Infect Dis Clin N Am 17 (2003) 243259

Emerging antibiotic resistance in urinary

tract pathogens
Kalpana Gupta, MD, MPH
Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington
School of Medicine, BB1221, Box 356523, Seattle, WA 98195, USA

Perhaps one of the most important factors impacting the management of

urinary tract infections (UTIs) over the past decade is the emergence of
antimicrobial resistance among uropathogens, particularly among isolates
causing community-acquired UTIs. Numerous studies have been published
examining the rates of in vitro resistance among uropathogens within individual institutions or geographic areas. These studies have encompassed
a variety of patient populations, including men, women, children, the
elderly, inpatients, outpatients, and people with normal or abnormal urinary
tracts. Taken together, these studies demonstrate that in vitro resistance
is a signicant problem, not only among nosocomial, complicated UTIs
where it has traditionally been recognized, but also in community-acquired,
uncomplicated UTIs where it has traditionally been absent or of little
consequence.
The most signicant recent issues involving antimicrobial resistance in
UTI include an increase in trimethoprim-sulfamethoxazole (TMP-SMX)
resistance rates, specically among community-acquired UTI isolates;
correlation between in vitro susceptibility and clinical and bacteriologic
outcomes in acute uncomplicated UTIs; and improved knowledge of the
determinants of TMP-SMX resistance among uropathogenic Escherichia
coli. This article will focus on these topics as well as the problems of
emerging uoroquinolone resistance and multi-drug resistance among
community-acquired UTI isolates.

E-mail address: kalg@u.washington.edu

0891-5520/03/$ - see front matter 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0891-5520(03)00006-0

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K. Gupta / Infect Dis Clin N Am 17 (2003) 243259

Acute uncomplicated cystitis

A 3-day course of TMP-SMX has been the standard antimicrobial
regimen used for management of acute uncomplicated cystitis for at least
a decade [1,2]. In many settings, this therapy is completely empiric, without
a urine culture or susceptibility testing to guide antimicrobial choice. This
approach has been considered safe and cost-eective for acute uncomplicated cystitis because the spectrum of etiologic organisms is predictably weighted toward E coli (85%90% prevalence), with Staphylococcus
saprophyticus being the second most common but much less frequent isolate
(5%10% prevalence), and Klebsiella pneumoniae, Proteus mirabilis, and
enterococci making up the remaining few percent. When isolated from
women with community-acquired uncomplicated cystitis, these organisms
used to be reliably susceptible to commonly used antimicrobials. Data from
selected studies that focus on acute uncomplicated cystitis in women
(Table 1) clearly demonstrate, however, that the in vitro susceptibility of E
coli to some of these antimicrobials has markedly diminished over the past
decade. The overall trends in the resistance patterns of E coli causing acute
uncomplicated cystitis over the past decade are shown in Fig. 1.
Trimethoprim-sulfamethoxazole
The rate of TMP-SMX in vitro resistance among E coli causing acute
uncomplicated cystitis has increased from approximately 7% to 18% in
the United States (Fig. 1). Before 1990, resistance to TMP-SMX among
community-acquired cystitis isolates was negligible, ranging from 0% to 5%
[1113]. By the early 1990s, a multi-center treatment trial comparing TMPSMX to two uoroquinolones for therapy of acute uncomplicated cystitis
demonstrated a TMP-SMX resistance rate of 7% [3]. A population-based
study of susceptibilities among uropathogens isolated from outpatient
women in western Washington with acute uncomplicated cystitis found that
the prevalence of TMP-SMX resistance among E coli was still relatively
low (9%) in 1992 [5]. There was a linearly increasing trend in resistance,
however, with rates of TMP-SMX resistance at 18% by 1996. A similar
increasing trend in TMP-SMX resistance among E coli isolates collected
from women in Michigan with acute uncomplicated cystitis was recently
reported, with rates of 8.1% in 1992 and 1993, and 15.8% in 1998 and
1999 [6]. Surveys of outpatient urinary E coli isolates from women of
reproductive age in the United States also demonstrate TMP-SMX resistance rates of 16% to 18% in 1998 and 1999 [8,10]. Canadian rates of E
coli resistance to TMP-SMX among outpatients were similarly high in 1998
(Table 1) [9]. The most recently published US survey of urine isolates from
female outpatients of all ages found that TMP-SMX resistance among E coli
was still at approximately 16% in 2001, suggesting that the increasing trend
in resistance over the past decade may now be plateauing, perhaps because
of decreased usage of this drug for acute uncomplicated cystitis as well as for

