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Urinary Tract Infections: Current and Emerging Management Strategies

Article in Clinical Infectious Diseases · May 2013

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 Clinical Infectious Diseases Advance Access published May 23, 2013

INVITED ARTICLE C L I N I CA L P R AC T I C E
Ellie J. C. Goldstein, Section Editor

Urinary Tract Infections: Current and Emerging

Management Strategies
Amelia E. Barber,1 J. Paul Norton,1 Adam M. Spivak,2 and Matthew A. Mulvey1
1
Department of Pathology, Division of Microbiology and Immunology and 2Department of Medicine, Division of Infectious Diseases, University of Utah
School of Medicine, Salt Lake City

Acute cystitis is one of the most commonly encountered bacterial infections and is responsible for substantial
morbidity and high medical costs in the United States and across the globe. Though generally considered to be
self-limiting and easily treated with antibiotics, urinary tract infections (UTIs) are often incompletely resolved

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by antibiotic therapy and frequently recur. This is in part due to the ability of uropathogenic bacteria to
invade, replicate, and persist within host epithelial cells. The biological complexity of these infections combined
with a dramatic rise in antibiotic-resistant pathogens highlight the need for alternative therapies. In this review
we examine current management strategies for UTIs, as well as emerging treatments, including novel com-
pounds that block bacterial interactions with the urothelium and vaccines focused on preventing both acute
and recurrent infections.
Keywords. UPEC; antibiotic resistance; vaccine; cystitis; recurrent UTI.

A urinary tract infection (UTI) is defined as microbial EPIDEMIOLOGY OF UTIs

infiltration of the otherwise sterile urinary tract and is
one of the most common bacterial infections world- UTIs are the most frequent bacterial infection seen in
wide. UTIs encompass infections of the urethra (ure- the outpatient setting: 1 in 3 women will develop a UTI
thritis), bladder (cystitis), ureters (ureteritis), and requiring antibiotic treatment by age 24, and 50% expe-
kidney ( pyelonephritis). There is an estimated annual rience at least 1 UTI during their lifetime [1]. The inci-
occurrence of well over 8 million UTIs in the United dence of cystitis is significantly higher in women than
States, many of which result in a visit to a physician [1]. men, likely the result of anatomic differences. Specifi-
Nearly all patients with UTI are prescribed a regimen cally, the shorter female urethra can facilitate bacterial
of antibiotics, with roughly 1% of patients requiring transit from the urethral opening to the bladder. Colo-
hospitalization. The annual cost of UTI treatment in nization of the vaginal introitus by gastrointestinal
the United States is estimated at $2.14 billion [2], a pathogens can also increase the likelihood of urinary
value compounded by the frequency of recurrent infec- tract infiltration [3, 4]. Other factors, including urinary
tions. In this review we discuss the epidemiology of tract obstruction, incomplete voiding, and aberrant
acute and recurrent UTIs, detail current management structural anatomy also predispose individuals to UTIs.
strategies, and explore emerging therapeutics. Additional risk factors include prior history of UTIs,
vaginal intercourse within the past 2 weeks, use of con-
traception with spermicide, low vaginal estrogen lev-
els [1, 5], and individual genetic background (extensively
Received 14 January 2013; accepted 13 April 2013. reviewed in [6]). While a number of comorbidities in-
Correspondence: Matthew A. Mulvey, PhD, University of Utah School of Medi-
cine, 15 N Medical Dr E, #2100, Salt Lake City, UT 84112 (mulvey@path.utah.edu).
crease susceptibility to UTI, the majority of UTIs occur
Clinical Infectious Diseases in otherwise healthy women.
© The Author 2013. Published by Oxford University Press on behalf of the Infectious The most common bacterial cause of uncomplicated
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.
community-acquired UTI is uropathogenic Escherichia
DOI: 10.1093/cid/cit284 coli (UPEC), representing >80% of infections [1]. These

