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Antibiotic resistance in Gram-negative uropathogens is a major global concern. Worldwide, the prevalence of Enterobacteriaceae that produce extended-spectrum beta-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.
The University of
Queensland, UQ Centre
for Clinical Research,
Building 71/918 Royal
Brisbane Hospital,
Herston, QLD 4006,
Australia (H.M.Z.,
P.N.A.H., M.J.R., D.L.P.).
Division of Infectious
Diseases, National
University Health
System, 1E Kent Ridge
Road, 119228,
Singapore (P.A.T.).
School of Chemistry
and Molecular
TheUniversity of
Queensland, Brisbane,
QLD 4072, Australia
(M.A.S.). Department of
Biomedical and Clinical
Sciences L. Sacco,
University of Milan,
G.B. Grassi 74,
20157Milan, Italy
(M.D.P.). Department
NewZealand (D.A.W.).
Correspondence to:
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
Zowawi, H.M. etal. Nat. Rev. Urol. advance online publication 1 September 2015; doi:10.1038/nrurol.2015.199
In 1833, the mathematician and cleric William Foster
Lloyd published his lecture entitled “Two Lectures on the
Checks to Population.
He described how farmers using
common grazing areas for their sheep could deplete this
shared resource to the eventual detriment of all, while
still acting in rational self-interest.
The economist
Garret Hardin later encapsulated this concept as “the
tragedy of the commons.
A similar dilemma could be
said to have arisen from our use of antibiotics. In seeking
to maximize benefit for individual patients, clinicians
now risk diminished utility of this precious shared
resource for the many.
Bacterial resistance to our antibiotic arsenal is not a
new phenomenon. Indeed, multiple resistance deter-
minants have been found in bacteria isolated from
environments that have been separated from human
activity for millions of years.
However, the antimicro-
bial resistance crisis we currently face reflects the rapid
expansion, diversification and extension of host range
for a multitude of resistance determinants under selec-
tion pressure from the widespread use of antibiotics.
This man-made crisis threatens many of the advances
in modern medicine, as well as our ability to treat
c ommonly encountered infectious diseases.
Urinary tract infections (UTIs) are among the most
common types of infectious disease, with approximately
150–250million cases globally per year.
About 40–50%
of women and 5% of men will develop a UTI at least once
during their lifetime.
In the USA alone, the attributed
cost of UTI-related medical expenses has been estimated
to range from US$1.6billion to $3.5billion annually if
broader societal costs are also considered.
totheir high prevalence, UTIs are a major contrib utorto
global antibiotic use and resistance.
Without effec-
tive antibiotics active against common uropathogens,
many urological procedures would carry excessive risk.
Accordingly, this Review aims to summarize the current
global epidemiology of resistance in Gram-negative
uropathogens, describe the genetic and molecular
mechanisms underlying the resistance of these pheno-
types, examine the effect of resistance on common
urological procedures and discuss therapeutic and
Key resistance mechanisms
For many years, resistance profiles for common Gram-
negative uropathogens such as Escherichia coli or
Klebsiella pneumoniae were relatively predictable and
stable over time. In the past few decades, however, this
picture has changed dramatically. During the 1980s,
we witnessed the emergence of extended-spectrum
β-lactamases (ESBLs) in Enterobacteriaceae. ESBLs are
Competing interests
P.A.T. has received research support from ADAMAS, Baxter,
Fabentech, Inviragen, Merlion Pharmaceuticals and Sanofi
Pasteur, and has received honoraria from AstraZeneca
andNovartis. D.L.P. has participated in advisory boards and
receivedhonoraria from AstraZeneca, Bayer, Cubist,
LeoPharmaceuticals, Merck and Pfizer. The other authors
declare nocompeting interests.
© 2015 Macmillan Publishers Limited. All rights reserved
characterized by an ability to inactivate commonly used
antibiotics such as ceftriaxone or ceftazidime.
producing E.coli or K.pneumoniae are now common-
place, not only in health-care facilities but also in the
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.
However, the world-
wide consumption of carbapenems has increased
signifi cantly over the past two decades, particularly in
developing countries,
and carba penem resistance in key
Gram-negative pathogens is now a rapidly developing
facilitated by international travel and
Of particular concern is the increasing
prevalence of carbapenem- resistant Enterobacteriaceae
(CRE), e specially E.coli and K.pneumoniae, as these
Gram-negative species cause the vast majority of
Carbapenem resistance among Enterobacteriaceae
most commonly arises as a result of the produc tion
of carbapenemases, such as KPC-type (K.pneumo-
niae carbapenemase),
NDM-type (New Delhi
and OXA-48-type
(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).
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
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
Enterobacteriaceae, Pseudomonas aeruginosa,
and Acinetobacter baumannii with MDR phenotypes
are now increasingly reported.
Definitions of MDR,
extensively drug resistant (XDR) and pan-drug resistant
(PDR) bacteria have been provided recently for common
Gram-negative species.
Broadly, MDR bacteria are
defined as having acquired nonsusceptibility to at least
one anti biotic 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
all classes.
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- modifying enzymes (for example,
acetyl transferase, phosphotransferase or adenyltrans-
ferase activity against aminoglycosides
) are frequently
present. Resistance can also occur via mutations at the
inter acting site with an antibiotic (for example, gyrA
mutations leading to reduced binding of quinolones
over production of the target of antibiotic (for example,
mutations in a promoter region leading to increased
expression of dihydrofolate reductase, the target for tri-
) 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 classes
In order to interact with their target, anti biotics 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 resistance
(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.
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.
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.
