REVIEWS

The emerging threat of multidrug-resistant

Gram-negative bacteria in urology
Hosam M. Zowawi, Patrick N. A. Harris, Matthew J. Roberts, Paul A. Tambyah, Mark A. Schembri,
M. Diletta Pezzani, Deborah A. Williamson and David L. Paterson
Abstract | Antibiotic resistance in Gram-negative uropathogens is a major global concern. Worldwide, the
prevalence of Enterobacteriaceae that produce extended-spectrum β‑lactamase or carbapenemase enzymes
continues to increase at alarming rates. Likewise, resistance to other antimicrobial agents including
aminoglycosides, sulphonamides and fluoroquinolones is also escalating rapidly. Bacterial resistance has
major implications for urological practice, particularly in relation to catheter-associated urinary tract infections
(UTIs) and infectious complications following transrectal-ultrasonography-guided biopsy of the prostate or
urological surgery. Although some new drugs with activity against Gram-negative bacteria with highly resistant
phenotypes will become available in the near future, the existence of a single agent with activity against
the great diversity of resistance is unlikely. Responding to the challenges of Gram-negative resistance
will require a multifaceted approach including considered use of current antimicrobial agents, improved
diagnostics (including the rapid detection of resistance) and surveillance, better adherence to basic measures
of infection prevention, development of new antibiotics and research into non-antibiotic treatment and
preventive strategies.
Zowawi, H. M. et al. Nat. Rev. Urol. advance online publication 1 September 2015; doi:10.1038/nrurol.2015.199

Introduction
In 1833, the mathematician and cleric William Foster in modern medicine, as well as our ability to treat
Lloyd published his lecture entitled “Two Lectures on the c­ommonly encountered infectious diseases.
Checks to Population”.1 He described how farmers using Urinary tract infections (UTIs) are among the most
common grazing areas for their sheep could deplete this common types of infectious disease, with approximately
The University of
Queensland, UQ Centre shared resource to the eventual detriment of all, while 150–250 million cases globally per year.4–6 About 40–50%
for Clinical Research, still acting in rational self-interest. 1 The economist of women and 5% of men will develop a UTI at least once
Building 71/918 Royal
Brisbane Hospital,
Garret Hardin later encapsulated this concept as “the during their lifetime.5,7 In the USA alone, the attributed
Herston, QLD 4006, tragedy of the commons”.2 A similar dilemma could be cost of UTI-related medical expenses has been estimated
Australia (H.M.Z., said to have arisen from our use of antibiotics. In seeking to range from US$1.6 billion to $3.5 billion annually if
P.N.A.H., M.J.R., D.L.P.).
Division of Infectious to maximize benefit for individual patients, clinicians broader societal costs are also considered.5,8–10 Owing
Diseases, National now risk diminished utility of this precious shared to their high prevalence, UTIs are a major contrib­utor to
University Health
System, 1E Kent Ridge resource for the many. global antibiotic use and resistance.11,12 Without effec-
Road, 119228, Bacterial resistance to our antibiotic arsenal is not a tive antibiotics active against common uropathogens,
Singapore (P.A.T.).
School of Chemistry
new phenomenon. Indeed, multiple resistance deter- many urological procedures would carry excessive risk.
and Molecular minants have been found in bacteria isolated from Accordingly, this Review aims to summarize the current
Biosciences, environments that have been separated from human global epidemiology of resistance in Gram-negative
The University of
Queensland, Brisbane, activity for millions of years.3 However, the antimicro- uropathogens, describe the genetic and molecular
QLD 4072, Australia bial resistance crisis we currently face reflects the rapid mechanisms underlying the resistance of these pheno­
(M.A.S.). Department of
Biomedical and Clinical
expansion, diversification and extension of host range types, examine the effect of resistance on common
Sciences L. Sacco, for a multitude of resistance determinants under selec- urological procedures and discuss therapeutic and
University of Milan, tion pressure from the widespread use of antibiotics. preventive options.
G. B. Grassi 74,
20157 Milan, Italy This man-made crisis threatens many of the advances
(M.D.P.). Department Key resistance mechanisms
of Pathology,
University of Otago,
For many years, resistance profiles for common Gram-
Competing interests
23A Mein Street, P.A.T. has received research support from ADAMAS, Baxter, negative uropathogens such as Escherichia coli or
Newtown,
Fabentech, Inviragen, Merlion Pharmaceuticals and Sanofi Klebsiella pneumoniae were relatively predictable and
Wellington 6242,
New Zealand (D.A.W.).
Pasteur, and has received honoraria from AstraZeneca stable over time. In the past few decades, however, this
and Novartis. D.L.P. has participated in advisory boards and
picture has changed dramatically. During the 1980s,
Correspondence to: received honoraria from AstraZeneca, Bayer, Cubist,
H.M.Z. Leo Pharmaceuticals, Merck and Pfizer. The other authors we witnessed the emergence of extended-spectrum
h.zowawi@uq.edu.au declare no competing interests. β‑lactamases (ESBLs) in Enterobacteriaceae. ESBLs are