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245

Table 1
Antimicrobial resistance rates of Escherichia coli (E coli) isolates from women with acute
uncomplicated cystitis in North America
Period Site

Study
year

% of E coli resistant to:

TMP- Nitrofu- FluoroSMX rantoin quinolone Ampicillin Cephalothin

1990 USA [3]

1990s
545 7
1993
Los Angeles, 1991
198 15
CA [4]
Washington 1992
567 9
[5]
1993
931 10
Michigan [6] 1992
123 8
1993
1994 Los Angeles, 1994
263 32
1997
CA [4]
1997
208 15
Seattle,
1995
499 11
WA [7]
Washington 1994
967 9
[5]
1995
691 12
1996
580 18
Michigan [6] 1994
107 7
1995
1996
206 12
1997
1998 USA [8]
1998
33,462 18
2002
Canada [9]
1998
1681 19
Michigan [6] 1998
165 16
1999
USA [10]
1999
1956 16

NA

NA

NA

0.5

30

17

0.2

26

20

1
0

0
0

29
34

25
54

45

15

0
0.6

0
0.2

39
25

15
8

0.1

31

38

1
0.2
0

0
0.2
0

32
34
29

32
28
49

26

48

40

NA

0.1
3

1.2
1

41
31

NA
59

0.7

NA

17

Abbreviation: N, sample size; NA, not available; TMP-SMX, trimethoprim-sulfamethoxazole.

other indications such as prophylaxis of pneumocystis pneumonia in

patients with HIV [14].
Another important feature of TMP-SMX resistance in communityacquired cystitis is that the rates are not uniform across the United States.
A study of urinary isolates from outpatient women who were 15 to 50 years
old found that TMP-SMX susceptibility varied greatly within US Bureau
of Census regions, with TMP-SMX susceptibility at almost 90% in the
northeastern, but as low as 78% in the western and southern, United States
[8]. Similarly, in a 2001 survey of urine isolates from female outpatients,
TMP-SMX resistance varied from a low of 12% in the east-north-central
region to a high of 22% in the west-south-central region [14]. Rates of

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K. Gupta / Infect Dis Clin N Am 17 (2003) 243259

Fig. 1. Trends in resistance rates of Escherichia coli isolated from female subjects with acute
uncomplicated cystitis. Data represent weighted averages from studies listed in Table 1.

TMP-SMX resistance in most European countries and in the Asia-Pacic

region are similar to those found in North America [15,16]. Higher rates of
TMP-SMX resistance among uncomplicated cystitis isolates have been
reported, however, from Spain and Portugal (35% resistant) and Israel
(25%29% resistant) [15,17,18]. In addition, rates of TMP-SMX resistance
among urinary E coli from hospitalized patients in Latin America are
approximately 50% [19].
Fluoroquinolones
Fluoroquinolones are, as a class, the only antimicrobial agents that have
ecacy rates equivalent to TMP-SMX when given in a 3-day treatment
regimen for acute uncomplicated cystitis [2]. Thus, these antimicrobials are
being used as an alternative to trimethoprim alone or TMP-SMX when the
latter agents cannot be used because of patient-specic reasons (such as drug
allergy) or when the prevalence of resistance to the latter agents exceeds
approximately 20%. Most studies within the United States and Canada
demonstrate that uoroquinolone resistance among E coli isolates from
acute uncomplicated cystitis has been minimal (Table 1) and has not increased appreciably in the past decade. Karlowsky et al found, however,
that there was a signicant increase in resistance to ciprooxacin from 0.7%
in 1995 to 2.5% in 2001 among urinary E coli isolated from outpatient
female patients of all ages. Whether this trend is occurring within the
population of adult women with acute uncomplicated cystitis is not clear
because there is little published data available after 1999 for this specic
group. Most laboratory surveys will tend to overestimate resistance because
urine cultures are not routinely performed for truly uncomplicated cystitis.