CLINICAL PRACTICE • CID • 1

bacteria inhabit the lower intestinal tract of warm-blooded ver- RECURRENT UTIs AND INTRACELLULAR
tebrates where they lead a seemingly innocuous existence until BACTERIAL RESERVOIRS
they gain access to a niche, such as the urinary tract, where they
can cause disease. Other pathogens commonly associated with The burden of UTIs is compounded by their high rate of recur-
uncomplicated UTI include Staphylococcus saprophyticus, Kleb- rence. Recurrent UTI (rUTI)—defined as 2 uncomplicated
siella species, Proteus mirabilis, and Enterococcus faecalis [7]. infections in a 6-month time period or 3 infections within a
One of the more ominous issues on the horizon for bacterial year—cause a tremendous amount of morbidity and are frustrat-
infections, with UTIs being no exception, is the rise of antibiot- ing to patients and physicians alike [1]. Despite administration
ic-resistant organisms. One especially troubling example is the of antibiotics that seemingly clear the infection (determined by
heightened incidence of sequence type 131 (ST131) strains of negative urine cultures), the probability that a patient will
UPEC around the world. These strains often exhibit high levels develop a second UTI within 6 months is 25%, with the chance
of resistance to multiple antibiotics and have undergone rap- of recurrence over a 12-month period increasing to 46%. The
id intercontinental dispersal over the last decade [8]. ST131 historical view of rUTI pathogenesis is that each recurrence
strains are an increasingly common cause of community-acquired represents an independent inoculation of the urinary tract.
UTIs, spurring efforts to better identify and treat these resilient However, this model does not satisfactorily explain many
pathogens [8, 9]. Factors driving the global spread of ST131 (>50%, by some estimates) rUTI episodes in which the bacterial
strains are incompletely understood, but likely include the ac- strains responsible for both the initial infection and the recur-

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quisition of antibiotic resistance genes, such as those encoding rence are genetically identical [11]. An alternative mechanism
extended-spectrum β-lactamases (ESBLs), and the capacity to for recurrence involves the establishment of protected, intracel-
effectively utilize a broad range of metabolites [8, 10]. These lular bacterial reservoirs within the bladder mucosa (Figure 1).
characteristics may give ST131 strains a competitive advantage UPEC can invade host epithelial cells, including the termi-
within host environments, increasing the likelihood of their nally differentiated superficial umbrella cells that line the
dissemination within and between individuals. lumen of the bladder, as well as the underlying, immature

Figure 1. Events that promote the establishment and recurrence of urinary tract infection (UTI). (1) During a UTI, uropathogenic Escherichia coli (UPEC;
green) can replicate within the lumen of the bladder or (2) attach to and invade bladder epithelial cells. (3) Following invasion, UPEC is either shuttled back
out to the lumen or trafficked into late endosome-like compartments. (4) Disruption of these compartments and subsequent entry of UPEC into the host
cytosol allows for rapid intracellular bacterial growth and the development of intracellular bacterial community. During these events, UPEC can acquire al-
ternate morphologies, including the formation of long, filamentous cells that are resistant to host defenses such as neutrophils. (5) Infection can trigger the
exfoliation of bladder cells, a process that aids in the elimination of adherent and internalized bacteria. The efflux of UPEC from host bladder cells, includ-
ing those undergoing exfoliation, facilitates pathogen dissemination within and between hosts. (6) UPEC that remains bound within late endosome-like
compartments in the urothelium can establish long-lived intracellular quiescent reservoirs that are often enmeshed within actin filaments (red) and ex-
tremely difficult to eradicate with antibiotic treatments. The resurgence of UPEC from these reservoirs can initiate recrudescent infections. Abbreviation:
IBC, intracellular bacterial community.

2 • CID • CLINICAL PRACTICE

intermediate and basal cells [12]. Within superficial bladder confirmation of an uncomplicated UTI is classically defined as
cells, UPEC can enter the host cytosol and rapidly multiply, ≥105 colony-forming units (CFU)/mL of urine. However, this
forming a biofilm-like assembly known as an intracellular bac- definition has recently been modified based on observations
terial community (IBC) [12, 13]. The development of IBCs can that many uropathogens are capable of eliciting clinical pathol-
enhance the ability of UPEC to establish itself within the ogy in the urinary tract even with low levels of bacteriuria [1].
urinary tract, building up large numbers of bacteria while se- Consequently, as little as 103 CFU/mL urine, in the presence of
questered away from the flow of urine and the influx of inflam- overt UTI symptoms, is now considered sufficient for diagnosis
matory cells and antibacterial molecules. IBCs, however, are of acute cystitis [15]. Current recommended treatments for
not long-lived and will eventually disperse or be shed along acute uncomplicated cystitis are described in Table 1 [1, 16].
with the infected host cells [14]. Indeed, the remnants of IBC-
containing host cells can be detected in urine samples isolated Treatment of rUTI
from women seeking treatment for UTIs [3]. The efflux of For women who suffer from rUTI, low-dose antibiotic prophy-
UPEC from within IBCs, as well as the eventual exfoliation of laxis such as nitrofurantoin (100 mg per day), cephalexin (250
the infected superficial cells, may potentiate the dissemination mg daily) or trimethoprim-sulfamethoxazole (40 mg/200 mg
of UPEC both within the urinary tract and between hosts. daily) can provide symptomatic relief and protection against
Rather than forming an IBC, UPEC can enter a dormant subsequent infections [17]. For women whose UTIs are coinci-
state within host epithelial cells after trafficking into mem- dent with sexual activity, a single, postcoital prophylactic antibi-

