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Efcacy of Antibacterial
Prophylaxis for Preventing
Urinary Tract Infections in Renal
Transplant Recipients
1 Pharmaceutical Sciences Department,
College of Pharmacy, King Saud
bin Abdulaziz University for Health
Sciences, Riyadh, 11426, KSA.
2 Pharmacy Practice Department, College
of Pharmacy, King Saud bin Abdulaziz
University for Health Sciences, Riyadh,
11426, KSA.
3 King Abdulaziz Medical City, National
Guard Health Affairs, Riyadh, 11426,
KSA.
4 Department of Medicinal Chemistry and
Pharmacognosy, Jordan University of
Science and Technology, Irbid 22110,
Jordan.
Corresponding author:
katheria@ngha.med.sa
Dr. Abdulmalik M. Alkatheri
Tel: (+966) 11 4299 999 ext. 95017.
Fax: (+966) 11 4295075
Wesam S. Abdel-Razaq
1
,
Abdulmalik M.
Alkatheri
2, 3*,

Abdulkareem M.
Albekairy
2, 3,

Shemylan Alharbi
2, 3,

Abdullah A. Alsayyari
3
,
Amjad M. Qandil
1, 4
Abstract
Background: The increased incidence of urinary tract infections (UTIs)
following organ transplantation necessitates the use of antibacterial
prophylaxis. The goal of this review is to describe observational stud-
ies concerning the use of antibacterial prophylaxis to prevent UTIs in
renal transplant recipient (RTRs).
Methods and Findings: Materials were gathered through a structured
search of the databases available at the King Saud bin Abdulaziz
University for Health Sciences on-line library for articles published be-
tween 2007 and 2013. However, due to the scarcity of prospective
trials in this topic during this period, this review will be comprehensive
rather than systematic. The increased recurrent UTIs in RTRs were
associated with immunosuppressive therapy, which necessitates the
use of antibacterial prophylaxis to reduce during the rst year post-
transplantation. However, the efcacy and optimal duration of anti-
bacterial prophylaxis for UTIs remains debatable.
Conclusions: Although many studies have agreed on the importance of
routine antibacterial therapy, UTI prevalence in RTRs is high. Reducing
infection complications may be accomplished by properly choosing of
immunosuppressants and antibacterials to achieve a correct balance.
However, there was no sufcient evidence to conrm the potential
efcacy of antibacterial prophylaxis, hence; more research is needed
to further delineate the consequences of using antibacterials in RTRs.
Keywords: Nosocomial Infections; Urinary Tract Infections; Renal Trans-
plant Recipients; Antibacterial Prophylaxis.
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Introduction
Kidney transplantation is still the treatment of choice
and a life-saving measure for patients with end-stage
kidney disease where dialysis is not feasible. The risk
of death for renal transplant recipients (RTRs) is less
than half of that for dialysis patients [1]. The main
challenge after successful organ transplantation is
to avoid the immune reaction of recipient against
the donor organ, which could lead to rejection and
loss of the transplant. Immunosuppressive drugs are
usually used to prevent rejection and to maintain
organ function [2]. However, the immunosuppres-
sive agents currently used to suppress immunologi-
cal functions expose patients to a higher rate of
infectious complications which occur as a result of
patient exposure to nosocomial pathogens [3].
Nosocomial infections are considered common
causes of morbidity and mortality among hospital-
ized patients [4]. Nosocomial infections are often
infections of the urinary tract, the lower respira-
tory tract, and surgical wounds. According to the
World Health Organization, a nosocomial infection
or hospital-acquired Infections is dened as an in-
fection acquired in a hospital or other health care
facility by a patient 48 hours after admission who
was admitted for a reason other than that infec-
tion. [5]. Recently the term healthcare-associated
infection has been suggested to incorporate nos-
ocomia or hospital-acquire infection [6]. These
infections are usually occurred as a consequence
of the surgical procedures or intervention used in
diagnose or treatment of the patients complaints.