Even within regions,
resistance can vary considerably; in Greece, carba-
penem resistance is as high as 59.4% in K.pneumoniae,
yet carba penem resistance in K.pneumoniae is only 0.2%
in the Netherlands.
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
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
e xtraintestinal infections.
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.
such as VIM-types and IMP-types have been found in
Enterobacteriaceae and P.aeruginosa mostly in Europe
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
© 2015 Macmillan Publishers Limited. All rights reserved
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
Key features of ESBLs are
cephalosporinase activity
and resistance to 3GCs
Usually inhibited by clavulanate–
tazobactam invitro (except KPC)
ESBLs usually arise from mutations in ‘parent’
narrow-spectrum β-lactamase or have been
‘captured’ from environmental bacteria
(e.g.CTX-M from Kluyvera spp.)
Transmissible on mobile genetic elements,
such as plasmids, carrying multiple other
resistance determinants
ESBLs are most common in
Escherichia coli, Klebsiella spp.
andProteus spp., but have
beendescribed in most
Enterobacteriaceae and
inPseudomonas spp.
KPC is seen in K.pneumoniae
variants, CTX-M
Carbapenemase: KPC
Production of class B* β‑lactamases
Contain metal ions (for example, Zn
Have carbapenemase activity, not inhibited
by clavulanate/tazobactam
Aztreonam not hydrolysed by class B
Usually highly transmissible on plasmids
carrying multiple other resistance determinants
E.coli, Klebsiella spp. but described
in many Enterobacteriaceae and
Acinetobacter spp.
Intrinsic carbapenem resistance
inStenotrophomonas maltophilia
viaclass B enzyme (L-1)
Production of class C* β‑lactamases
Also known as ‘AmpC’ enzymes
Broad cephalosporinase activity
including3GCs, but cefepime stable
Not inhibited effectively by clavulanate
Chromosomally encoded in many species,
butcan also be inducible in
Mutations in regulatory genes (for example,
ampD or ampR) involved in cell-wall recycling
can lead to high-level AmpC expression and
resistance to a broad range of β-lactams
Increasing plasmid-AmpC
Enterobacter cloacae, E.aerogenes,
Serratia marcescens, Citrobacter
freundii, Pseudomonas aeruginosa,
Providencia spp. and Morganella
morganii all contain inducible
AmpCenzymes that are
chromosomally encoded
Plasmid-mediated AmpC (e.g. CMY)
increasing in E.coli
Production of class D* β‑lactamases
Oxacillinases that can have
carbapenemase activity and are only
weakly inhibited by clavulanate
Can be acquired or naturally occurring
chromosomal genes
Acinetobacter baumanii
(e.g.OXA-23), Enterobacteriaceae
(e.g. OXA-48), Pseudomonas spp.
Efux pumps and porin mutations
Membrane transport systems to extrude
multiple antimicrobials or mutations in
outer membrane proteins to hinder entry
of active drug
Poly-specic transporters; for example, the
resistance-nodulation-division (RND) family
Porin changes or loss via mutation
Pseudomonas aeruginosa,
Acinetobacter baumanii,
(e.g.Enterobacter spp.)
Efux: AcrAB-like
Porin: OprD channel
Target site mutations
Methylation of 16S rRNA with high-level
resistance, including against amikacin
Carried by plasmids, often mediated by rmtA
and related genes
Methylases: RmtA,
RmtB or ArmA
Altered DHPS—essential for folate
synthesis in bacteria—leads to
sulphonamide resistance and altered DHFR
with loss of inhibition by trimethoprim
sul1 gene part of class 1 integron—frequently
integrated into plasmids
Plasmid-borne dhfrI and dhfrII genes
Stenotrophomonas maltophilia, E.coli sul1 and dhrf genes
DNA gyrase mutations prevent activity
Often single mutations in quinolone resistance-
determining region (QRDR) on gyrA gene
Pseudomonas aeruginosa,
Salmonellaspp., other
Point mutations in
gyrA, gyrB, parC
andparE genes
Protein binding of quinolone active site,
low-level resistance
Protein binding encoded by plasmid-mediated
qnr genes
E.coli, Klebsiella spp., Salmonella
qnrA, qnrB, qnrC,
qnrD and qnrS
Overproduction of enzymes
Sulphonamide or trimethoprim resistance
by overproduction of DHPS or DHFR
felP gene produces DHPS and folA encodes
E.coli Mutations in
promotor regions
result in increased
production of DHFR
and trimethoprim
Drug modication
Acetylation, nucleotidylation or
phosphorylation of aminoglycosides
Some can also inactivate uoroquinolones
Often carried on transmissible elements such
as plasmids or transposons
Can be chromosomal in some species
Pseudomonas aeruginosa
Intrinsic to Providencia spp.
AAC(2’), ANT(2”),
AAC(6’)-lb-cr (also
confers quinolone
*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.
© 2015 Macmillan Publishers Limited. All rights reserved
and Asia,
and have been reported in Middle Eastern
whereas the NDM-type that first occurred
in South Asia is now found on almost every conti-
OXA-48-type is another carbapenemase and
has been mostly reported in the Middle East, Europe
and India.
Carbapenem resistance in A.baumannii
is usually a ttributed to the production of OXA-types,
mainly OXA-23.