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REVIEWS
Key points
■■ Multidrug-resistant Gram-negative pathogens are rapidly emerging and
spreading globally
■■ These multidrug-resistant pathogens are frequently associated with major
pathologies, including urinary tract infections
■■ Routine urological practices are affected by multidrug-resistant pathogens
■■ Knowledge of the local epidemiology of multidrug-resistant Gram-negative
bacteria is essential for determining empirical antimicrobial therapy
characterized by an ability to inactivate commonly used
antibiotics such as ceftriaxone or ceftazidime.13 ESBL-
producing E. coli or K. pneumoniae are now common-
place, not only in health-care facilities but also in the
community.14 Because of their resistance to hydrolysis
by ESBLs, carbapenems have been the most frequently
recommended antibiotics for treatment of infections
caused by these resistant strains.13 However, the world-
wide consumption of carbapenems has increased
signifi­cantly over the past two decades, particularly in
developing countries,15 and carba­penem resistance in key
Gram-negative pathogens is now a rapidly developing
phenomenon,16,17 facilitated by international travel and
globalization.18 Of particular concern is the increasing
prevalence of carbapenem-­resistant Enterobacteriaceae
(CRE), e­specially E. coli and K. pneumoniae, as these
Gram-negative species cause the vast majority of
clinical infections.
Carbapenem resistance among Enterobacteriaceae
most commonly arises as a result of the produc­t ion
of carbapenemases, such as KPC-type (K. pneumo­
niae carbapenemase), 19 NDM-type (New Delhi
Metallo‑β-lactamase)20 and OXA‑48-type21 enzymes
(Table 1). Carbapenem resistance can also arise from
other mechanisms, such as high-level expression of
ESBL or AmpC β‑lactamases in conjunction with
outer-­membrane porin changes and increased activ-
ity of efflux pumps (Table 1, Figure 1).22 Carbapenem-
resistant Enterobacteriaceae have been described by the
Centers for Disease Control and Prevention (CDC) as
posing an urgent antibiotic resistance threat; about 50%
of patients who develop bloodstream infections with
carbapenem‑resistant Enterobacteriaceae will die from
the infection.17
A key aspect of the acquisition of ESBL or carbapen-
emase genes is that they are frequently co-located
with other antimicrobial resistance determinants on
plasmids (mobile genetic elements that spread easily
between bacteria), rendering strains multidrug resistant
(MDR).23 Enterobacteriaceae, Pseudomonas aeruginosa,
and Acinetobacter baumannii with MDR phenotypes
are now increasingly reported.22 Definitions of MDR,
extensively drug resistant (XDR) and pan-drug resistant
(PDR) bacteria have been provided recently for common
Gram-negative species.24 Broadly, MDR bacteria are
defined as having acquired nonsusceptibility to at least
one anti­biotic in three or more classes, XDR bacteria
are defined as having nonsusceptibility to at least one
agent in all but two or fewer classes and PDR bacteria
are defined as having nonsusceptibility to all agents in
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all classes.24 Gram-negative bacteria frequently possess or
acquire a wide variety of different mechanisms to resist
the activity of antibiotics. In addition to β‑lactamases,
other antibiotic-­m odifying enzymes (for example,
acetyl­transferase, phosphotransferase or adenyltrans-
ferase activity against aminoglycosides25) are frequently
present. Resistance can also occur via mutations at the
inter­acting site with an antibiotic (for example, gyrA
mutations leading to reduced binding of quinolones26),
over­production of the target of antibiotic (for example,
mutations in a promoter region leading to increased
expression of dihydrofolate reductase, the target for tri-
methoprim27) or active export of antibiotics via efflux
pumps (for example, the resistance-nodulation-cell divi-
sion [RND] family of efflux pumps that possess broad
substrate specificity for a range of antibiotic classes28).
In order to interact with their target, anti­biotics must
cross the outer membrane present in all Gram-negative
bacteria. Mutations that lead to loss or alterations in
outer-membrane channels (porins) can, therefore, also
contribute to resistance29 (Table 1, Figure 1).
Epidemiology of MDR uropathogens
Despite the existence of several large national surveil-
lance networks for MDR bacteria, notable deficiencies
remain in current global surveillance data.16 However,
it is clear that the prevalence of antibiotic resistance in
Gram-negative uropathogens varies considerably across
the world (Figures 2–4, Supplementary Table 1 online).
For example, quinolone resistance in urinary E. coli from
China, India and Vietnam has been reported to be as
high as 70%, with around 60% of strains also express-
ing ESBLs.30 This finding contrasts with the situation in
countries such as Australia, where resistance rates are
significantly lower; in a 2012 national survey, 4.2% of
E. coli causing community-onset infections were resis-
tant to third-generation cephalosporins and 6.9% were
resistant to fluoroquinolones.31 Even within regions,
resistance can vary considerably; in Greece, carba­
penem resistance is as high as 59.4% in K. pneumoniae,
yet carba­penem resistance in K. pneumoniae is only 0.2%
in the Netherlands.32
The most common globally disseminated ESBL
associated with uropathogenic Enterobacteriaceae is
the CTX‑M-type ESBL. Approximately 97% of ESBL-
producing E. coli reported from Europe and North
America have been found to produce a CTX‑M-type
ESBL.33 The most prevalent type of CTX‑M-type enzyme
in E. coli is CTX‑M-15, which is associated with the
epidemic clone known as sequence type 131 (ST131),
which has emerged as a dominant global strain causing
e­xtraintestinal infections.34
Carbapenem resistance tends to emerge in areas where
ESBL prevalence is high, driven by selection pressure
from carbapenem use, and can subsequently dissemi-
nate. KPC-type carbapenemases were first reported in
the USA and subsequently in other geographic settings,
most notably southern Europe.35 Metallo‑β-lactamases
such as VIM-types and IMP-types have been found in
Enterobacteriaceae and P. aeruginosa mostly in Europe
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 REVIEWS

Table 1 | Mechanisms of resistance in Gram-negative bacteria

Structure and function Genetics Common species Common examples
Production of class A* β‑lactamases ‡

Contain serine residues ESBLs usually arise from mutations in ‘parent’ ESBLs are most common in ESBLs: TEM and SHV
Key features of ESBLs are narrow-spectrum β‑lactamase or have been Escherichia coli, Klebsiella spp. variants, CTX‑M
cephalosporinase activity ‘captured’ from environmental bacteria and Proteus spp., but have Carbapenemase: KPC
and resistance to 3GCs (e.g. CTX‑M from Kluyvera spp.) been described in most
Usually inhibited by clavulanate– Transmissible on mobile genetic elements, Enterobacteriaceae and
tazobactam in vitro (except KPC) such as plasmids, carrying multiple other in Pseudomonas spp.
resistance determinants KPC is seen in K. pneumoniae
Production of class B* β‑lactamases‡
Contain metal ions (for example, Zn2+) Usually highly transmissible on plasmids E. coli, Klebsiella spp. but described Carbapenemase:
Have carbapenemase activity, not inhibited carrying multiple other resistance determinants in many Enterobacteriaceae and IMP, NDM, VIM
by clavulanate/tazobactam Acinetobacter spp.
Aztreonam not hydrolysed by class B Intrinsic carbapenem resistance
β‑lactamases in Stenotrophomonas maltophilia
via class B enzyme (L‑1)
Production of class C* β‑lactamases‡
Also known as ‘AmpC’ enzymes Chromosomally encoded in many species, Enterobacter cloacae, E. aerogenes, Cephalosporinase:
Broad cephalosporinase activity but can also be inducible in Serratia marcescens, Citrobacter CMY, DHA, ACT
including 3GCs, but cefepime stable some Enterobacteriaceae freundii, Pseudomonas aeruginosa,
Not inhibited effectively by clavulanate Mutations in regulatory genes (for example, Providencia spp. and Morganella
or tazobactam ampD or ampR) involved in cell-wall recycling morganii all contain inducible
can lead to high-level AmpC expression and AmpC enzymes that are
resistance to a broad range of β‑lactams chromosomally encoded
Increasing plasmid-AmpC Plasmid-mediated AmpC (e.g. CMY)
transmission described increasing in E. coli
Production of class D* β‑lactamases‡
Oxacillinases that can have Can be acquired or naturally occurring Acinetobacter baumanii Carbapenemase:
carbapenemase activity and are only chromosomal genes (e.g. OXA‑23), Enterobacteriaceae OXA-type
weakly inhibited by clavulanate (e.g. OXA‑48), Pseudomonas spp.
Efflux pumps and porin mutations
Membrane transport systems to extrude Poly-specific transporters; for example, the Pseudomonas aeruginosa, Efflux: AcrAB-like
multiple antimicrobials or mutations in resistance-nodulation-division (RND) family Acinetobacter baumanii, or MexAB-OprM
outer membrane proteins to hinder entry Porin changes or loss via mutation Enterobacteriaceae Porin: OprD channel
of active drug (e.g. Enterobacter spp.) loss
Target site mutations
Methylation of 16S rRNA with high-level Carried by plasmids, often mediated by rmtA Enterobacteriaceae Methylases: RmtA,
resistance, including against amikacin and related genes (e.g. K. pneumoniae) RmtB or ArmA
Altered DHPS—essential for folate sul1 gene part of class 1 integron—frequently Stenotrophomonas maltophilia, E. coli sul1 and dhrf genes
synthesis in bacteria—leads to integrated into plasmids
sulphonamide resistance and altered DHFR Plasmid-borne dhfrI and dhfrII genes
with loss of inhibition by trimethoprim
DNA gyrase mutations prevent activity Often single mutations in quinolone resistance- Pseudomonas aeruginosa, Point mutations in
of quinolones determining region (QRDR) on gyrA gene Salmonella spp., other gyrA, gyrB, parC
Enterobacteriaceae and parE genes
Protein binding of quinolone active site, Protein binding encoded by plasmid-mediated E. coli, Klebsiella spp., Salmonella qnrA, qnrB, qnrC,
low-level resistance qnr genes spp. qnrD and qnrS
Overproduction of enzymes
Sulphonamide or trimethoprim resistance felP gene produces DHPS and folA encodes E. coli Mutations in
by overproduction of DHPS or DHFR DHFR promotor regions
result in increased
production of DHFR
and trimethoprim
resistance
Drug modification
Acetylation, nucleotidylation or Often carried on transmissible elements such Pseudomonas aeruginosa AAC(2’), ANT(2”),
phosphorylation of aminoglycosides as plasmids or transposons and Enterobacteriaceae APH(2”)
Some can also inactivate fluoroquinolones Can be chromosomal in some species Intrinsic to Providencia spp. AAC(6’)-lb-cr (also
confers quinolone
resistance)
*Ambler Classification Scheme based on amino acid sequence and protein structure. ‡β-lactamase enzymes hydrolyse the β‑lactam ring and inactivate the drug. Abbreviations: 3GC,
third‑generation cephalosporins; AAC, aminoglycoside acetyltransferase; ANT, aminoglycoside nucleotidyltransferase; APH, aminoglycoside phosphotransferase; DHFR, dihydrofolate reductase;
DHPS, dihydropteroic acid synthase; ESBLs, extended-spectrum β-lactamases; KPC, Klebsiella pneumoniae carbapenemase.

