. High-dosage co-amoxiclav
in a single dose versus 7 days of co-trimoxazole as treat-
ment of uncomplicated lower urinary tract infection in
women. J Antimicrob Chemother 1995 Jan;35(1):129-
37.
11. Warren JW, Abrutyn J, Hebel R, Johnson JR, Schaeffer
AJ, Stamm WE. Guidelines for antimicrobial treatment
of uncomplicated acute bacterial cystitis and acute pye-
lonephritis in women. Infectious Disease Society of
America (IDSA). Clin Infect Dis 1999;29:745-58.
12. Nicolle LE. Urinary tract infection: traditional pharma-
cologic therapies. Dis Mon 2003;49(2).
13. Henry DC, Bettis RB, Riffer E, Haverstock DC, Kowal-
sky SF, Manning K, et al. Comparison of once-daily ex-
tended-release ciprofloxacin and conventional twice-
daily ciprofloxacin for the treatment of uncomplicated
urinary tract infection in women. Clin Ther 2002;24
(12):2088-2104.




Correction
Rosuvastatin (Crestor): A New Statin
for the Treatment of Dyslipidemia

The number of patients listed for the
STELLAR Trial in the October Issue
should be 2,431 not 12,569.


Daptomycin (CubicinTM) is the first of a new
class of antibiotics called cyclic lipopeptide
antibacterial agents. It works by binding to
bacterial membranes causing a rapid depola-
rization of the membrane potential which
leads to inhibition of protein, DNA, and
RNA synthesis resulting in bacterial cell
death. It has been approved for the treatment
of complicated skin and skin structure
infections caused by susceptible strains of
Gram-positive organisms including MRSA.





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UF Family Practice Medical Group,
Departments of Community Health
and Family Medicine and Pharmacy
Practice
University of Florida


John G. Gums Editor
Pharm.D.

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John M. Tovar Assistant Editor
Pharm.D.


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