However, they also include infections acquired in
the hospital but appear after discharge, in addition
to occupational infections among health care pro-
viders [7]. Nosocomial infections occur both in the
developed and developing countries [8]. Nosocomial
infections do not only affect the general health of
patients, but also impose a signicant burden to pa-
tients and public health. Nosocomial infections lead
to increased length of stay and require additional
medical interventions that results in additional costs
[9]. Although many of those nosocomial infections
are preventable, the incidence of nosocomial infec-
tions has remained almost stable during the last two
decades in spite of the improved health system [10].
Urinary tract infections (UTIs) are the most common
nosocomial infections, which account for more than
40% of all nosocomial infectious cases [11]. More-
over, recurrent UTIs are very common complication
post renal transplantation [12]. Therefore, surveil-
lance for UTIs in RTRs is regarded as an important
factor for an effective infection control program.
The aim of this review is to provide a broad contex-
tual understanding of the association between anti-
bacterial use and prevention of UTIs in RTRs. This re-
view will also discuss the epidemiology, prophylaxis
and the treatment strategies for UTIs in RTRs and to
critically examine literature about the effectiveness
of antibacterial prophylaxis for preventing UTIs in
RTRs; in addition to providing relevant recommen-
dations. This review is comprehensive rather than
systematic, and is limited to literature available in
databases at the on-line library of King Saud bin
Abdulaziz University for Health Sciences (KSAU-HS).
Material and methods
(literature search)
A structured search of these databases was utilized
for search of relevant articles published between
the years 2007 and Dec. 2013. Initially literature was
located using combinations of subject headings in-
cluding nosocomial or hospital-acquired infections,
urinary tract infections, antibiotic or antibacterial
prophylaxis, Kidney or renal transplant. Only ar-
ticles published in English were included. In addi-
tion, a manual search of the reference lists of the
identied articles and recent reviews was included
to identify additional articles.
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Table 1. Summary of retrospective studies addressing UTIs after renal transplantation included in this
review.
Reference
Number
of patients
Median
Age
Study
period
Follow-
up period
Post-operative
prophylaxis
Incidence
of UTIs
Frequency of
recurrent UTIs
Risk factors
[15]
27 recipients
(48% females)
41.3
16.2 yr
NA NA Noroxacin 55.5% 40.1%
Female gender
Advanced age
[16]
99 recipients
(70% females)
53.3
11.1 yr
2002 to
2012
53.5
months
(average)
Cotrimoxazole NA 36%
The immune-
suppressant
tacrolimus
[17]
154 recipients
(53% females)
52
15 yr
2010 to
2011
24 months NA 48.2%
56.4% (6
months)
73.6%
(12months)
multidrug-resistant
bacteria
[18]
77 recipients
(41% females)
53.4
11.2 yr
2008 to
2011
12 months NA NA NA Non-infected donor
[19]
344 recipients
(72% females)
41.1 1.2
yr
2000 to
2010
36 months
Cotrimoxazole
3rd
cephalosporin
Ciprooxacin
54.0% 46.0% Renal calculi
[20]
393 recipients
(31% females)
32.8
9.5 yr
1986 to
2009
92 months NA 53.69% NA Female gender
Unfortunately, no recent (2007-2013) prospective
controlled randomized therapeutic studies were
found in which antibacterial drugs were used for
prophylaxis or treatment of UTIs in RTRs. A recent
systematic review by Green et al. [12] about the
use of antibacterial prophylaxis for UTIs in RTRs
included all the randomized controlled studies of
antibacterial prophylaxis given after renal transplan-
tations up to 2009. However, most included stud-
ies were outdated (1982-1997) and only one recent
randomized controlled study by Khosroshahi et al.
[13] was found and included in Green et al. review
[12]. Therefore, due to the lack of prospective ran-
domized controlled trials on the use of antibacterial
prophylaxis for UTIs in RTRs after 2006, this review
will include retrospective studies between 2007 and
2013 (see Table 1). One prospective randomized
study has only been found [14], which investigated
the efcacy of antibacterial prophylaxis to prevent
UTIs at indwelling urinary catheter removal and was
not specically related to RTRs.