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brane–bound compartments that become enmeshed within otic can be effective in preventing infections [18]. Self-initiated
host actin filaments [12]. The quiescent nature and intracellular antibiotics are also useful for women with frequent recurrent
localization of these bacteria renders them resistant to most an- infections. After diagnosing themselves based on symptoms
tibiotics and inaccessible to infiltrating neutrophils and other and/or a urine dipstick, they can initiate a 3-day regimen
host defenses [13, 14]. Experimental models indicate that these without needing to visit a physician [18].
quiescent intracellular UPEC reservoirs can persist for long The increasing prevalence of antibiotic-resistant uropatho-
periods in the absence of any overt clinical symptoms, even gens is likely to limit the effectiveness of our current antibiotic
with the use of antibiotic treatments that effectively sterilize the arsenal. For example, individuals who suffer from serious re-
urine [14]. Environmental signals, such as the reorganization of current or chronic UTIs due to ESBL-producing ST131 strains
actin filaments that occurs as bladder cells undergo terminal may benefit greatly from carbapenems such as ertapenem [9],
differentiation, can trigger the resurgent growth of UPEC, but these antibiotics are considered one of our last lines of
prompting the development and dispersal of IBCs and the rein- defense and so should be used cautiously. The ongoing emer-
itiation of clinical symptoms. According to this model, rUTIs gence of antibiotic-resistant strains, in conjunction with the
may in many instances be more accurately defined as recrudes- high frequency of rUTIs, highlights the need for a better under-
cent infections. These issues highlight the need for therapeutic standing of these infections and the development of new thera-
strategies that effectively target both active and dormant stages peutic strategies.
of UTI.
EMERGING THERAPIES
CURRENT MANAGEMENT OF UTIs
As noted above, many rUTIs are thought to arise from the
Initial diagnosis of acute uncomplicated cystitis is typically ability of bacteria to attach to and invade the bladder mucosa,
based on patient medical history, taking into account past indi- where they can form intracellular reservoirs protected from an-
vidual and family health issues, sexual activity, and current tibiotics and host defenses. As such, many emerging treatments
symptoms. Common indicators of acute cystitis include urinary for UTIs are aimed at blocking adhesion of bacteria to the
urgency and frequency, pain when voiding (dysuria), lower ab- urothelium and thereby preventing the establishment of trou-
dominal discomfort, and cloudy or dark urine. The diagnosis blesome reservoirs. Type 1 pili (or fimbriae), which are multi-
of patients presenting with these classic symptoms may be con- protein filamentous adhesive structures encoded by virtually all
firmed by urinalysis showing the presence of red blood cells, UPEC isolates, are generally indispensible for colonization of
high nitrite levels, and leukocyte esterase in the urine. the urinary tract [11]. The adhesin protein FimH, which is lo-
Although medical history and urinalysis are sufficient for the calized at the distal tip of each type 1 pilus, binds mannose resi-
diagnosis of most uncomplicated UTIs, the gold standard for dues on host glycoprotein receptors and allows UPEC to
diagnosis of acute cystitis includes a bacteriological urine adhere to and invade host bladder cells [19]. Type 1 pili also
culture with identification of the causative agent and antimicro- promote biofilm formation and the development of IBCs [20].
bial susceptibility testing. Using fresh, midstream urine, clinical Because type 1 pili are important colonization factors, the

CLINICAL PRACTICE • CID • 3

Table 1. Common Treatment Options for Uncomplicated Cystitis

Antibiotic Mechanism Dosage Notes

Nitrofurantoin Inhibits protein, DNA, 100 mg orally, twice daily Low resistance rates and risk
monohydrate/macrocrystals RNA, and cell wall for 5 d of adverse side effects.
synthesis Similar efficacy compared to
a 3-d regimen of
trimethoprim-
sulfamethoxazole
Trimethoprim- Inhibits nucleic acid 160 mg/800 mg (1 double- Only for use when local
sulfamethoxazole synthesis by folate strength tablet), twice resistance rates do not
synthesis inhibition daily for 3 d exceed 20% and in patients
who do not have sulfa drug
allergies
Fosfomycin trometamol Blocks cell wall 3 g in a single dose Minimal resistance and risk of
synthesis by collateral damage. Inferior
inactivating efficacy compared to other
enolpyruvyl regimens
transferase
Pivmecillinam Disrupts synthesis of 400 mg, once daily for 3–7 d Low resistance rates and risk
cell wall by of adverse side effects. Not
inhibiting formation available in North America