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REVIEWS

a
Mutation in Outer Inner Overexpression
lipopolysaccharide membrane membrane of efflux pumps
(polymixin resistance) (multidrug resistance)
Antibiotic

Periplasmic Porin
space Plasmid
Modified drug target
(e.g. quinolones)

β-lactam Antibiotic modification

antibiotics e.g. AmpC (e.g. aminoglycosides)
Chromosomal
DNA

Hydrolysis by β-lactamase
(plasmid-acquired Porin loss
or overexpressed Cell wall or mutation
chromosomal genes) (peptidoglycan) Antibiotic

b Luminal replication
and attachment of
fimbriated UPEC

Attachment Invasion
Superficial
bladder
epithelial cell
Transitional
epithelial cell
Filamentation Intracellular bacterial
and exfoliation community formation

Quiescent
intracellular
reservoir

c
Antibiotic

Planktonic
bacteria
Exopolymer
Urinary production
catheter

Urinary catheter surface Attachment Expansion Maturation and resistance

Prostate Bladder

Bacteria Reservoir of resistant

bacteria and transmissible
Biopsy resistance genes (from
needle oral ingestion and selection
Ultrasound
probe by prior antibiotic exposure)

Rectum

Nature Reviews | Urology

and Asia,35,36 and have been reported in Middle Eastern
countries,37 whereas the NDM-type that first occurred
in South Asia is now found on almost every conti-
nent. 38 OXA‑48-type is another carbapenemase and
has been mostly reported in the Middle East, Europe
and India.37,39 Carbapenem resistance in A. baumannii
is usually a­ttributed to the production of OXA-types,
mainly OXA‑23.37
Effect of bacterial pathogenesis on UTI
The success of certain uropathogenic species and clones
in causing UTI is not only attributable to their MDR
phenotype. Among the Gram-negative organisms, uro-
pathogenic E. coli (UPEC) cause the majority of com-
munity-acquired and hospital-acquired UTIs. Besides
being frequently resistant to antibiotics, UPEC strains
possess an arsenal of virulence factors that contribute to

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◀ Figure 1 | Infection and resistance in urological practice. a | Antibiotic resistance
mechanisms in Gram-negative bacteria. These include antibiotic hydrolysis by
β‑lactamase enzymes (including carbapenemases) or other antibiotic-modifying
enzymes (for example, against aminoglycosides). Porin loss or mutation can
reduce antibiotic permeability; increased expression or activity of efflux pumps can
prevent an antibiotic reaching its target site; a modified drug target can stop
antibiotics (for example, quinolones) binding to the active site; mutation in
lipopolysaccharide can render the bacteria resistant to the polymyxin group of
antibiotics. b | UPEC pathogenesis. UPEC attach to and invade uroepithelial cells
and form intracellular bacterial communities. These aid evasion of the host
immune system and provide some protection against antibiotic exposure. The
formation of a quiescent reservoir within the transitional cell layer might contribute
to relapsing or persistent infection. c | Biofilm formation enables the organism to
avoid host defences, resist antibiotic therapy and provides a reservoir for ongoing
infection if the catheter is not removed. d | Transrectal prostate biopsy allows
direct transfer of bacteria from the rectum to the prostate, including a potential
reservoir of resistance that can be enhanced by prior antibiotic exposure.
Abbreviation: UPEC, uropathogenic E. coli.
their ability to cause disease, including adhesins, toxins,
flagella, surface polysaccharides (for example, various
types of O antigen and capsule) and iron-acquisition
systems that utilise siderophores (for example, entero-
bactin).5,40,41 Many of these virulence factors have been
extensively characterized in mouse models of UTI, and
are strongly associated with UPEC strains isolated from
UTI patients.9,40
The best-defined UPEC virulence factors are fim-
briae,42,43 of which multiple different types can be pro-
duced.44 Type 1 fimbriae, as an example, confer the ability
to bind to α‑D-mannosylated glycoproteins such as uro-
plakins in the bladder, and in animal infection models
promote enhanced colonization, induction of host
responses, bladder cell invasion and biofilm develop­
ment through the formation of intracellular bacterial
communities.40,45,46 Fimbriae-mediated adhesion is also
an important virulence characteristic of most other uro-
pathogens; for example, Proteus mirabilis also has the
potential to produce several types of fimbriae, some of
which contribute to UTI.47 In addition to adherence, bac-
terial pathogens that successfully colonize the urinary
tract and cause UTI must possess a virulence arsenal that
enables them to avoid host-killing mechanisms such as
antimicrobial peptides and cytokines, neutrophil influx,
inflammation, apoptosis and exfoliation of host cells.5,41
UPEC can evade host responses through the develop-
ment of intracellular bacterial communities as a pro-
tected intracellular niche within epithelial cells during
the early acute stages of UTI, and through prolonged sur-
vival in quiescent intracellular reservoirs that may serve
as a reservoir for recurrent infection (Figure 1b).40,48
Antibiotic resistance in urology
Antibiotic resistance has a number of implications
for urological practice, including the treatment of
catheter-­associated urinary tract infections (CAUTIs)
and treatment of infections associated with transrectal-
ultrasonography-guided biopsy of the prostate (TRUBP).
Catheter-associated UTIs
CAUTIs are the most common nosocomial infections
suffered by patients in hospitals49,50 and long-term care
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REVIEWS
facilities.51 Such infections are associated with a cost of
approximately US$500 per episode52 and, especially in
situations in which urinary catheter obstruction has
occurred, have associated risks of morbidity and mortal­
ity.53 Indwelling urinary catheters have been associated
with an increased risk of community and nosocomial
UTIs, including infections caused by ESBL-producing 54,55
and carbapenem-resistant 56 organisms.
Patients with indwelling urinary catheters are a major
reservoir of antimicrobial-resistant uropathogens in
health-care settings.57 Such patients are often elderly
and have comorbidities and many of them are residents
of care facilities. In addition, patients with indwelling
urinary catheters are often exposed to antibiotics and
are at risk of cross-transmission of multidrug-resistant
pathogens. Once colonized, catheterized patients are
vulnerable to both symptomatic CAUTI and long-term
colon­ization. The indwelling urinary catheter bypasses
the normal host defences along the urethra, giving micro­
organisms that colonize the perineum direct access to the
bladder.58 In the past, when catheter drainage was open,
with urine collected in a drainage container, bac­teriuria
was almost universal within 1 week.59 In the 1970s, closed
catheter drainage was one of the biggest advances in the
prevention of CAUTI; however, breaks in the collection
system do occur,60 leading to colonization of the drainage
bag and intraluminal entry of bacteria into the catheter-
ized urinary tract. Bacteria can also enter the bladder
through the extraluminal route along the external surface
of the catheter. In this situation, organisms ascend into
the bladder from the perineum through the biofilm
that forms rapidly on the external surface.61 In a large
prospective study of 1,497 newly catheterized patients,
the intraluminal route of entry was as common as the
extraluminal route along the external surface of the
catheter for Gram-negative bacterial infection, whereas
Gram-positive bacterial infection was more frequently
associated with colonisation via the extraluminal route.61
Once microorganisms gain entry into the catheterized
urinary tract, they form a biofilm on both surfaces of the
catheter (Figure 1c). Such biofilms become encased in a
polymeric matrix that provides protection against host
immune defences and enhanced resistance to most anti-
microbial agents.62 Attempts have been made to prevent
the adherence of organisms to the catheter surface. These
attempts have included the use of hydrophilic surfaces63
and the modification of the surface through use of anti-
microbial agents or antiseptics. The most commonly
used agents to coat the surface of the catheter have been
silver or nitrofural, but such modifications have yielded
limited benefits. 64,65 A randomized trial of impreg-
nated catheters showed a limited reduction in CAUTI
in patients with nitrofural-coated catheters compared
with patients with standard polytetrafluoroethylene-­
coated catheters, but this finding was not seen as clini-
cally significant, and was associated with greater patient
discomfort and an increased requirement for catheter
removal.66 Currently, no international guidelines rec-
ommend the routine use of catheters coated with anti-
microbial agents,67,68 although such catheters can be
REVIEWS