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
Nature Reviews | Urology
Cell wall
Luminal replication
and attachment of
mbriated UPEC
Attachment Invasion
epithelial cell
epithelial cell
and exfoliation
Intracellular bacterial
community formation
Urinary catheter surface Attachment Expansion Maturation and resistance
e.g. AmpC
Porin loss
or mutation
Antibiotic modication
(e.g. aminoglycosides)
of efux pumps
(multidrug resistance)
Mutation in
(polymixin resistance)
Hydrolysis by β-lactamase
or overexpressed
chromosomal genes)
Modied drug target
(e.g. quinolones)
Reservoir of resistant
bacteria and transmissible
resistance genes (from
oral ingestion and selection
by prior antibiotic exposure)
© 2015 Macmillan Publishers Limited. All rights reserved
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-
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.
The best-defined UPEC virulence factors are fim-
of which multiple different types can be pro-
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
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.
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.
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).
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 hospitals
and long-term care
Such infections are associated with a cost of
approximately US$500 per episode
and, especially in
situations in which urinary catheter obstruction has
occurred, have associated risks of morbidity and mortal-
Indwelling urinary catheters have been associated
with an increased risk of community and nosocomial
UTIs, including infections caused by ESBL-producing
and carbapenem-resistant
Patients with indwelling urinary catheters are a major
reservoir of antimicrobial-resistant uropathogens in
health-care settings.
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
colon ization. The indwelling urinary catheter bypasses
the normal host defences along the urethra, giving micro-
organisms that colonize the perineum direct access to the
In the past, when catheter drainage was open,
with urine collected in a drainage container, bac teriuria
was almost universal within 1week.
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,
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.
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.
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.
Attempts have been made to prevent
the adherence of organisms to the catheter surface. These
attempts have included the use of hydrophilic surfaces
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.
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
Currently, no international guidelines rec-
ommend the routine use of catheters coated with anti-
microbial agents,
although such catheters can be
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.
© 2015 Macmillan Publishers Limited. All rights reserved
considered if the CAUTI rate has not declined after the
implementation of a comprehensive strategy aimed at
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.
This situation is
particularly likely in individuals with a long-term indwell-
ing catheter owing to neurogenic bladder.
The most
effective approaches to prevent CAUTI and subsequent
biofilm formation involve a reduction in the duration of
Such approaches have included the use
of electronic or nurse-driven reminder systems
and have
been shown to be effective in various settings. By contrast,
strategies using antiseptic irrigation of the catheterized
bladder, antiseptic lubricants or topical t herapies for
meatal care have not been found to be effective.
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
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.
antimicrobial therapy has been shown to reduce the
risk of infection, and is the current standard of care.
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.
Infection after TRUBP is likely to
occur via the direct inoculation of bacteria that exist
n aturally in the rectum into the prostate, urinary tract or
local vasculature (Figure1d).
In the past decade, an increase in hospital admission
rates secondary to TRUBP-related infection has been
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%.
A consistent theme of
TRUBP-associated infections is antimicrobial resistance,
specifically fluoroquinolone resistance, with or without
concurrent ESBL production.
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%).
Nature Reviews | Urology
0 10 20 30 40 50 60 70 80
Prevalence (%)
Figure 2 | Global epidemiology of resistance in Gram-negative uropathogens—fluoroquinolones. Prevalence of resistance
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.
© 2015 Macmillan Publishers Limited. All rights reserved
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.
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.
Furthermore, active surveillance pro-
tocols, requiring prostate biopsy every 3years, have been
promoted as a method of managing low-volume prostate
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
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.
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.
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,
the economic burden must be con-
sidered together with the unmeasurable psychological
burden, which is scarcely documented in this context.
Current TRUBP prophylaxis strategies
Periprocedural antimicrobial therapy has been shown
to reduce TRUBP-associated infections,
and is
recommended by international urology bodies.
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
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.
This relation ship has also been
reported for trimethoprim,
but this ratio is lower for
β-lactams (10–20%) and amikacin (50%).
recommended antimicrobials (in the presence of peni-
cillin hypersensitivity) include aminoglycosides and
metro nidazole or clindamycin.
Other first-line alterna-
tives include first-, second- and third-generation cephalo-
sporins (American Urological Association Guidelines
and trimethoprim– sulfamethoxazole (European
Association of Urology Guidelines
). The duration of
TRUBP anti microbial use varies.
Current evidence sug-
gests that prolonged duration of antimicrobial use shows
no beneficial effect over a single dose.
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
Nature Reviews | Urology
0 10 20 30 40 50 60 70
Prevalence (%)
Figure 3 | Global epidemiology of resistance in Gram-negative uropathogens—third-generation cephalosporins. Prevalence
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.
© 2015 Macmillan Publishers Limited. All rights reserved
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.
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%.
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.
fosfomycin trometamol, given as a 3 g dose, could be
a potential option for the prolonged outpatient treat-
ment of TRUBP-associated infections.
Fosfomycin tro-
metamol achieves reasonable prostatic concentrations,
although these concentrations are lower in the periph-
eral zone,
where most prostate cancer is located,
possibly reflecting differences in vascularity in differ-
ent regions of the prostate.
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;
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%).
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 i nhibitory
c oncentration (MIC) is >4 mg/l.
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.
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.
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.
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-
In areas with a low prevalence of antimicrobial
resistance, use of these agents should be limited to the
treatment of serious TRUBP-related infections.
Nature Reviews | Urology
0 5 10 15 20 25 30 35
Prevalence (%)
Figure 4 | Global epidemiology of resistance in Gram-negative uropathogens—carbapenems. Prevalence of carbapenem-
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
© 2015 Macmillan Publishers Limited. All rights reserved
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.
Fluoroquinolone resistance
in rectal flora can occur as a result of selection pressure
exerted by fluoroquinolone use, or it can be acquired
follow ing travel to areas where fluoroquinolone resistance
is endemically high.