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247

In a recently completed treatment trial of 62 university women presenting

with acute uncomplicated cystitis, none of the E coli isolates were resistant
to ciprooxacin (K. Gupta, T.M. Hooton, and W.E. Stamm; unpublished
data). Fluoroquinolones also continue to have excellent activity against
non-E coli gram-negative organisms. There is a relatively high rate of uoroquinolone resistance, however, among enterococciranging from 20% to
60%, depending on the location and year of study. The low prevalence of these organisms in acute uncomplicated cystitis mitigates this
problem. S saprophyticus is in general susceptible to most uoroquinolones,
although the mean inhibitory concentrations (MICs) of ciprooxacin and
ooxacin are higher than those of the newer uoroquinolones and compared
with E coli MICs [20,21].
By contrast with North America, resistance rates to the uoroquinolones
among urinary isolates from the community in some European countries,
and especially in Latin America and Asia, are quite high. A survey of E coli
isolates from general practitioners in Spain revealed a ciprooxacin resistance rate of 7% in 1992, up from 0.8% in 1989 [22]. A 1999 survey of
isolates from women with acute uncomplicated cystitis across Europe
demonstrated a ciprooxacin resistance rate of 19.6% in Spain and Portugal
[15]. Rates of resistance in the other regions represented in this survey were
much lower (0%2.8%), consistent with other European studies of
community-acquired UTIs [23,24].
Nitrofurantoin
Nitrofurantoin is one of the oldest urinary anti-infectives in use.
Surprisingly, resistance to this drug remains minimal among E coli causing acute uncomplicated cystitis (Fig. 1). As seen in Table 1, a majority of
studies have found E coli resistance to be 1% to 2%, regardless of the study
site or year. The lack of resistance may be related to the fact that nitrofurantoin has multiple mechanisms of action, requiring organisms to
develop more than a single mutation to develop resistance. In addition,
because nitrofurantoin does not attain appreciable tissue or serum levels, it
is used primarily for the treatment of uncomplicated cystitis rather than for
complicated UTIs or for other infections. This limited usage may also be
a contributing factor to the lack of development of widespread resistance to
this drug.
Nitrofurantoin also retains excellent activity against gram-positive
organisms causing acute uncomplicated cystitis, including S saprophyticus
and enterococci. Even vancomycin-resistant enterococci are usually susceptible to nitrofurantoin, although these organisms are virtually never seen
in uncomplicated cystitis. Resistance rates of non-E coli gram-negative
urinary isolates to nitrofurantoin tend to be higher than those seen with E
coli [25]. This is partially caused by the intrinsic resistance of P mirabilis
to nitrofurantoin. Because Proteus sp occur in low frequency in acute

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K. Gupta / Infect Dis Clin N Am 17 (2003) 243259