Prevalence (%)

0 10 20 30 40 50 60 70 80
Figure 2 | Global epidemiology of resistance in Gram-negative uropathogens—fluoroquinolones. Prevalence of resistance
Nature Reviews | Urology
to fluoroquinolones in Gram-negative urinary pathogens by country. Data obtained from studies published 2009–2014.
The accuracy of these prevalence estimates is affected by the number and heterogeneity of studies undertaken in each
country, and reflects resistance data from clinical isolates, which only represent a subset of the total resistance burden
in colonized patients.

considered if the CAUTI rate has not declined after the
implementation of a comprehensive strategy aimed at
reducing infections.69
Once the biofilm is established, eradication of the
infection is very difficult, which exacerbates the problem
of antimicrobial resistance. Attempts to treat CAUTI
without catheter removal almost invariably result in the
selection of more-resistant organisms.70 This situation is
particularly likely in individuals with a long-term indwell-
ing catheter owing to neurogenic bladder.70 The most
effective approaches to prevent CAUTI and subsequent
biofilm formation involve a reduction in the duration of
catheterization.71 Such approaches have included the use
of electronic or nurse-driven reminder systems72 and have
been shown to be effective in various settings. By contrast,
strategies using antiseptic irrigation of the catheterized
bladder, antiseptic lubricants or topical t­herapies for
meatal care have not been found to be effective.58
Although no evidence is available from randomized
controlled trials, the implementation of robust infection
control policies and reminders to shorten the duration
of catheterization are widely believed to be important
in preventing CAUTI. In addition, close attention to
aseptic technique and adherence to principles of good
hand hygiene are essential in reducing device-­associated
infections.67–69 Prevention of CAUTI would be an impor-
tant step in reducing the reservoir of nosocomial MDR
Gram-negative organisms in hospitals and nursing
homes worldwide.
TRUBP-associated infections
Incidence and clinical context
TRUBP is commonly used to diagnose prostate cancer.
This method is time-efficient, cost-effective and is often
performed under local anaesthesia, with minimal adverse
effects that are mostly self-limiting.73,74 Periprocedural
antimicrobial therapy has been shown to reduce the
risk of infection, and is the current standard of care.75
Infection complicating TRUBP can cause cystitis, pros-
tatitis, sepsis and very rarely, disseminated abscess forma-
tion, mostly caused by Gram-negative Enterobacteriaceae
such as E. coli.74,76,77 Infection after TRUBP is likely to
occur via the direct inoculation of bacteria that exist
n­aturally in the rectum into the prostate, urinary tract or
local vasculature (Figure 1d).78
In the past decade, an increase in hospital admission
rates secondary to TRUBP-related infection has been
reported.74,79,80 The incidence of infectious complications
following TRUBP varies between regions, with emer-
gency department presentations ranging from 0% to 6%,
hospitalization rates of up to 4% and severe sepsis rates
ranging from 0% to 0.6%.77,81,82 A consistent theme of
TRUBP-associated infections is antimicrobial resistance,
specifically fluoroquinolone resistance, with or without
concurrent ESBL production.82–85 Fortunately, most iso-
lates remain sensitive to aminoglycosides (particularly
amikacin) and carbapenems. Despite the risk of infectious
complications and antimicrobial resistance, the 30-day
mortality related to post-TRUBP sepsis is low (0.1–1%).79,80

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 REVIEWS

Prevalence (%)

0 10 20 30 40 50 60 70

Figure 3 | Global epidemiology of resistance in Gram-negative uropathogens—third-generation cephalosporins.

Nature ReviewsPrevalence
| Urology
of resistance to third-generation cephalosporins in Enterobacteriaceae isolated from patients with urinary infections by
country. Data obtained from studies published 2009–2014. The accuracy of these prevalence estimates is affected by the
number and heterogeneity of studies undertaken in each country, and reflects resistance data from clinical isolates, which
only represent a subset of the total resistance burden in colonized patients.