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
fluoro quinolone sensitivity (7.1% versus 1.1%).
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 hospital ization (OR 4.77, 95% CI 2.50–9.10) after
TRUBP, and that these risks increased further in those
who received fluoroquinolone prophylaxis alone.
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
varying concentrations (1–10 mg/l) corresponding to
pathogen MIC estimates.
To date, three studies have
shown that this principle of targeted therapy is success ful
in reducing the incidence of TRUBP-associated infec-
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%]).
Taylor and colleagues
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 colleagues
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)
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.
In a
system atic review and meta-analysis of seven trials, rectal
disinfection prior to TRUBP using povidone iodine was
reported to significantly reduce fever, bacteriuria and bac-
teraemia (relative risk 0.31, 95% CI 0.21–0.45).
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
d isinfection was not performed (0.3% versus 0.8%).
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.
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,
with some studies
reporting a sepsis rate approaching zero at the expense of
acute urinary retention (approximately 5%)
and higher
o perational 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
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.
The presence of fluoroquinolone-resistant rectal flora
has been consistently reported as the most important
predictor of TRUBP-associated infection.
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.
specific risk factors include previous prostate biopsy,
indwelling urinary catheterization, history of infec-
tion (prostatitis or UTI), asymptomatic bacteriuria
Preventing and reducing TRUBP-related infections
requires collaboration between colleagues in the fields
of urology, infectious diseases and micro biology 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
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
© 2015 Macmillan Publishers Limited. All rights reserved
guidelines for the treatment of uncomplicated UTI and
pyelo nephritis in women in 2010.
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.
Considerable regional variation
in resistance requires clini cians 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
t rimethoprim–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.
A more recent review of 27 randomized controlled trials,
six systematic reviews and 11 observational studies have
broadly supported these recommendations.
In addition
to concerns about resistance, β-lactam antibiotics such
as amoxicillin–clavulanate and cefpodoxime are not as
e ffective 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
have suggested that men should
receive a longer duration of antibiotic therapy (714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.
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.
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-
If the patient does not require hospitalization,
treatment choices include a fluoroquino lone for 7days
or trimethoprim–sulfamethoxazole for 14days, depend-
ing on the local pattern of resistance.
fosfomycin or pivmecillinam should be avoided for the
treatment of pyelonephritis owing to concerns that they
do not achieve adequate levels in renal tissue.
treatment duration of 7days for a fluoro quinolone 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,
and has been confirmed by a
meta-analysis of eight randomized, controlled trials.
However, only three of the randomized, controlled trials
evaluated antibiotics other than fluoroquinolones, which
is noteworthy given current rates of resistance. In an
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).
The evi-
dence, although hampered by small sample sizes, would
therefore suggest that pyelonephritis in the setting of
ur ogenital a bnormality 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.
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.
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
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 o ccasions to
just 12%, with no untoward effects.
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
© 2015 Macmillan Publishers Limited. All rights reserved
has been renewed in drugs such as polymyxins (colis-
tin and polymyxin B) or tigecycline for XDR isolates
where few alternatives exist.
Although colistin has
broad Gram-negative activity (with a few exceptions
such as Proteus or Serratia spp.) it can cause renal toxi-
city. Tigecycline p enetrates 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.
Combination therapy
with carba penems, even if carbapenem resistance is
detected, is often used.
Hopefully, in the near future
newer agents active against Gram-negative organisms
will be available for clinical use (Table3). The novel
β-lactamase inhibitor avibactam has activity against
ESBLs, AmpC, KPC-type and some OXA-type enzymes
(but not metallo-β-lactamases such as NDM-type) and
has been developed to be given in combination with
established antibiotics such as ceftazidime.
combination of ceftazidime and avibactam has com-
pleted phaseIII trials (including complicated UTI
and abdominal infections)
and was granted FDA
approval in February 2015 for the treatment of compli-
cated UTI and intra-abdominal infections. Ceftolozane is
a novel cephalosporin that has enhanced activity against
It can be inacti vated by β-lactamases so
is formulated with tazobactam, a β-lactamase inhibitor.
This combination shows good invitro activity against
a range of Gram-negative organisms, including MDR
and XDR strains,
and was granted FDA approval for
the treatment of complicated UTI and intra-abdominal
infections in December 2014. Novel aminoglycosides,
and carbapenems
also in development for the treatment of UTI caused by
MDR Gram-negative bacteria (Table3). Temocillin, a
previously overlooked agent (owing to its lack of activ-
ity against Gram-positive bac teria, P.aeruginosa and
), is being re- evaluated and has performed
well in the treatment of urinary and bloodstream infec-
tions caused by ESBL-producing and AmpC-producing
Nitroxoline is an older antibiotic
that has broad-spectrum activity against many uropatho-
gens (except P.aeruginosa) and is being re-evaluated as
an option for treatment of uncomplicated UTI, although
it is not widely available outsideEurope.
An important measure to help prevent MDR infections
is the effective implementation of antimicrobial steward-
ship (a systematic approach within health-care services to
optimize the use of antimicrobial agents).
The uncon-
trolled use of broad-spectrum antibiotics leads to high
rates of resistance, especially in countries with less-robust
health-care systems.
Novel approaches to recurrent UTI
Recurrent UTI is defined as the occurrence of three
symptomatic UTIs within 12months or two sympto matic
episodes occurring within 6months following clinical
resolution of a previous UTI. A novel method has been
developed for the management of recurrent UTI, based on
the concept of bacterial interference whereby bacteria of
low virulence compete with and protect against coloniza-
tion and infection by pathogens.