Additionally, data analysis was performed to esti-
mate the variable determinant associated with in-
creased risks of UTIs in RTRs. The impact of the
female gender, immunosuppressive treatment and
cytomegalovirus (CMV) infection as risk factors on
UTIs was expressed as odd ratios of the pooled
data from the corresponding studies with 95% con-
dence intervals computed with Fishers exact test
using Graphpad Prism version 6 software packages.
Odd ratio was interpreted as an approximation of
the relative risk. All relevant determinants were
grouped together by adding together the numbers
of subjects. The use of pooled summary estimates
has been declared to show more stability to risks of
bias in random system generation, study features,
and denitions of UTIs.
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[21]
89 recipients
(42% female)
48
14 yr
2009 to
2009
12 months Cotrimoxazole 55% 12.5%
Female gender
CMV infection
[22]
76 recipients
(43 %female)
13.4 yr NA
as per
December
2006
Cotrimoxazole
Nitrofurantoin
Amoxicillin +
Clavulonic acid
Cephazolin
75.1% NA
Female gender
Urinary dysfunction
Prior VUR
Immunosuppression
[23]
104 recipients
(51% females)
49.6 yr
(14-76)
1995 to
2005
50 months
Cotrimoxazole
Ciprooxacin
NA NA None
[24] 76 patients
46.1
10.2yr
2001 to
2006
Minimum
6 months
Cotrimoxazole
Cefotaxime
(3days)
NA 51%
Antibiotics
Resistance
[25]
68 recipients
(46% females)
14.4
4.2yr
(5-20)
2002 to
2003
15 years NA 49% 76%
Urinary tract
malformations
[26] 63 recipients
36.5 yr
(16-58)
2001 to
2006
NA
Cotrimoxazole
Ciprooxacin
13.3% 17.5%
Antibiotics
Resistance
[27]
136 recipients
(35% females)
32
10 yr
1999 to
2006
38 months Cotrimoxazole 41% 14.7% Female gender
Where: CMV: Cytomegalovirus; VUR: Vesicoureteric Reux; yr: Year, NA: Not available.
Results
Descriptive Epidemiology of UTIs in RTRs
UTIs are the most frequent nosocomial infections
in RTRs. It has been estimated that UTIs occur with
frequencies ranging from slightly less than 10% to
more than 90% among RTRs during the rst year
post-transplantation [8, 15, 28-30]. This highly vari-
able incidence rate of post renal transplantation
UTIs was attributed mainly to variations in the study
design, infection outburst and investigation criteria.
Whilst, UTIs are associated with less morbidity than
other nosocomial infections, many reviews have
reported that nosocomial UTIs in RTRs are associ-
ated with signicant morbidity and mortality [31,
32]. Nosocomial UTIs are so troublesome in RTRs
since their health is already compromised by the
condition for which they were originally hospital-
ized. Nosocomial infections can occasionally lead to
septicaemia and death. The most common cause of
septicaemia in RTRs is UTIs which are usually related
to the early rejection problems [3].
UTIs are generally dened by means of microbio-
logical measures as a positive quantitative urine cul-
ture of 100,000 colony-forming units per milliliter
(c.f.u/ml) of clean voided mid-stream urine speci-
men. While this denition is general, the diagno-
sis of UTIs in female is dened as microorganisms
(bacteria) count 10,000 c.f.u/ml urine, in addi-
tion to a microscopical inspection of the urine to
dismiss vaginal contamination, which may result in
false-positive cultures [33]. Some studies have sug-
gested that low bacterial counts between 100 and
10,000c.f.u/ml in majority of patients might be an
early phase of UTIs [34]. UTIs are characterized by
a wide range of clinical symptoms ranging from as-
ymptomatic bacteriuria to mild irritative voiding to
severe septic shock [35]. UTIs after renal transplan-
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tation exist commonly as asymptomatic bacteriuria
[21, 36]. The termUTIsapplies to a heterogeneous
group of clinical syndromes including the infec-
tions of the lower urinary tract involves the bladder
(cystitis), the urethra (urethritis), and prostate gland
(prostatitis) and infections of the upper urinary tract
involveing the kidneys (pyelonephritis). Cystitis is the
most common type of UTI and occurs most fre-
quently in women.