For urologists, this concerning trend of resistance to
antimicrobials has broad implications for prostate cancer
control, with over 1 million TRUBPs performed annually
in the USA alone.74 Diagnosis of prostate cancer on initial
biopsy is poor at <30%, with repeat biopsy (up to four)
often performed owing to ongoing high clinical suspicion
of prostate cancer.86 Furthermore, active surveillance pro-
tocols, requiring prostate biopsy every 3 years, have been
promoted as a method of managing low-volume prostate
cancer.87,88 A North American study in 591 consecutive
men undergoing TRUBP, mostly for active surveillance,
reported an increased risk of an infection of 1.3 (odds
ratio [OR] 1.33, 95% CI 1.01–1.74) for every previous
biopsy.89 TRUBP complications cause a considerable
burden on health-care systems. A mean readmission cost
of $5,900 following a TRUBP-associated infection was
reported from a hospital in Texas, USA.90 A UK model
(based on severe infection with a median stay of 14.2 days)
described a cost of £4,260 per readmission, totalling
£7.7–£11.1 million per year.91 Although this figure might
be an overestimation in the context of TRUBP-associated
infections, for which the median length of stay is in the
range 1–4 days,79,92,93 the economic burden must be con-
sidered together with the unmeasurable psychological
burden, which is scarcely documented in this context.76
Current TRUBP prophylaxis strategies
Periprocedural antimicrobial therapy has been shown
to reduce TRUBP-associated infections, 94 and is
recommended by international urology bodies.75,95 The
clinical implementation of periprocedural TRUBP anti-
microbial therapy is varied, with different classes of agents
and durations used, as well as use of bowel preparation
agents.96 Oral fluoroquinolones are the most commonly
recommended agent, owing to a high bioavailability
(70–99%), with peak serum concentrations achieved
within 1 h, and good prostatic tissue penetration. In addi-
tion, high tissue:serum concentration ratios (~150%)
have been reported.77,97 This relation­ship has also been
reported for trimethoprim,77 but this ratio is lower for
β‑lactams (10–20%) and amikacin (50%).77,98 Alternative
recommended antimicrobials (in the presence of peni-
cillin hypersensitivity) include aminoglycosides and
metro­nidazole or clindamycin.99 Other first-line alterna-
tives include first‑, second- and third-generation cephalo­
sporins (American Urological Association Guidelines99)
and trimethoprim–­s ulfamethoxazole (European
Association of Urology Guidelines75). The duration of
TRUBP anti­microbial use varies.96 Current evidence sug-
gests that prolonged duration of antimicrobial use shows
no beneficial effect over a single dose.74,94
TRUBP prophylaxis in the era of resistance
With increasing concern surrounding a rise in infec-
tious complications following TRUBP, and in the
context of increasing antimicrobial resistance, the use
of broader spectrum antimicrobial prophylaxis before
TRUBP has been suggested. The addition of amikacin to

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REVIEWS

Prevalence (%)

0 5 10 15 20 25 30 35

Figure 4 | Global epidemiology of resistance in Gram-negative uropathogens—carbapenems. Prevalence of carbapenem-

Nature Reviews | Urology
resistant Enterobacteriaceae in urinary isolates by country. Data obtained from studies published 2009–2014.
The accuracy of these prevalence estimates is affected by the number and heterogeneity of studies undertaken in each
country, and reflects resistance data from clinical isolates, which only represent a subset of the total resistance burden
in colonized patients.

empirical fluoroquinolone-based regimens (in compari-
son to fluoroquinolone-­based regimens alone) has been
reported to result in fewer TRUBP infectious complica-
tions, with a reduction from 8% to 1.7% over a 5‑year
period in a North American study.100 Similar findings
were reported from a UK study, where the addition of
amikacin over a 2‑year period reduced bacteraemia
rates from 2.5% to 0.3%.101 However, despite the use of
ciprofloxacin (a fluoroquinolone) and amikacin pro-
phylaxis, a consistent 2.1% emergency admission rate
as a result of infectious sequelae was reported in one
study, with all E. coli bacteraemia isolates being resis-
tant to ciprofloxacin, but susceptible to amikacin.93 Oral
fosfomycin trometamol, given as a 3 g dose, could be
a potential option for the prolonged outpatient treat-
ment of TRUBP-associated infections.76 Fosfomycin tro-
metamol achieves reasonable prostatic concentrations,
although these concentrations are lower in the periph-
eral zone,102 where most prostate cancer is located,103
possibly reflecting differences in vascularity in differ-
ent regions of the prostate.104 Both nonrandomized and
randomized prospective studies comparing oral fosfo-
mycin trometamol with fluroquinolones have shown
these agents to have equivalent efficacy in reducing
TRUBP-associated infections;103 despite a higher rate
of bacteriuria reported with fosfomycin trometamol
than with fluoroquinolones (8.6% versus 4.2%), less
resistance was reported for fosfomycin trometamol
than for fluoroquinolones (41.9% versus 69.2%).105,106
Modelling based upon fosfomycin trometamol concen-
trations measured in prostate tissue suggests that the
optimal dosing of fosfomycin trometamol prophylaxis
is 1–4 h prior to surgery and that such treatment might
be ineffective if the organism minimum i­n hibitory
c­oncentration (MIC) is >4 mg/l.102
Pivmecillinam, a synthetic penicillin, has been used
extensively for outpatient treatment of UTI for 15 years,
and since 2011, has been investigated for use against
ESBL-producing organisms in vitro.107 Administration
of carbapenems in addition to standard prophylaxis
prior to TRUBP in high-risk patients has been reported
to reduce the rate of infection to below that seen in
low-risk patients treated with standard therapy.108 Nine
TRUBP patients in whom MDR E. coli was detected via
a rectal swab culture were given ertapenem in an out-
patient setting before TRUBP and no infectious com-
plications occurred.109 Although the need to reduce the
incidence of TRUBP-associated infections might be met
by use of broad-spectrum agents such as carbapenems,
the potential for subsequent development of resistance
to these agents and transmission is concerning. Even
brief exposure to a carbapenem can increase the risk of
subsequent colonization with carbapenem-resistant bac-
teria.110 In areas with a low prevalence of antimicrobial
resistance, use of these agents should be limited to the
treatment of serious TRUBP-related infections.85