This method was first
performed with E.coli 83972, a strain originally isolated
from a young Swedish girl with asymptomatic bac teriuria.
This patient carried the low-virulence organism for at least
3years without development of clinical features of urinary
tract infection.
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.
E.coli 83972 contains muta-
tions in the genes encoding a number of different UPEC
fimbriae, and thus is unable to express these o rganelles as
functional adhesive surface structures.
Table 2 | Treatment options for MDR Gram-negative uropathogens
Indication First-choice antibiotic therapy Second-choice antibiotic therapy
lower UTI with
MDR organisms
Fosfomycin, nitrofurantoin,
Quinolone, temocillin (if available),
nitroxoline (if available)
UTI with MDR
advice required)
Carbapenems (for example,
against ESBL or
Piperacillin–tazobactam might
be an alternative against
ESBL-producers that are
susceptible (but their role
Combination therapy (including
XDR isolates)
Colistin* plus carbapenem
Colistin* plus aminoglycoside
(forexample, amikacin)
plus aminoglycoside
Dual carbapenems
*Polymyxin B is an alternative to colistin but is less widely available.
Consider extended or continuous
infusions of carbapenems to optimize pharmacokinetic and pharmacodynamic parameters.
Abbreviations:MDR, multidrug resistant; UTI, urinary tract infection; XDR, extensively drug resistant.
Table 3 | Future treatment options for MDR Gram-negative uropathogens
Drug PhaseI* PhaseII* PhaseIII* FDA approved
β‑lactam combined with β‑lactamase inhibitors
Ceftaroline fosamil–avibactam
β‑lactamase inhibitors combined with carbapenem
Relebactam (MK-7655)–
imipenem cilastatin
Other agents in development
GSK2251052 (Boron-
containing agent targeting
Leucyl tRNA synthetase)
*Clinical trial phases according to
Only approved in China, Korea and Japan.
Onlyapproved in Japan.
© 2015 Macmillan Publishers Limited. All rights reserved
Several clinical trials have been designed in order to
assess whether deliberate colonization of the urinary
tract with E.coli 83972 or E.coli HU2117
(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
Clinical trials using E.coli 83972 to pre-coat
urinary catheters have also yielded promising results, with
these trials currently being extended.
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.
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.
Molecules that
prevent the biogenesis or adhesion of UPEC fimbriae have
shown great promise in animal infection models
are also highly effective against MDR strains such as E.coli
Vaccines based on the FimH and PapG adhes-
ins provide protective efficacy in mouse and/or primate
models of UTI,
and together with vaccines targeted
against iron-regulated surface antigens,
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.
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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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
© 2015 Macmillan Publishers Limited. All rights reserved
... Data shows that antimicrobial resistance is of high concern in gram-negative organisms. 12 A multicenter retrospective cohort study in south and eastern Europe found that multidrug resistant (MDR) UTIs were more likely to develop in men, where infections were acquired in a medical care facility, those with an indwelling catheter, those who had a UTI within the last year and those with prior antibiotic treatment within 30 days. 13 Resistance rates in those with urosepsis were higher than other clinical diagnoses of healthcare associated UTIs. ...
... Patients with catheters are often elderly, reside in a long-term care facility and have been widely exposed to multiple antibiotics. 12 This ultimately increases the risk of formation of biofilms with MDR pathogens. Although there have been many attempts to minimize the formation of these biofilms, including hydrophilic catheters, antibiotic-coated catheters and catheter irrigations, there has been mixed efficacy and the ISDA does not recommend their use. ...
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Joanna Marantidis, Rachael D Sussman Department of Urology, MedStar Georgetown University Hospital, Washington, DC, USACorrespondence: Joanna Marantidis, 3800 Reservoir Road NW, Washington, DC, 20007, USA, Tel +1 202 444 9922, Fax +1 458 203 5006, Email joanna.c.marantidis@medstar.netAbstract: While urinary tract infections (UTIs) are one of the most common types of infections globally, the wide variety of presentations and of severity of disease can make it difficult to manage. The definition for uncomplicated UTIs (uUTIs) is generally regarded as UTIs in healthy, non-pregnant women whereas all other UTIs are considered complicated. There is, however, a lack of consensus definition of complicated UTIs (cUTIs), leading to global differences in management. In addition, the patients who develop complicated UTIs generally have other comorbidities that warrant more urgent intervention. One of the biggest challenges in treating cUTIs is the rise of antimicrobial resistance (AMR). While there have been recent drug approvals for new antibiotic to treat these resistant organisms, a multidisciplinary approach, including regulatory frameworks, provider education and public awareness campaigns, is crucial to limiting unnecessary treatments for asymptomatic bacteriuria (ASB) and uUTIs that can ultimately lead to more severe infections.Keywords: antimicrobial resistance, regulatory frameworks, catheter-associated urinary tract infection, clinical trial
... But some exceptional bacteria show resistance to that antibiotic (Tokajian, 2014). Urinary Tract Infections (UTIs) are among the most occurring infection around 150-250 million cases globally per year (Zowawi et al., 2015). So, one of the species of staphylococci is S. saprophyticus a Gram-positive bacterium, usually the causative agent of UTIs, which especially occurs in young sexually active females (Argemi et al., 2019). ...