uncomplicated cystitis, the overall rates of resistance of acute uncomplicated

cystitis isolates to nitrofurantoin remain low. In addition, there is no signicant geographic variation in nitrofurantoin resistance prevalence across
the United States or in other countries [8,15].
Fosfomycin
Fosfomycin trometamol is one of the newer agents available for
treatment of acute uncomplicated cystitis and the only agent licensed
for single dose therapy. Few data regarding susceptibility patterns of
cystitis isolates are available, especially from the United States. In a recent
treatment trial of acute uncomplicated cystitis in university women in
Seattle, 2 out of 62 women had a uropathogen resistant to fosfomycin (K.
Gupta, T.M. Hooton, and W.E. Stamm; unpublished data). In Europe,
where this drug is more widely used, susceptibility remains very high among
uncomplicated UTI isolates, ranging from 98.6% to 100% [15]. Like
nitrofurantoin, fosfomycin tends to retain activity against uropathogens
that are resistant to other drugs. A laboratory survey of vancomycin-resistant enterococcal isolates from across the United States demonstrated
that 100% of Enterococcus faecalis and 67% of Enterococcus faecium were still
susceptible to fosfomycin [26]. Another study demonstrated that 100% of 79
quinolone-resistant urinary E coli retained susceptibility to fosfomycin [27].
b-lactams
Resistance among urinary isolates to the b-lactams is not a new
phenomenon. Rates of ampicillin and cephalothin resistance among acute
uncomplicated cystitis E coli isolates were already quite high in the early
1990s, averaging approximately 25% from 1990 to 1993. Rates have risen
steadily, albeit less steeply than TMP-SMX resistance rates, to approximately 40% from 1998 to 2002 (Fig. 1). There is much less data available
regarding the activity of amoxicillin/clavulanate and the advanced generation cephalosporins against E coli isolated from acute uncomplicated
cystitis cases. In general, susceptibility to these agents is much higher than to
the aminopenicillins or rst-generation cephalosporins [4,15]. However,
therapeutic outcome with amoxicillin/clavulanate may not be optimal in the
setting of ampicillin resistance [28].
Among non-E coli bacterial isolates, P mirabilis and gram-positive
organisms retain reasonable susceptibility to the aminopenicillins. The
majority (> 95%) of enterococci isolated from studies of acute uncomplicated cystitis are susceptible to ampicillin [9]. Most S saprophyticus
isolates appear to be resistant to oxacillin (and therefore to ampicillin) by
disk diusion, but studies have shown that this nding does not correlate
with the presence of the mecA gene, and, thus, oxacillin testing is no longer
recommended for these organisms [29,30]. In general, ampicillin and
cephalothin retain excellent activity against S saprophyticus.

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249

Acute uncomplicated pyelonephritis

Pyelonephritis is much less common than cystitis, and there are fewer
studies from which to obtain susceptibility data. Even with little data
available, however, it is evident that the issues of resistance that are being seen
with acute uncomplicated cystitis are also a problem in uncomplicated
pyelonephritis. In the mid-1980s, a treatment trial of 85 women with acute
uncomplicated pyelonephritis in Seattle demonstrated that 66% of isolates
were susceptible to ampicillin, and 99% of isolates were susceptible to TMPSMX [31,32]. Approximately 1 decade later, only 57% and 70% of 50 isolates
from women with uncomplicated pyelonephritis were susceptible to ampicillin
and TMP-SMX, respectively [12]. Almost all (98%) of these isolates were
susceptible to the uoroquinolones. Similarly, a nationwide treatment trial of
uncomplicated pyelonephritis in women conducted from 1994 to 1997 found
that almost all (99%) of the 255 isolates were susceptible to ciprooxacin and
to ceftriaxone, but that only 82% were susceptible to TMP-SMX. The rate of
TMP-SMX resistance in this study varied greatly by geographic region, with
rates of resistance of 7% among E coli strains from the eastern, 14% from the
midwestern, and 32% from the western United States [33]. Thus, as in cystitis,
resistance to the aminopenicillins and TMP-SMX among uropathogens
causing uncomplicated pyelonephritis has increased appreciably in certain
parts of the United States over the past decade.
Complicated urinary tract infections
Antimicrobial resistance has long been recognized as an important problem
in managing complicated UTIs. There are several surveillance systems that
monitor resistance in hospitalized patients from across the United States, such
as The Surveillance Network, the SENTRY Antimicrobial Surveillance
Program, Project ICARE (Intensive Care Antimicrobial Resistance Epidemiology), and the National Nosocomial Surveillance system. Data from these
surveillance systems highlight the fact that the spectrum of organisms isolated
from the urine in complicated UTIs is much broader than that seen in
uncomplicated cystitis, with a higher frequency of non-E coli gram-negative
rods such as Klebsiella sp, Proteus sp, Pseudomonas sp, and Serratia sp, as well
as other organisms such as enterococci and yeast. E coli is usually still the
predominant pathogen but is often more resistant than E coli isolates from the
community, as are the other organisms. Three issues that deserve further
comment because of their frequency in complicated UTIs include vancomycin
resistance, extended-spectrum b-lactamase (ESBL)-mediated resistance, and
uoroquinolone resistance.
Vancomycin-resistant enterococci
The prevalence of vancomycin-resistant enterococci (VRE) varies by
institution and by site of infection [34]. Overall, the proportion of urinary