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Fluoroquinolone resistance
The role of fluoroquinolone resistance in TRUBP-
associated infection is important in the setting of fluoro-
quinolone therapy following TRUBP. A growing body of
evidence has suggested that fluoroquinolone resistance is
highly prevalent in microorganisms that cause TRUBP-
associated infections.82,83,85,93 Fluoroquinolone resistance
in rectal flora can occur as a result of selection pressure
exerted by fluoroquinolone use, or it can be acquired
follow­ing travel to areas where fluoroquinolone resistance
is endemically high.77,83
The findings of a recent meta-analysis, comprising
nine studies and 2,541 patients, further support a caus-
ative relationship between TRUBP-associated infections
and fluoroquinolone-resistant rectal flora. The prevalence
of fluoroquinolone resistance was higher in rectal cul-
tures obtained after TRUBP antimicrobial therapy than
in those obtained before (20.4% versus 12.8%); fluoro-
quinolone resistance was associated with a sevenfold
increased incidence of TRUBP-associated infections over
fluoro­quinolone sensitivity (7.1% versus 1.1%).85 Another
study reported that men colonized with fluoroquinolone-
resistant organisms before TRUBP had an increased
overall risk of infection (OR 3.98, 95% CI 2.37–6.71)
and hospital­ization (OR 4.77, 95% CI 2.50–9.10) after
TRUBP, and that these risks increased further in those
who received fluoroquinolone prophylaxis alone.111
Strategies against TRUBP-associated infection
In order to reduce the risk of TRUBP-associated infec-
tion, some new evidence supports the use of rectal culture
results to guide antimicrobial therapy prior to TRUBP.
Most methods currently utilize selective culture, such as
fluoroquinolone-impregnated MacConkey agar 112 with
varying concentrations (1–10 mg/l) corresponding to
pathogen MIC estimates.85 To date, three studies have
shown that this principle of targeted therapy is success­ful
in reducing the incidence of TRUBP-associated infec-
tions.113–115 When the results of these studies were com-
bined using meta-analysis, infection rates were higher in
patients who received empirical prophylaxis than in those
who received targeted therapy (3.3% [95% CI 2.6–4.2%]
versus 0.3% [95% CI 0–0.9%]).85 Taylor and colleagues113
estimated that targeted prophylaxis would result in a
cost saving of $4,499 per TRUBP-related infection pre-
vented, and that 38 men would require rectal culturing
to prevent one TRUBP-associated infection. Duplessis
and colleagues114 similarly reported that the cost of rectal
culturing was $350 per 100 patients ($2.10 per culture),
and resulted in no TRUBP-associated infections; by con-
trast, the cost of treating the three infectious complica-
tions that occurred in the 103 patients in the historical
control group (who did not receive targeted therapy)
was ~$15,000.
Methods aimed at assisting with TRUBP decontamina-
tion, including reducing the apparent load of rectal flora
mucosal density prior to TRUBP using disinfection and
bowel preparation, are inconsistently practiced.96 In a
system­atic review and meta-analysis of seven trials, rectal
disinfection prior to TRUBP using povidone iodine was
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REVIEWS
reported to significantly reduce fever, bacteriuria and bac-
teraemia (relative risk 0.31, 95% CI 0.21–0.45).116 A novel
method of needle disinfection using 10% formalin prior
to each biopsy in 1,642 patients insignificantly reduced
the rate of TRUBP-associated infection compared with the
rate in a previous series of TRUBPs in which formalin
d­isinfection was not performed (0.3% versus 0.8%).117
Transperineal prostate biopsy is a strategy that uses
a transcutaneous approach to avoid the ‘trans-faecal’
route for prostate biopsy, but has similar prostate cancer
detection rates.118 This transcutaneous method predomi-
nantly uses traditional surgical prophylactic agents tar-
geting Gram-positive microorganisms, whilst enabling
better sterilization of the biopsy surface. Transperineal
prostate biopsy is associated with an overall complica-
tion rate that is similar to TRUBP,74,118 with some studies
reporting a sepsis rate approaching zero at the expense of
acute urinary retention (approximately 5%)119 and higher
o­perational costs.
Multiparametric MRI (mpMRI)-guided biopsy is
an approach that can facilitate fewer biopsies, both
per session and in total for the patient, compared with
TRUBP.120 However, early experience with mpMRI-guided
biopsy suggests that risks of UTI (1%), sepsis (0–2%) and
urinary retention (1%) are still present and broadly similar
to that seen with a conventional approach, although the
overall number of biopsies required for each patient might
be reduced.120
The presence of fluoroquinolone-resistant rectal flora
has been consistently reported as the most important
predictor of TRUBP-associated infection.85,99 Broader-
spectrum prophylaxis or pre-procedure screening for
resistance might be best targeted towards patients at
higher risk. A number of risk factors are currently used
in determining whether a patient is at high risk for coloni­
zation by fluoroquinolone-resistant organisms in the
rectum: previous prostate biopsy with or without TRUBP-
associated infection; recurrent UTI or prostatitis; fluoro-
quinolone use in the past 12 months; travel to South-East
Asia or South America in the previous 6 months; diabe-
tes mellitus; and immunosuppression.83,121,122 Urological-
specific risk factors include previous prostate biopsy,
indwelling urinary catheterization, history of infec-
tion (prostatitis or UTI), asymptomatic bacteriuria
and cystolithiasis.74,75,80,89,123,124
Preventing and reducing TRUBP-related infections
requires collaboration between colleagues in the fields
of urology, infectious diseases and micro­biology to
determine the optimal prophylactic regimen, taking
into account local resistance patterns and patient
demographics. Future research areas in identifying the
optimal solution relate to the role of targeted prophylaxis
using selective rectal cultures and/or analysis of patient
risk factors.
Treatment of established UTI
Uncomplicated UTI in the community setting
The Infectious Diseases Society of America (IDSA)
and the European Society for Clinical Microbiology
and Infectious Diseases (ESCMID) produced joint
REVIEWS
guidelines for the treatment of uncomplicated UTI and
pyelo­nephritis in women in 2010.125 Increasing antibi-
otic resistance in common uropathogens clearly had a
significant influence on antibiotic choice for all forms of
UTI. Even in the 2010 guidelines, fluoroquinolones were
no longer the first-line choice for uncomplicated UTI,
despite their effectiveness when organisms are suscep-
tible to this drug class.126 Considerable regional variation
in resistance requires clini­cians to be aware of the local
epidemiology relevant to their practice.
The IDSA/ESCMID guidelines for the treatment
of uncomplicated UTI recommended the following
four agents: nitrofurantoin, fosfomycin, pivmecillinam
and trimethoprim–­sulfamethoxazole. Of these, only
t­rimethoprim–sulfamethoxazole was recommended for
patients with suspected early pyelonephritis. However,
avoidance of trimethoprim–sulfamethoxazole was rec-
ommended if local resistance patterns were known to
exceed 20% or if this antibiotic combination had been
administered to the patient in the previous 3 months.125
A more recent review of 27 randomized controlled trials,
six systematic reviews and 11 observational studies have
broadly supported these recommendations.126 In addition
to concerns about resistance, β‑lactam antibiotics such
as amoxicillin–clavulanate and cefpodoxime are not as
e­ffective as other first-line choices.
For women with acute uncomplicated cystitis, typical
treatment durations range from a single dose for fosfo-
mycin, 3 days for trimethoprim–sulfamethoxazole or
fluoroquinolones, and 5 days for nitrofurantoin. Expert
recommendations127 have suggested that men should
receive a longer duration of antibiotic therapy (7–14 days),
although the evidence base for this approach is not strong.
A randomized controlled trial of 3 days versus 14 days of
ciprofloxacin for UTI in patients with spinal cord injury
(70% of whom were male) suggested improved clinical
and microbiological outcome with 14 days of therapy.128
However, in a large observational study of UTI in men, a
treatment duration of >7 days had no additional benefit
over shorter-duration treatment, but carried an increased
risk of Clostridium difficile infection.129
For the treatment of pyelonephritis in areas where resis-
tance of E. coli to fluoroquinolones exceeds 10%, an initial
single dose of ceftriaxone or an aminoglycoside is recom-
mended.125 If the patient does not require hospitalization,
treatment choices include a fluoroquino­lone for 7 days
or trimethoprim–sulfamethoxazole for 14 days, depend-
ing on the local pattern of resistance.125 Nitrofurantoin,
fosfomycin or pivmecillinam should be avoided for the
treatment of pyelonephritis owing to concerns that they
do not achieve adequate levels in renal tissue.125 The
treatment duration of 7 days for a fluoro­quinolone for
the treatment of pyelonephritis was established follow-
ing the results of a large randomized, controlled trial in
Sweden in which 7 days of therapy was found to be just
as effective as 14 days,130 and has been confirmed by a
meta-analysis of eight randomized, controlled trials.131
However, only three of the randomized, controlled trials
evaluated antibiotics other than fluoroquinolones, which
is noteworthy given current rates of resistance. In an
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© 2015 Macmillan Publishers Limited. All rights reserved
evaluation of a subgroup of studies in which more than
20% of patients had urogenital abnormalities, microbio-
logic failure occurred more frequently in patients given
short-course therapy (≤7 days) than in those receiving
treatment for longer durations (>7 days).131 The evi-
dence, although hampered by small sample sizes, would
therefore suggest that pyelonephritis in the setting of
ur­ogenital a­bnormality should be treated for >7 days.
CAUTI and health-care-associated UTI
Treatment of CAUTI with antibiotics is typically only
useful in patients with appropriate symptoms or signs
(for example, fever, chills, altered mental state or costo-
vertebral tenderness). The presence of pyuria or malo­
dorous urine alone should not be regarded as a reason
for treatment. A large study of bloodstream infection
in catheterized individuals showed that 34% of patients
did not receive appropriate empirical therapy within the
first 24 h after the blood cultures were collected.132 In this
study, although E. coli was the most common organism
isolated (accounting for 40% of bloodstream infections),
P. aeruginosa accounted for 21% of cases and enterococci
were responsible for 8% of cases.132 Empirical therapy
comprising piperacillin–tazobactam or ampicillin plus
gentamicin might therefore be appropriate in many cir-
cumstances, until therapy can be targeted according to
antibiotic susceptibilities. However, such decisions should
always be directed by knowledge of local resistance
rates—high prevalence of aminoglycoside resistance in
Enterobacteriaceae or P. aeruginosa, for instance, will
influence the choice of empirical therapy.
As is the case with CAUTI, antibiotic overuse is
common in the context of hospital-acquired, non-
catheter-­associated UTI. In the vast majority of circum­
stances, asymptomatic bacteriuria does not require
antibiotic therapy. In an innovative approach to this
problem, Leis and colleagues 133 suppressed results
on urine cultures from hospitalized, noncatheterized
patients, instead asking clinicians to call the micro­
biology laboratory for the results if UTI was suspected.
They found that 89% of urine samples from hospitalized
patients failed to meet the CDC criteria for UTI and,
compared with baseline, suppression of results dropped
initiation of antibiotic therapy from 48% of o­ccasions to
just 12%, with no untoward effects.133
UTI caused by MDR Gram-negative bacteria
Treatment guidelines are frequently insufficient when
infections with MDR uropathogens are encountered.
Assuming that antibiotic treatment is required (that is,
culture results do not reflect asymptomatic colonization)
and that infectious source control has been addressed
adequately, options are often limited. Empirical antibiotic
choice is determined by risk factors for MDR pathogens
specific to local circumstances, prior antibiotic exposure
and the severity of illness (Table 2). Consultation with
an infectious disease practitioner is recommended for
complicated UTI with MDR or XDR pathogens as addi-
tional susceptibility testing, use of uncommon agents or
use of combination therapy is often required. Interest
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 REVIEWS