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of peptidoglycan
cross-links

The choice of antibiotics should be made after considering patient allergy and compliance history, local resistance rates, drug availability, and cost.
Fluoroquinolones such as ciprofloxacin are highly effective and can be given if none of the recommended antimicrobials can be used. However, resistance rates to
these drugs are on the rise and it is recommended that they be reserved for conditions other than acute cystitis. β-lactam antibiotics, such as amoxicillin, cefdinir,
cefaclor, or cefpodoximine, in 3- to 7-day treatment regimens can be given when other recommended agents cannot be used. However, β-lactam antibiotics have
inferior efficacy and a higher rate of resistance, particularly in ST131 strains. Ampicillin should not be used because it displays relatively poor efficacy in the
treatment of urinary tract infections and resistance rates to ampicillin are typically high.

therapeutic potential of inhibiting the assembly or function of Both mannosides and pilicides have exciting potential as
these adhesive organelles has received considerable attention. future therapies for the treatment of uncomplicated cystitis and
rUTI, and both types of reagents may help circumvent the
Pilicides and Mannosides rising tide of antibiotic-resistant organisms. However, one po-
The assembly of type 1 pili occurs through the chaperone- tential concern with the systemic administration of either man-
usher pathway, relying on the periplasmic chaperone FimC for nosides or pilicides is potential adverse effects on commensal
the stabilization, folding, transport, and assembly of pilus sub- E. coli strains and other members of the intestinal microbiota,
units [21]. Small synthetic molecules known as pilicides, which many of which also express type 1 pili [28]. Current thinking
are designed to target periplasmic chaperones and consequent- by many in the field is that use of pilicides and mannosides will
ly interfere with pilus assembly, provide an attractive approach likely be less disruptive than current antibiotic treatment proto-
for blocking bacterial adhesion and subsequent reservoir for- cols, but this supposition requires additional investigation.
mation. In vitro, pilicides effectively inhibit pilus biogenesis, re-
ducing UPEC adherence to bladder epithelial cells as well as Vaccinology
type 1 pili–dependent biofilm formation [22, 23]. The efficacy An alternate strategy for the prevention of recurrent and
of pilicides in animal infection models has not been reported. chronic UTIs is the development of systemic or mucosal vac-
Researchers have also specifically targeted the FimH adhesin cines. Over the past 20 years, several vaccination approaches
by use of soluble receptor analogues, or mannosides, that act as have been explored, including the use of heat-killed whole bac-
antiadhesives. These molecules bind FimH and prevent it from teria, bacterial cell extracts, and purified UPEC-associated viru-
interacting with host receptors [24]. Recently, orally available lence factors as antigens. Vaccination of women using a vaginal
mannoside derivatives have been developed that show great suppository containing 10 heat-killed strains of uropathogenic
promise as therapeutics [25, 26]. In a murine UTI model, these bacteria showed much promise in recent years [29, 30]. This
agents work prophylactically, preventing bacterial invasion into multivalent vaccine formulation, known as Solco Urovac, in-
bladder tissue [26]. They can also be used to treat established cluded 6 E. coli strains plus 1 strain each of P. mirabilis,
and catheter-associated infections, acting synergistically with Morganella morganii, Klebsiella pneumoniae, and E. faecalis.
standard antibiotic treatments to reduce UPEC titers within the Urovac passed phase 2 clinical trials and was shown to reduce
urinary tract of infected mice [27]. the incidence of UTI caused by E. coli in sexually active women