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enterococci resistant to vancomycin in US hospitals ranges between 6%

to 7% [34,35]. A European survey of the microbiology of nosocomial
UTIs in 228 hospitals across Europe demonstrated an even lower rate of
VRE; only 1.3% of enterococcal isolates were vancomycin-resistant [36].
The high frequency of enterococcal UTIs in hospitalized patients results,
however, in a signicant absolute number of urinary VRE isolates [34].
Fortunately, many of these cases probably represent asymptomatic
bacteriuria or colonization rather than true infection [37]. In cases where
treatment is warranted, the coresistance of vancomycin-resistant E
faecium to ampicillin and other commonly used antimicrobials can make
it dicult to nd an active antimicrobial agent. The agents most likely to
have in vitro activity against VRE in the urinary tract include
nitrofurantoin, fosfomycin, quinupristin/dalfopristin (E faecium only)
and linezolid [38]. The optimal agent will vary by individual case,
depending on specic patient characteristics and the organism susceptibility prole [38].
Extended-spectrum b-lactamases
The prevalence of ESBLs is particularly relevant to UTIs because E coli is
still the most common cause of hospitalized UTIs, with K pneumoniae and
P mirabilis close behind. Fortunately, the ESBL phenotype among
nosocomial UTI pathogens is still uncommon in the United States as
a whole, although rates vary greatly by institution [34]. The 1998 SENTRY
survey of UTI pathogens from hospitalized patients found that only 0.4% to
1.4% of E coli, 4.2% to 6.6% of Klebsiella spp, and 2.7% to 4.0% of
P mirabilis isolates had MICs of more than 2 lg/mL to aztreonam,
ceftriaxone, or ceftazidime [35]. Although the frequency of ESBL production among UTI isolates remains low, urinary origin has been shown to
be an independent risk factor for bacteremia, with ESBL producing E coli
[39]demonstrating the important clinical impact of these multi-drugresistant organisms.
Fluoroquinolone resistance
The uoroquinolones are often the preferred agents for treatment of
complicated UTIs because of their high ecacy and bioavailability, and,
thus, resistance to these agents is particularly problematic. Resistance of
Pseudomonas aeruginosa to ciprooxacin, levooxacin, and gatioxacin
varies by institution but was found to be approximately 23% among urinary
isolates collected from 26 US laboratories in 2000 [14]. Much higher rates
are seen in surveys of urinary P aeruginosa from Europe (43% resistant),
Asia (33%37% resistant), and Latin America (70% resistant) [16,19,36].
Ciprooxacin still has the best in vitro activity against P aeruginosa based on
MIC values [14].

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251

Fluoroquinolone resistance has traditionally not been a frequent problem

among E coli isolates from complicated UTIs in the United States. In 1997
and 1998, surveillance from hospitals across the United States found an E
coli uoroquinolone resistance rate of 3% to 4% [35]. Another national
survey demonstrated that this rate was essentially stable at approximately
4% among urinary E coli isolated in the United States in 2000 [40]. Much
higher rates of resistance have been reported, however, within specic
institutions. An E coli ciprooxacin resistance rate of 6% was reported from
a rehabilitation center in California in 1996, up from a rate of 0.6% in 1989
[41]. The prevalence of ciprooxacin-resistant E coli has continued to
increase and is up to 15% in that institution as of 2001 [42]. Fluoroquinolone resistance among urinary E coli from Europe has also increased
substantially in the past 5 years, with rates up to 10% in some centers
[36,43,44].