Table 2 | Treatment options for MDR Gram-negative uropathogens will be available for clinical use (Table 3). The novel
β‑lactamase inhibitor avibactam has activity against
Indication First-choice antibiotic therapy Second-choice antibiotic therapy
ESBLs, AmpC, KPC-type and some OXA-type enzymes
Uncomplicated Fosfomycin, nitrofurantoin, Quinolone, temocillin (if available), (but not metallo‑β-lactamases such as NDM-type) and
lower UTI with pivmecillinam nitroxoline (if available)
MDR organisms has been developed to be given in combination with
established antibiotics such as ceftazidime.136,137 The
Complicated Carbapenems (for example, Combination therapy (including
UTI with MDR against ESBL or XDR isolates) combination of ceftazidime and avibactam has com-
infection AmpC‑producers) Colistin* plus carbapenem‡ pleted phase III trials (including complicated UTI
(specialist Piperacillin–tazobactam might Colistin* plus aminoglycoside and abdominal infections)137,138 and was granted FDA
advice required) be an alternative against (for example, amikacin) approval in February 2015 for the treatment of compli-
ESBL-producers that are Carbapenem‡ plus aminoglycoside
susceptible (but their role Dual carbapenems cated UTI and intra-abdominal infections. Ceftolozane is
is controversial) a novel cephalosporin that has enhanced activity against
*Polymyxin B is an alternative to colistin but is less widely available. ‡Consider extended or continuous P. aeruginosa.134 It can be inacti­vated by β‑lactamases so
infusions of carbapenems to optimize pharmacokinetic and pharmacodynamic parameters. is formulated with tazobactam, a β‑lactamase inhibitor.
Abbreviations: MDR, multidrug resistant; UTI, urinary tract infection; XDR, extensively drug resistant.
This combination shows good in vitro activity against
a range of Gram-negative organisms, including MDR
Table 3 | Future treatment options for MDR Gram-negative uropathogens and XDR strains,139 and was granted FDA approval for
the treatment of complicated UTI and intra-abdominal
Drug Phase I* Phase II* Phase III* FDA approved
infections in December 2014. Novel aminoglycosides,140
β-lactam combined with β‑lactamase inhibitors quinolones,141 tetracyclines142 and carbapenems143,144 are
Ceftazidime–avibactam138 also in development for the treatment of UTI caused by
Ceftolozane–tazobactam139 MDR Gram-negative bacteria (Table 3). Temocillin, a
previously overlooked agent (owing to its lack of activ-
Ceftaroline fosamil–avibactam – –
ity against Gram-positive bac­teria, P. aeruginosa and
Carbapenems anaerobes145), is being re-­evaluated and has performed
Panipenem–betamipron143‡ – well in the treatment of urinary and bloodstream infec-
Biapenem 144§
– – tions caused by ESBL-producing and AmpC-producing
Quinolones
Enterobacteriaceae.146 Nitroxoline is an older antibiotic
that has broad-spectrum activity against many uropatho-
Finafloxacin141 – –
gens (except P. aeruginosa) and is being re-evaluated as
Aminoglycosides an option for treatment of uncomplicated UTI, although
Plazomicin140 – – it is not widely available outside Europe.147
Tetracyclines An important measure to help prevent MDR infections
is the effective implementation of antimicrobial steward-
Eravacycline142 – –
ship (a systematic approach within health-care services to
β-lactamase inhibitors combined with carbapenem optimize the use of antimicrobial agents).148 The uncon-
Relebactam (MK‑7655)– – trolled use of broad-spectrum antibiotics leads to high
imipenem cilastatin rates of resistance, especially in countries with less-robust
RPX7009–meropenem – – health-care systems.15
Other agents in development
S‑649266 – –
Novel approaches to recurrent UTI
(novel cephalosporin) Recurrent UTI is defined as the occurrence of three
GSK2251052 (Boron- – –
symptomatic UTIs within 12 months or two sympto­matic
containing agent targeting episodes occurring within 6 months following clinical
Leucyl tRNA synthetase) resolution of a previous UTI. A novel method has been
*Clinical trial phases according to ClinicalTrials.gov. ‡Only approved in China, Korea and Japan. developed for the management of recurrent UTI, based on
Only approved in Japan.
the concept of bacterial interference whereby bacteria of
§