Timing of UTI after renal transplantation
Most studies have reported that the highest inci-
dence of UTIs in RTRs occur during the rst 3 to 6
months after renal transplantation [27, 37-39]. Inter-
estingly, it has been reported that the risk of UTIs
was comparable in both men and women during
the rst 6 months post-transplantation, but signi-
cantly higher for female recipients than males after
6 months post transplantation period [31].
However, Di Cocco et al. [24] have reported that
UTIs most frequently occurred within the rst month
after renal transplantation. A consistent result has
been reached in a surveillance by Parapiboon et al.
[30] for bacteriuria by urine culture in RTRs, who re-
ported that most of bacteriuria, whether it is symp-
tomatic on not, occur at 1 month post transplanta-
tion period. A similar conclusion was reached by a
recent study by Alkatheri [15], who has conrmed
that most of the UTIs were detected within the rst
month post transplantation.
Although many RTRs have asymptomatic bacteriuria
during the rst year post transplantation, there is
still no solid evidences for the benet of long term
antibacterial treatment [36, 40]. According to the
Infectious Diseases Society of America Guidelines;
there is no recommendations available for monitor-
ing or treating of asymptomatic infections in organ
recipients [41]. Moreover, the common screening of
bacteriuria for asymptomatic RTRs, which is regu-
larly done by transplant centers to determine the
efcacy of antibacterial prophylaxis did not dem-
onstrate benets in reducing the incidence of UTIs
[42]. Therefore, an efcient antibacterial prophylaxis
against UTIs should be continued for at least one
month and not exceeding three months after renal
transplantation, since most studies did not reveal
signicant advantage of long-term antibacterial
prophylaxis after renal transplantation.
Recurrent of UTI after renal
transplantation
Recurrent UTIs was usually dened as at least two
symptomatic UTIs with more than 2 weeks apart
between each episode in the interval of 12 months
[16]. Many reports have stated that the highest in-
cidence of recurrent UTIs was apparent during the
rst six months after renal transplantation, despite
antibacterial prophylaxis treatment [12, 16, 17, 40].
This usually coincides with the greatest immune de-
pressing effects of the immunosuppressive regimens
[29]. This is also probably due to recurrent bacterae-
mia caused by a mixed population of Gram-negative
microorganisms namely, Escherichia coli and Entero-
bacteriaceae bacteria, which can develop resistance
to the antibacterial therapy during that time [43].
This might increase the burden on the health team
in the determining of the best antibacterial therapy
in such immunocompromised hosts.
Consequently, early recognition of UTIs in symptom-
atic patients during the rst 3 to 6 months after
renal transplantation to initiate antibacterial therapy
could be a better option than long-term antibac-
terial prophylaxis for asymptomatic bacteriuria that
increases the risk of developing bacterial resistance.
Cadaveric vs. Living Kidney
Transplantation
Most of the reviewed studies have implied that re-
cipients of cadaveric kidneys may be at higher risk
of post-transplant UTIs than the recipients of grafts
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from living donors [7, 30, 32, 44-46]. However,
none of these studies have given a rational expla-
nation for this risk except for the fact that kidneys
from cadaveric donors may be more susceptible to
UTIs due to the prolonged ischemia time leading
to major harm of the kidney [32]. This might result
in reduced/delayed graft function and/or survival as
indicate in a recent review by van der Vliet and
Warl [47] rather than increasing the likelihood of
UTIs. Nevertheless, Outerelo et al. [18] has reported
a controversial results in which renal transplanta-
tion using organs from infected donors was not
associated with a greater risk of UTIs. Outerelo et
al. (2013) has justied these eccentric results owing
to the antibacterial therapy initiated in the donor,
which perhaps reducing infectious complications in
the recipient. However, almost all the studies have
agreed on the importance of other risk factors, such
as gender, bladder catheter and the impaired im-
mune responses due to immunosuppressive drugs.