Determinants of resistance
There is limited understanding of the individual risk factors associated
with having a TMP-SMX-resistant E coli UTI. Most studies that have
evaluated this issue have done so retrospectively via chart review or as
secondary analysis. Interesting, despite these limitations, most of these
studies have been consistent in their ndings regarding the main risk factors
for having a TMP-SMX-resistant UTI. Wright et al conducted a case
control study of patients being evaluated at a hospital emergency room for
symptoms of cystitis. Diabetes, recent hospitalization, current use of
any antibiotic, and current or recent use of TMP-SMX were independently
associated with TMP-SMX resistance. After excluding patients who were
recently hospitalized, diabetes was no longer associated with resistance.
TMP-SMX use was the strongest predictor of TMP-SMX resistance in this
study, with a vefold increased risk of TMP-SMX resistance among patients
who were currently using TMP-SMX or had used it in the past 3 months.
More recently, Brown et al found in a retrospective analysis that use of an
antimicrobial other than TMP-SMX within 2 weeks of a UTI diagnosis was
associated with a twofold increased risk of having a TMP-SMX-resistant
uropathogen. Use of TMP-SMX in the preceding 2 weeks was associated
with a 17 fold increased risk of resistance. Undoubtedly, some of the female
patients who had used TMP-SMX in the preceding 2 weeks had done so for
a TMP-SMX-resistant UTI and had returned because of therapeutic failure;
however, many of the women in the study were experiencing their rst UTI.
In addition, a history of recurrent UTI, dened as 3 or more UTIs during
the past 12 months, was not independently associated with resistance,
similar to the ndings of Wright et al.
Thus, there is ample evidence suggesting that current or recent use of
TMP-SMX increases the risk that a patient with acute cystitis is infected

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with an organism resistant to TMP-SMX. This is probably true for

recent use of other antimicrobials as well, although the associations are
not as strong and it is not clear which antimicrobials in particular are
contributory. At least two studies have shown, however, that TMP-SMX
exposure is not the only factor driving TMP-SMX resistance among
urinary isolates because areas where TMP-SMX use is absent or infrequent still experience increasing TMP-SMX resistance rates [44,45].
Additional factors that have been reported to increase the risk of having
a TMP-SMX-resistant uropathogen include international travel or Asian,
Latin American, or Hispanic ethnicity [46,47]. These potential associations need to be validated in larger studies. In addition, factors associated
with intestinal carriage of TMP-SMX-resistant E coli, including travel to
areas with high rates of TMP-SMX resistance and secondary exposure to
antimicrobials via household members on antibiotics or children in day
care, need further delineation in relationship to TMP-SMX resistance in
UTIs [4850].
The risk of having a TMP-SMX-resistant UTI may also be related to the
prevalence of genetically similar uropathogenic E coli strains circulating in
the community, most probably from a common source such as contaminated food or water [51]. An outbreak of UTI in South London in 1987 and
1988 was found to be caused by a specic E coli serotype [52]. This strain
was multi-drug-resistant and particularly virulent, causing not only cystitis,
but also pyelonephritis and septicemia, aiding in the recognition of the
epidemic. The source of the strain was not identied. More recently, Manges
et al found that 28/55 (51%) of TMP-SMX-resistant E coli isolates collected
from female patients with acute uncomplicated cystitis in Michigan,
Minnesota, and California were similar by DNA ngerprinting [52]. By
comparison, only 2/50 (4%) of TMP-SMX susceptible E coli isolates had
a similar ngerprint pattern. The E coli in this genetically similar group,
called clonal group A, were much more likely to be resistant not only to
TMP-SMX, but also to multiple antimicrobials, including ampicillin,
streptomycin, chloramphenicol, and tetracycline. E coli isolates from
uncomplicated pyelonephritis which were characterized as belonging to
clonal group A were also more likely to be resistant to TMP-SMX and to
multiple drugs than E coli not belonging to clonal group A [31]. Other
studies of E coli isolated from acute UTIs have not found a clonal
relatedness among resistant isolates, suggesting that additional research is
needed on the predictors of antimicrobial resistance among uropathogenic
E coli [46].