low virulence compete with and protect against coloniza-

has been renewed in drugs such as polymyxins (colis-
tin and polymyxin B) or tigecycline for XDR isolates
where few alternatives exist.134 Although colistin has
broad Gram-negative activity (with a few exceptions
such as Proteus or Serratia spp.) it can cause renal toxi­
city. Tigecycline p­enetrates poorly into the urinary tract
and achieves limited serum levels, with a meta-analysis
suggesting that it is associated with increased mortal-
ity in the treatment of sepsis.135 Combination therapy
with carba­p enems, even if carbapenem resistance is
detected, is often used.134 Hopefully, in the near future
newer agents active against Gram-negative organisms
tion and infection by pathogens.149 This method was first
performed with E. coli 83972, a strain originally isolated
from a young Swedish girl with asymptomatic bac­teriuria.
This patient carried the low-virulence organism for at least
3 years without development of clinical features of urinary
tract infection.150 E. coli 83972 is well adapted for growth
in the urinary tract where it establishes persistent coloni­
zation and outcompetes UPEC strains as well as other
pathogenic organisms.151 E. coli 83972 contains muta-
tions in the genes encoding a number of different UPEC
fimbriae, and thus is unable to express these o­rganelles as
functional adhesive surface structures.152,153

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© 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS

Several clinical trials have been designed in order to
assess whether deliberate colonization of the urinary
tract with E. coli 83972 or E. coli HU2117154 (a genetically
modified derivative of E. coli 83972) could be of benefit in
preventing recurrent UTI, and thereby replace antibiotic
therapy for this purpose. Most patients whose urinary
tract was successfully colonized by E. coli 83972 or E. coli
HU2117 were reported to have a significant reduction in
the incidence of UTI during the period of colonization.
Furthermore, in colonized patients who developed UTI,
the infection was caused by uropathogens other than
E. coli.152,155 Clinical trials using E. coli 83972 to pre-coat
urinary catheters have also yielded promising results, with
these trials currently being extended.156 These results high-
light a possible new management strategy for recurrent
UTI; however, further studies are required before bacterial
interference strategies such as those using E. coli 83972 can
be adopted more widely in the clinical setting.149
The biological importance of fimbriae in UPEC colo-
nization of the urinary tract is confirmed by the fact that
the prevention of this adherence mechanism represents
an attractive anti-virulence strategy.157–159 Molecules that
prevent the biogenesis or adhesion of UPEC fimbriae have
shown great promise in animal infection models160–162 and
are also highly effective against MDR strains such as E. coli
ST131.163 Vaccines based on the FimH and PapG adhes-
ins provide protective efficacy in mouse and/or primate
models of UTI,164,165 and together with vaccines targeted
against iron-regulated surface antigens,166,167 provide a
framework for the development of new prevention strat­
egies. However, the effectiveness of these approaches for
the prevention of UPEC-mediated UTI in different patient
groups requires further investigation.
Conclusions
Safe urological practice relies upon the availability of effec-
tive antibiotics, which is now threatened by the ongoing
rapid evolution of resistance in bacterial uropathogens.
Although some new drugs with activity against Gram-
negative bacteria, including activity against strains with
highly resistant phenotypes, might be available in the near
future, they are likely to be expensive and might be best left
for situations when no alternatives exist. Furthermore, the
existence of a single agent with activity against the great
diversity of resistance is unlikely.
Responding to the challenges of Gram-negative resis-
tance will require a multifaceted approach including
considered use of current antimicrobial agents, enhanced
diagnostics (including rapid detection of resistance) and
surveillance, improved adherence to basic measures of
infection prevention, development of new antibiotics and
research into non-antibiotic treatment and prevention
strategies. An improved understanding of the biology
of pathogens that cause UTI will provide opportunities
for the development of strategies aimed at interrupting
key processes such as bacterial attachment, persistence,
immune evasion and biofilm formation.
Human ingenuity is most productive when faced with
seemingly impenetrable problems. As such, limitations
do exist in the concept of the “tragedy of the commons”,
which underestimates the adaptability of human societ-
ies and the possibility that rational self-interest might still
generate solutions to mutual problems—especially when
the status quo is in the interest of nobody.
Review criteria
Relevant articles published between January 2009 and
September 2014 were identified via PubMed using the
following search criteria: “urinary tract infection” AND
“resistant OR resistance” AND “E. coli OR Klebsiella OR
Proteus OR Enterobacter OR Citrobacter OR Pseudomonas
OR Acinetobacter”. Only articles published in English or
with English translation were included. Additional sources
relevant to the Review were identified by the authors
from personal bibliographies and citations in articles
identified by the search strategy. In order to summarize
prevalence data, articles reporting resistance rates in
urinary pathogens were identified. Those reporting only
data from neonatal units, intensive care units or other
highly selected populations were excluded. Studies
where denominators were not described or where data
were collected prior to 2004 were also excluded. Pooled
estimates of resistance prevalence by country for
each antibiotic class were extracted from 98 articles.
Where more than one study was reported for a country,
prevalence estimates were pooled by meta-analysis using
MetaXL (EpiGear, University of Queensland, Brisbane,
Australia) with a random effects model. Intensity maps
were generated using Tableau®(Tableau Software,
Seattle, WA, USA).

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Acknowledgements
H.M.Z. acknowledges an academic scholarship from
the government of Saudi Arabia to pursue
postgraduate studies in the field of clinical
microbiology and infectious diseases, and research
support from the Ministry of National Guard, Health
Affairs, King Abdullah International Medical Research
Centre, Saudi Arabia (project no. IRBC/193/12).
P.N.A.H. is supported by an Australian Postgraduate
Award from the University of Queensland, Australia.
M.J.R. is supported by a Doctor in Training Research
Scholarship from Avant Mutual Group Ltd., a Cancer
Council Queensland PhD Scholarship and Professor
William Burnett Research Fellowship from the
Discipline of Surgery, School of Medicine,
The University of Queensland, Australia.
Author contributions
H.M.Z., P.N.A.H., M.J.R. and M.D.P. researched data
for the article, all authors provided a substantial
contribution to the discussion of content, H.M.Z.,
P.N.A.H., M.J.R., P.A.T., M.A.S., M.D.P. and D.L.P.
helped write the article, and all authors reviewed/
edited the manuscript before submission. H.M.Z.
and P.N.A.H should be considered joint first authors
on the manuscript.
Supplementary information is linked to the online
version of the paper at www.nature.com/nrurol.