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Staphylococcus saprophyticus (S. saprophyticus) is the second most constant acute agent of urinary tract infections (UTIs) mostly in young females. The study aimed to determine the prevalence, antibiotic susceptibility profiles, MDR pattern, and resistance to various classes of antibiotics of S. saprophyticus in patients coming to tertiary care hospitals. A total of 475 clinical isolates were collected and initially confirmed by Gram staining and further confirmation was done through Standard Microbiological Procedures. Generally, S. saprophyticus was identified by novobiocin resistance, absence of hemolysis, and by Remel RapID TM Staph Plus System. Antibiogram was done using the Kirby Bauer Disk Diffusion method. Results interpretation was done using the Clinical & Laboratory Standards Institute (CLSI) (2021) guidelines. Overall, out of 475 isolates 375 were coagulase-negative and 100 were coagulase-positive, out of coagulase-negative 164 were confirmed as S. saprophyticus in which females were dominant as compared to males. while the rest were confirmed as other coagulase-negative staphylococci. Urine was the main sample source. The highest resistance to tobramycin (91%), followed by ofloxacin (85%), penicillin G (91%), and erythromycin (67%) was observed respectively. The highest sensitivity was noticed to vancomycin (92%), gentamicin (57%), and oxacillin (44%). About 96.3% of the isolates were termed as multi-drug resistant (MDR). The highest resistant to various class of antibiotic that showed resistance to erythromycin, gentamycin, levofloxacin, ofloxacin, oxacillin, penicillin, tobramycin, and amoxicillin with a percent prevalence of 15%. There is no association found between the two variables i.e. antibiotic susceptibility pattern of S. saprophyticus and gender. The high prevalence of MDR and resistance to various classes of antibiotics among S. saprophyticus pose a challenge for clinicians and public health experts which needs to be investigated.
... It has been observed that the prevalence of AMR in E. coli has skyrocketed during the past several years [9]. Most commonly, bacteria produce beta-lactamase enzymes, which, by hydrolyzing the betalactam ring, can render the antibiotic ineffective [10]. The fast spread of enzyme-mediated resistance and the resulting rise of multidrugresistant bacteria have earned it recognition as a global public health problem [11]. ...
... This has led women to not trust the medical profession to look after them [12], and for them to seek alternatives that may not be safe or effective. Then, there is the specter of rising antimicrobial resistance, an acknowledged major worldwide problem [13]. Such antimicrobial resistance can lead to management difficulties in patients taking many and varied antibiotic doses or prolonged prophylaxis but it also affects the treatment of all infectious diseases as our antibiotic pipeline dries up. ...
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Uncomplicated recurrent urinary tract infections (rUTIs) in women are associated with episodic bothersome symptoms and have a significant impact on the mental and physical quality of life. Treatment with antibiotics (short- and long-term dosing) results in acute and chronic side effects and costs and promotes general antibiotic resistance. Improved nonantibiotic management of rUTI in women represents a true, unmet medical need. MV140 is a novel sublingual mucosal-based bacterial vaccine developed for the prevention of rUTI in women. Based on observational, prospective, and randomized placebo-controlled studies, MV140 has been shown to safely prevent (or reduce the risk of) UTIs, reduce antibiotic use, overall management costs, and patient burden while improving the overall quality of life in women suffering from rUTIs.
... Although bacterial pathogens responsible for UTIs include Gram-negative and Gram-positive organisms, Gram-negative bacteria are the most prevalent, with the vast majority being caused by infection with E. coli [14,15]. The current research has established the prevalence of UTI in the study participants, together with the identified causative agents and their pattern of antibiotic susceptibility. ...
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Urinary tract infections (UTIs) are common diseases in pediatric age groups. The emergence of bacterial strains that exhibit resistance to specific antimicrobial agents has led to several therapeutic challenges. This study aimed to evaluate the frequency and antimicrobial susceptibility patterns of common types of bacteria isolated from urine samples of patients with urinary tract infections in Karbala Teaching Hospital for Children. The study was conducted between September 2021 and January 2022. The susceptibilities of antimicrobial agents were determined using the Kirby-Bauer disk diffusion technique. Positive cultures from 56 patients were included in the analysis. Escherichia coli and Proteus spp. were the most common organisms identified in pediatric patients suspected of a UTI (50% and 14.3%, respectively), while Ra-outella ornithimolytics and Enterobacter sp. represented 7.14%. Other bacteria like Pseudomonas aeruginosa, Staphylococcus saprophyticus, Acinetobacter bau-mannii, Serratia spp., and Kluyvera spp. represented 3.6%. The sensitivity of E. coli isolates to imipenem, amikacin, and chloramphenicol were 92.9%, 85.7%, and 78.6%, respectively. Proteus spp. isolates solely exhibited susceptibility to amikacin and nalidixic acid. The current study concluded that E. coli was the most frequently arising underlying pathogen UTI in pediatric patients. In this clinical setting, the organisms identified exhibited high susceptibility to imipenem, amikacin, and chloram-phenicol.
... Multi drug resistance increases the severity in treating people with burns [19,20]. Development of resistance has also complicated urological practices [21]. The most prevalent bacteria in Urinary tract infections are E. coli, Klebsiella species, Proteus species and Pseudomonas species [22]. ...