Clinical implications of resistance

There has been some skepticism regarding the clinical relevance of the
emergence of in vitro resistance to TMP-SMX among uropathogens causing

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253

UTIs because it is known that most antimicrobials used to treat UTIs

achieve very high urinary concentrations. There are now both in vitro
and clinical data to suggest that in vitro TMP-SMX resistance occurs at a
high level and does result in therapeutic failure, both in cystitis and
pyelonephritis. Investigators have demonstrated that the majority of TMPSMX-resistant E coli isolates have MICs to TMP and TMP-SMX that are
higher than the achievable steady state concentration of the drugs in urine
[53,54]. Secondary analyses from treatment trials have shown that this
resistance does result in clinical failure in approximately 50% of female
patients treated with TMP-SMX for acute cystitis [3,6,55]. Despite very
small sample sizes and dierent study populations, the data from these
studies have been very consistent. There is less information on the rate of
bacteriologic failure to be expected in correlation with TMP-SMX
resistance, but one treatment trial found that 6/10 (60%) of female patients
did not achieve bacterial eradication when treated with TMP-SMX in the
setting of a TMP-SMX resistant uropathogen [3]. More recently, a large
prospective study specically designed to assess the issue of outcomes associated with TMP-SMX resistance has veried what these smaller studies
have hinted at [17]. Women with acute uncomplicated cystitis were treated
with a 5-day course of double-strength TMP-SMX twice a day. They were
continued on the regimen regardless of the susceptibility of the infecting
uropathogen. Overall, 29% of the subjects had a uropathogen resistant to
TMP-SMX. Clinical cure at the rst follow-up visit was achieved in 88% of
subjects with a TMP-SMX-susceptible uropathogen, and 54% with a TMPSMX-resistant uropathogena highly clinically and statistically signicant
dierence. Bacteriologic eradication was achieved in 86% of subjects with
a TMP-SMX-susceptible uropathogen, and 42% with a TMP-SMXresistant uropathogen. Long-term cure rates were also signicantly dierent
between women with a TMP-SMX-susceptible versus a TMP-SMXresistant uropathogen.
Data from another recent study demonstrate that in vitro resistance also
correlates highly with clinical and bacteriologic outcome in pyelonephritis.
Women seen in the outpatient setting were randomized to treatment with
ciprooxacin for 7 days or TMP-SMX for 14 days [33]. Women were continued on the drug to which they were randomized regardless of the
susceptibility prole of their infecting uropathogen. At 4 to 11 days posttherapy, 96% of the 76 women who were treated with TMP-SMX and had
a TMP-SMX-susceptible uropathogen had bacterial eradication compared
with 50% of the 14 TMP-SMX subjects treated with a TMP-SMX-resistant
uropathogen. The clinical cure rates were similarly disparate, with 92% of
TMP-SMX-treated women with a TMP-SMX-susceptible uropathogen, and
35% of TMP-SMX subjects treated with a TMP-SMX-resistant uropathogen achieving clinical cure. Thus, TMP-SMX resistance clearly is associated with lower bacterial and clinical cure rates in both cystitis and
pyelonephritis.