Caustic Microorganisms of UTIs
It had been recognized that the most predominant
caustic agents of UTIs in RTRs are similar to the
general population (see Figure 1). Escherichia coli (E
coli) is being usually emerged from the individuals
own fecal ora either normal or acquired in hospi-
tal [32, 42, 48]. Other bacterial pathogens include
Enterococcus, Staphylococcus, Klebsiella, and Pseu-
domonas species [28, 42, 49, 50]. Interestingly, un-
like most reports, a recent report by Golebiewska
et al. [21] has implied that most of UTIs diagnosed
before patient discharge or during the rst month
Figure 1. Proportion of Causative
microorganisms of urinary tract infections
identied in urine of RTRs. Data taken
from [16], [29], [20], [67], [89], [26], [90],
[91] and [31].
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post-transplantation were due to bacteria other
than E coli such as Enterococcus faecium and Ser-
ratia marcescens. Whereas, E coli is the most com-
mon bacterium responsible for UTIs after patients
being discharged [21]. Although many reports have
shown that E coli is the most common isolate in the
urine of RTRs, followed by many organisms such
as Enterococcus, Staphylococcus, Klebsiella and oth-
ers, no study has identied the difference in caus-
tic agents of UTI between recipients of cadaveric
kidneys and living kidneys recipients or between
genders.
Antibacterial Prophylaxis
According to the Centers for Disease Control and
Prevetion (CDC), 40% of nosocomial infections are
preventable through strict adherence of health care
workers to the infection control guidelines when
caring for patients [6]. Recurrent or relapsing UTIs
are common in the early post-transplant period in
RTRs [40]. Additionally, the use of intensied im-
munosuppressive therapy, postoperatively, in organ
transplant recipients to treat or prevent acute re-
jection of the donor organ also renders patients
vulnerable to infections. Therefore, in light of the
increased incidence of infections in RTRs [21], it is
essential to use of antibacterial drugs to prevent fre-
quent hospitalizations as a result of infectious com-
plications. In an earlier retrospective study which
including all the adult RTRs at two US transplant
centers, it was found that UTIs are associated with
an increased risk of mortality and preventing these
infections is necessary to decrease post-transplant
mortality [32].
Many studies have reported that most RTRs re-
ceived postoperative antibacterial prophylaxis for a
period ranging from 3 to 6 month have signicantly
reduced the incidence of UTI after renal transplanta-
tion [51-54]. Nevertheless, it is has been reported
that even late UTIs occurring 6 months after renal
transplantation can produce serious risks, such as
bacterial septicemia [31]. This might necessitates
the use of an efcient antibacterial prophylaxis for
12-month period. Since, UTIs are most likely caused
by Gram-negative bacteria, (see Figure 1), empiric
antibacterial drugs selected to all RTRs should cover
Gram-negative bacteria. Additional consideration
of Gram-positive management should be handled
in the rst year post-transplantation [6]. However,
several important differences should also be con-
sidered, such as the immunocompromise status of
RTRs and the heterogeneity of pathogens respon-
sible for UTIs in those vulnerable patients.
Cotrimoxazole has been routinely used as the rst-
line prophylaxis in immunocompromized renal trans-
plant recipient. A study by Khosroshahi et al. [13]
which investigated the efcacy of cotrimoxazole for
prophylaxis of early UTIs in RTRs found that high-
dose of cotrimoxazole (1600/320mg) is required for
RTRs to reduce the UTI occurance during the rst
month post-transplantation. Other antibiotics have
been also used such as amoxicillin-clavulanate or
ciprooxacin [21].