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Increasing antibiotic resistance is a threat worldwide. Deep studies have to be done for correct and appropriate usage of antibiotics for treating infections efficiently and to curtail the spread of resistance. Hence, this study is aimed at understanding the prevalence of antibiotic resistance genes among 35 gram-negative bacterial isolates. By performing biochemical tests, the isolates were identified to be Escherichia coli (n = 15), Klebsiella oxytoca (n = 3), Klebsiella pneumoniae (n = 5), Proteus mirabilis (n = 4), Proteus vulgaris (n = 1) and Pseudomonas aeruginosa (n = 7). Antibiotic susceptibility tests showed that most E. coli isolates were resistant to ampicillin, levofloxacin and cefazolin. Ampicillin resistance was found in all of Klebsiella oxytoca, Klebsiella pneumoniae and Proteus mirabilis isolates. All Proteus mirabilis isolates were resistant to ciprofloxacin and co-trimoxazole. Pseudomonas aeruginosa showed maximum resistance to gentamycin and tobramycin. All 35 isolates were sensitive to amikacin, imipenem and meropenem. Polymerase Chain Reaction showed that AmpC and SHV genes were predominant in E. coli and Klebsiella species respectively. Among Proteus mirabilis and Pseudomonas aeruginosa, IntI gene was more prevailing. NDM1 gene was not detected in any of the isolates. This study also showed the prevalence of isolates resistant to multiple drugs due to the co-existence of resistant genes. Therefore, control of spread of infections, routine study in this field and proper guidelines for prescribing antibiotics is very necessary. HIGHLIGHTS This study is aimed at understanding the prevalence of antibiotic resistance genes among 35 gram-negative bacterial isolates A considerable number of isolates had antibiotic resistance genes and some isolates showed resistance to multiple drugs due to the co-existence of resistant genes Infections caused by bacteria that are resistant to antibiotics are difficult to treat and may sometimes lead to death Regular study and proper use of antibiotics is essential to curtail the spread of antibiotic resistant bacteria. Regular GRAPHICAL ABSTRACT
Humans frequently contract urinary tract infections (UTIs), which can be brought on by uropathogens (UPs) that are multi-drug resistant. Treatment for UTIs brought on by pathogenic UPs that produce extended-spectrum lactamases (ESBLs) is more costly and potentially fatal. As a result, the objective of this study was to use culture, biochemical, and 16S rRNA sequencing to identify and characterize UPs isolated from outpatients in Noakhali, Bangladesh, who had symptoms of UTIs. ESBL gene identification and quinolone resistance gene typing were then performed on the isolates using polymerase chain reaction (PCR). Throughout the trial’s 8-month duration, 152 (76%) of 200 urine samples were positive for the presence of UPs. The overall number of UPs recovered was 210, with 39 individuals having multiple UPs present in their samples. Among all of the isolates, Escherichia coli (45.24%, 95/210; 95% confidence interval (CI): 35.15–57.60%), Enterobacter spp. (24.76%, 52/210; CI: 19.15–35.77%), Klebsiella spp. (20.95%; 44/210; CI: 15.15–30.20%), and Providencia spp. (9.05%; 19/210; CI: 4.95–19.25%) were the four most prevalent bacteria found in the isolates. The UPs displayed a very high level of resistance to piperacillin 96.92% (126/130), ampicillin 90% (117/130), nalidixic acid 77.69% (101/130), cefazolin 70% (91/130), amoxicillin 50% (55/130), cefazolin 42.31% (55/130), nitrofurantoin 43.08% (56/130), and ciprofloxacin 33.08% (43/130), whereas resistance to netilmicin (3.85%), amikacin (4.62%), and imipenem (9.23%) was low. Individually, every species of E. coli and Providencia spp. showed greater ampicillin, amikacin, cefazolin, cefazolin, and nalidixic acid resistance than the others. The bivariate results indicate several antibiotic pairings, and isolates had meaningful associations. All MDR isolates were subjected to PCR, which revealed that blaCTX-M-15 genes predominated among the isolates, followed by the blaTEM class (37%). Isolates also had the qnrS, aac-6´-Ib-cr, and gyrA genes. The findings provide worrying indications of a major expansion of MDR isolates in the study locations, particularly the epidemiological balCTX-M 15, with the potential for the transmission of multi-drug-resistant UP strains in the population.
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Introduction: Ceftazidime-avibactam has proven activity against multidrug-resistant (MDR) bacteria in clinical trials and real-world studies. This study was conducted to describe the patterns of use of ceftazidime-avibactam (including indications and associated antibiotics), and the effectiveness and safety of ceftazidime-avibactam in real-world clinical practice. Methods: This non-interventional medical chart review study was conducted in 11 countries across the European and Latin American (LATAM) regions. Consecutive patients treated in clinical practice with at least one dose of ceftazidime-avibactam for an approved indication per country label since 01 January 2018 (or launch date in the country if posterior) were enrolled. Effectiveness analyses were conducted in patients treated with ceftazidime-avibactam for at least 72 h. Results: Of the 569 eligible patients enrolled, 516 (90.7%) were treated for at least 72 h (354 patients from Europe and 162 patients from LATAM); 390 patients (75.7%) had switched from another antibiotic line for Gram-negative coverage. Infection sources were intra-abdominal, urinary, respiratory, bloodstream infections, and other infections (approximately 20% each). K. pneumoniae was the most common microorganism identified in the latest microbiological evaluation before starting ceftazidime-avibactam (59.3%). Two-thirds of microorganisms tested for susceptibility were MDR, of which 89.3% were carbapenem-resistant. The common MDR mechanisms for K. pneumoniae were carbapenemase (33.9%), oxacillinase 48 (25.2%), extended-spectrum beta-lactamase (21.5%), or metallo-beta-lactamase (14.2%) production. Without prior patient exposure, 17 isolates (mostly K. pneumoniae) were resistant to ceftazidime-avibactam. Treatment success was achieved in 77.3% of patients overall (88.3% among patients with urinary infection), regardless of first or second treatment line. In-hospital mortality rate was 23.1%. Adverse events were reported for six of the 569 patients enrolled. Conclusion: This study provides important real-world evidence on treatment patterns, effectiveness, and safety of ceftazidime-avibactam in clinical practice through its recruitment in the European and LATAM regions. Ceftazidime-avibactam is one of the antibiotics to consider for treatment of MDR bacteria. Trial registration: identifier, NCT03923426.