4 • CID • CLINICAL PRACTICE

between 20 and 50 years of age with histories of rUTI [29]. pathogenesis may prove more fruitful. Along these lines, re-
Although some individual patients in the study showed increas- searchers have developed in silico approaches, known collec-
es in anti–E. coli antibody levels, no statistically significant dif- tively as reverse vaccinology, to probe the increasingly large
ferences between vaccinated and placebo control groups were number of sequenced bacterial genomes for pathogen-specific,
detected, possibly accounting for the lack of any follow-up surface-localized antigens [38, 39]. These traits in a vaccine
phase 3 trials. antigen should increase the efficacy of antibody responses
Specific bacterial factors that have been targeted as vaccine while limiting cross-reactivity with nonpathogenic bacteria.
candidates for UTI include the type 1 pilus–associated adhesin This approach to vaccine design is encapsulated in a publicly
FimH and UPEC-associated iron acquisition systems. Like pili- available, Web-based system known as Vaxign (http://www.
cides and mannosides, antibodies directed against FimH can violinet.org/vaxign/). By screening for outer membrane pro-
interfere with the functionality of type 1 pili, disrupting the teins with amino acid sequences that are conserved among
ability of UPEC to colonize the urinary tract. Vaccination with UPEC isolates, but absent from nonpathogenic E. coli strains as
purified FimH coupled to its periplasmic chaperone FimC well as humans and mice, Vaxign identified 22 putative UPEC-
offered protection against UPEC when administered systemi- specific vaccine targets [40]. Several of these are functionally
cally in both murine and primate models of cystitis [31–33]. A undefined, and a few are known to be expressed by UPEC
similar vaccine containing a truncated version of FimH protect- during UTI, but to date none have been shown to protect
ed mice from experimentally induced cystitis when given by against cystitis. The refinement of reverse vaccinology, coupled

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either intramuscular or intranasal (mucosal) inoculation, using with gene expression profiling, proteomic analyses, and emerg-
CpG oligonucleotides as adjuvant [34]. ing high-throughput genetic screens, promises to greatly
Most bacteria require iron for survival, and while there is enhance our ability to identify useful vaccine targets.
ample iron in the human body, it is sequestered and generally
inaccessible to bacteria. Consequently, UPEC and many other
pathogenic bacteria rely upon iron-chelating molecules and re-
CONCLUSIONS
ceptors that enable them to scavenge essential iron from the
host [35]. Use of purified bacterial iron receptor proteins for Although UTIs are often considered to be easily managed in-
vaccination against UPEC has had mixed results. Of 7 UPEC- fections, they remain a huge burden for millions of individuals
associated iron receptors tested as vaccines in mice, 2 (IreA and and our healthcare system. The increasing prevalence of antibi-
LutA) provided significant protection against experimentally otic resistance among uropathogens presents a major challenge
induced cystitis [36]. Vaccination with another iron receptor, to the clinical management of UTIs. Recurrent infections, in-
Hma, protected against kidney infection, but not cystitis. For cluding those caused by antibiotic-sensitive pathogens, are ex-
this analysis, the purified iron receptors were delivered intrana- ceptionally common and are likely attributable in part to the
sally after being conjugated to cholera toxin to increase antige- establishment of recalcitrant intracellular bacterial reservoirs
nicity. within the bladder mucosa. Eradication of these clinically rele-
In total, these studies highlight both FimH and iron recep- vant reservoirs will require a better understanding of the under-
tors as potentially valuable vaccine candidates that merit lying molecular mechanisms that allow for their persistence.
further investigation. However, as with mannosides and pili- The ongoing development of new antimicrobial approaches,
cides, the use of purified iron receptors, FimH, or other UPEC- such as the use of pilicides and mannosides in conjunction
associated factors as vaccines may have inadvertent effects on with antibiotics, will provide new treatment options, while the
members of the endogenous microbiota that should be consid- identification of new vaccine candidates and optimized vacci-
ered. In addition, the route of vaccine delivery and the types of nation protocols promises relief to individuals who suffer from
adjuvants utilized need to be optimized for maximal efficacy recurrent or chronic UTI.
in humans. While individuals prone to recurrent or chronic
UTIs may benefit greatly from the development of anti-UPEC
vaccines, the costs and risks of this strategy require further Notes
evaluation.
Financial support. This work was supported by the National Institutes
Despite these hurdles, initial success in the development of
of Health (NIH; grants AI095647, AI090369, and AI088086 to the Mulvey
anti-UPEC vaccines has spurred the search for additional laboratory; NIH Microbial Pathogenesis Training Grant T32 AI055434 to
vaccine antigens. Candidate approaches, in which known viru- A. E. B.; and NIH Genetics Training Grant T32 GM007464 to J. P. N.).
lence factors such as flagellin are targeted, continue to generate Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
promising results [37], but less biased methods that are not nec- Conflicts of Interest. Conflicts that the editors consider relevant to the
essarily reliant on our limited understanding of UTI content of the manuscript have been disclosed.

CLINICAL PRACTICE • CID • 5

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6 • CID • CLINICAL PRACTICE

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