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Emerging issues
Fluoroquinolone resistance in uncomplicated urinary tract infections
The increase in TMP-SMX resistance among community-acquired UTI
isolates has led some clinicians to use uoroquinolones for these infections
[56]. One major concern about this practice is that increased prescribing of
uoroquinolones has been linked in several studies to increased uoroquinolone resistance in urinary E coli [44,5759]. Most of these studies have
focused on E coli isolates from hospitalized patients or from patients with
complicated UTI. Studies of uoroquinolone use in women with acute
uncomplicated cystitis have, to date, not demonstrated an emergence of
uoroquinolone resistance after short-course (3-day) use. In fact, even a 10day course of noroxacin for treatment of acute uncomplicated cystitis did
not result in selection of resistant E coli in the fecal or vaginal ora [60].
Both 3- and 7-day courses of ooxacin for acute uncomplicated cystitis
likewise did not result in the demonstration of resistant rectal E coli [11].
These studies may have been too small, however, to demonstrate a low rate
of selection pressure toward uoroquinolone-resistant E coli associated with
short-term uoroquinolone use. On a population basis, it is likely that usage
of uoroquinolones for acute uncomplicated cystitis is going to contribute
to the problem of resistance to these drugs. We recently demonstrated the
emergence of a ciprooxacin-resistant E coli strain in the fecal ora of
an otherwise healthy woman who was treated with a 3-day course of
ciprooxacin for treatment of acute uncomplicated cystitis (K. Gupta, T.M.
Hooton, and W.E. Stamm; unpublished data). Reports from other countries
of increasing uoroquinolone resistance among community E coli isolates
are probably partially caused by use of these drugs for uncomplicated UTIs
[15,61]. The emergence of this resistance will probably further complicate
the management of uncomplicated UTIs over the next decade.
Multi-drug resistance
Resistance of E coli to three or more antimicrobials has traditionally been
a concern primarily in nosocomial infections. Two studies have now shown,
however, that multi-drug resistance (MDR) is a phenomenon in communityacquired urinary E coli isolates as well. A US-based national survey of UTI
isolates from 2000 demonstrated that 7.1% of E coli isolates were resistant
to 3 or more of the 5 drugs tested [40]. Many of the isolates were from
outpatient sources, although the rate of MDR E coli from acute uncomplicated cystitis cases is not specically reported. There was a higher
likelihood of MDR among E coli from complicated UTIs, ie, from males,
patients over 65 years of age, and inpatients. The majority (58%) of MDR
E coli cases in this study were resistant to ampicillin, cephalothin, and TMPSMX. Resistance to these agents and to ciprooxacin was the next most
common phenotype identied. The rate of MDR E coli also varied

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255

geographically, with higher rates in the Pacic and west-south-central US

Bureau of Census regions [40]. In a study of 435 patients presenting to an
emergency room with symptoms of UTI, 37% of uropathogens were
resistant to 2 or more antimicrobials (the criteria used to dene MDR in this
study) [62]. The rate of MDR from acute uncomplicated cystitis cases is not
reported, but 12% of isolates from healthy women age 50 or younger were
resistant to 2 or more drugs. Thus, the prevalence of MDR E coli in acute
uncomplicated cystitis remains unknown. It is probably very low at this time
but may become more of an issue as resistance to TMP-SMX and use of
uoroquinolones increases.
Summary
In vitro antimicrobial resistance is an evolving and growing problem in
UTI. Much of the increase is occurring in acute uncomplicated cystitis, an
infection that has traditionally been simple to treat. The current trend of
rising TMP-SMX and b-lactam resistance rates is worrisome. Of more
concern, however, are the emerging issues of uoroquinolone resistance and
MDR among community-acquired urinary isolates. Judicious use of
antibiotics and development of novel nonantimicrobial-based methods of
prevention of UTI are important strategies to help slow the progression of
resistance. In the meantime, ongoing surveillance of resistance trends and
enhanced understanding of the determinants of resistance are crucial for
optimal management of UTIs.

Acknowledgments
The author has received speaking honoraria, grant support, or consulting
fees from Bayer Pharmaceutical, Ortho McNeil, and Procter & Gamble, Inc.
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