Bacterial infections and antimicrobial resistance are a major cause for morbidity and mortality worldwide. Antimicrobial resistance often arises from antimicrobial misuse, where physicians empirically treat suspected bacterial infections with broad-spectrum antibiotics until standard culture-based diagnostic tests can be completed. There has been a tremendous effort to develop rapid diagnostics in support of the transition from empirical treatment of bacterial infections towards a more precise and personalized approach. Single-cell pathogen diagnostics hold particular promise, enabling unprecedented quantitative precision and rapid turnaround times. This Primer provides a guide for assessing, designing, implementing and applying single-cell pathogen diagnostics. First, single-cell pathogen diagnostic platforms are introduced based on three essential capabilities: cell isolation, detection assay and output measurement. Representative results, common analysis methods and key applications are highlighted, with an emphasis on initial screening of bacterial infection, bacterial species identification and antimicrobial susceptibility testing. Finally, the limitations of existing platforms are discussed, with perspectives offered and an outlook towards clinical deployment. This Primer hopes to inspire and propel new platforms that can realize the vision of precise and personalized bacterial infection treatments in the near future. Single-cell pathogen diagnostic tools are increasingly being used to identify and monitor bacterial infections and antimicrobial resistance. In this Primer, Li et al. discuss the assessment, design and implementation of single-cell pathogen diagnostics.
objective. The purpose of this study was to provide a national estimate of the number of healthcare-associated infections (HAI) and deaths in United States hospitals. Methods. No single source of nationally representative data on HAIs is currently available. The authors used a multi-step approach and three data sources. The main source of data was the National Nosocomial Infections Surveillance (NNIS) system, data from 1990-2002, conducted by the Centers for Disease Control and Prevention. Data from the National Hospital Discharge Survey (for 2002) and the American Hospital Association Survey (for 2000) were used to supplement NNIS data. The percentage of patients with an HAI whose death was determined to be caused or associated with the HAI from NNIS data was used to estimate the number of deaths. Results. In 2002, the estimated number of HAIs in U.S. hospitals, adjusted to include federal facilities, was approximately 1.7 million: 33,269 HAIs among newborns in high-risk nurseries, 19,059 among newborns in well-baby nurseries, 417,946 among adults and children in ICUs, and 1,266,851 among adults and children outside of ICUs. The estimated deaths associated with HAIs in U.S. hospitals were 98,987: of these, 35,967 were for pneumonia, 30,665 for bloodstream infections, 13,088 for urinary tract infections, 8,205 for surgical site infections, and 11,062 for infections of other sites. Conclusion. HAIs in hospitals are a significant cause of morbidity and mortality in the United States. The method described for estimating the number of HAIs makes the best use of existing data at the national level.
Antimicrobial resistance has emerged as a significant healthcare quality and patient safety issue in the twenty-first century that, combined with a rapidly dwindling antimicrobial armamentarium, has resulted in a critical threat to the public health of the United States. Antimicrobial stewardship programs optimize antimicrobial use to achieve the best clinical outcomes while minimizing adverse events and limiting selective pressures that drive the emergence of resistance and may also reduce excessive costs attributable to suboptimal antimicrobial use. Therefore, antimicrobial stewardship must be a fiduciary responsibility for all healthcare institutions across the continuum of care. This position statement of the Society for Healthcare Epidemiology of America, the Infectious Diseases Society of America, and the Pediatric Infectious Diseases Society of America outlines recommendations for the mandatory implementation of antimicrobial stewardship throughout health care, suggests process and outcome measures to monitor these interventions, and addresses deficiencies in education and research in this field as well as the lack of accurate data on antimicrobial use in the United States. Infect Control Hosp Epidemiol 2012; 33(4): 322-327
Objectives: It was the aim of this study to evaluate the efficacy of single-dose fosfomycin prophylaxis as an alternative to fluoroquinolone-based prophylaxis in transrectal ultrasound-guided biopsy of the prostate (TRUSBP). Methods: We evaluated the records of 620 patients who had undergone TRUSBP from January 2010 to July 2011. Patients received a single dose of 3 g oral fosfomycin or a single dose of 500 mg oral levofloxacin or 500 mg oral ciprofloxacin twice daily administered for 5 days starting 1 day before the prophylaxis procedure. We reviewed all febrile and afebrile urinary tract infections (UTIs) within 1 month after TRUSBP. Results: Of the 620 patients, 19 (3.0%) developed febrile UTI and 51 (8.2%) developed afebrile UTI after biopsy. Of the 19 patients with febrile UTI, 1/19 (5.2%) received fosfomycin, 4/19 (21%) received levofloxacin and 14/19 (73.6%) received ciprofloxacin for prophylaxis. Of the 51 patients with afebrile UTI, 4/51 (7.8%) received fosfomycin, 8/51 (15.6%) received levofloxacin and 39/51 (76.4%) received ciprofloxacin for prophylaxis. There were a total of 10 fluoroquinolone-resistant infections, and all of them occurred after the ciprofloxacin or levofloxacin prophylaxis and none after fosfomycin prophylaxis. Conclusions: The ease of use of fosfomycin, reducing the rate of fluoroquinolone-resistant infections and hospitalizations shows that it would be an alternative and effective drug for antimicrobial prophylaxis in TRUSBP.