On the other hand, it has been suggested that the
use of cephalosporins such as cefoxitin or cefazolin
[55] or cotrimoxazole [24] for surgical perioperative
antibacterial prophylaxis is effective in reducing the
frequency of UTIs. A recent study by Salehipour et
al. [38] has suggested that a perioperative intrave-
sicular application of antibiotic (e.g., amikacin) so-
lution into the patient bladder with a mean of a
catheter could also provide an efcient prophylaxis
against UTIs for at least 3 months after renal trans-
plantation. However, it has been suggested that the
increased emergence of resistant bacteria isolates in
RTRs was due to the use of perioperative prophy-
laxis regimen [56].
Interestingly, a recent study has reported that Uro-
mune, a novel sublingual bacterial vaccine, used to
prevent recurrent UTIs showed a signicant superior
effect compared to cotrimoxazole [57]. Uromune
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contains inactivated bacteria of selected bacterial
strains, such as E coli, K. pneumonia, P. vulgaris, and
E. faecalis. The signicant reduction in UTIs of this
vaccine was observed up to 15 months.
Although bacterial infections account for the major-
ity of cases of UTIs in RTRs, fungal UTI also have
been reported in these patients [58]. Fungal UTIs
represents a high-risk event posing a difcult thera-
peutic problem. Invasive fungal infections, although
rare, were associated with greatly increased mortal-
ity [28].The most common antifungal agents cur-
rently used to treat fungal UTIs are the azole deriva-
tives; such as uconazole and ketoconazole. These
agents have always been considered safe and effec-
tive antifungal agents for the treatment of fungal
infections such as candidiasis [58]. However, due to
common fungal resistance to azoles, other antifun-
gal agents have been used such as amphotericin B
[59], and caspofungin [60]. Although caspofungin
is well-tolerated and highly effective alternative for
the treatment of azole-resistant fungal infections in
RTRs, caspofungin is not use as rst-line treatment
for fungal infections due to its high cost [60].
In contrast, other studies have reported that there
is a lack of reliable evidence that the widespread
antibacterial prophylaxis can reduce the risk of UTI
recurrence [46, 61-64]. A recent systematic review
about the use of antibacterial prophylaxis for UTIs in
RTRs suggested that there is not any advantage for
such prophylactic treatment during the rst months
after renal transplantation, other than preventing
severe bacteremic sepsis [12]. A similar conclusion
was reached in a recent Cochrane review, which
stated that long-term antibacterial prophylaxis is not
justied, since most UTIs, especially in children, are
asymptomatic and do not affect the general health
of the patient [65]. Moreover, it has been proposed
that no further antibacterial is required in case of
asymptomatic UTIs, since no benet for the anti-
bacterial treatment had been observed for prevent-
ing future UTIs or preserving graft function [36].
The guidelines published in 2007 by the National
Institute for Health and Clinical Excellence in Eng-
land and Wales have also stated that antibacterial
prophylaxis should not be routinely recommended
in infants and children following rst-time UTI.
[66]. This was mainly attributed to the drawbacks
of antibacterial prophylaxis such as increasing risk
of resistant infections [67].
Antibacterial Resistance
It had been well recognized that the haphazard use
of antibacterial prophylaxis could result in the ap-
pearance of resistant microbial strains thus leads to
treatment failure and recurrent infections [65]. It has
been also reported that, the prevalence of antibac-
terial resistance among UTIs pathogenic bacteria is
increasing due to long-term use of these agents
[68]. In a retrospective study by Waller and Beattie
[62], it has been concluded that the daily antibac-
terial use to prevent recurrent UTIs was associated
with an increased risk of resistant infections. A simi-
lar conclusion was reached by Kawecki et al. [56]
and Silva et al. [17], who reported that recurrent
UTIs in RTRs attributed to the increased proportion
of isolates of multidrug-resistant bacteria was prob-
ably due to frequent use of postoperative antibac-
terial prophylaxis. Moreover, the increased bacterial
resistance can be also attributed to the impaired
immunity of RTRs resulting from the use of immu-
nosuppressants [16].
Being the most predominant pathogen of UTIs, E
coli was frequently studied by many researchers
(see Figure 2). It has been found that E coli isolate
showed considerable varying resistance patterns
among regions and countries [50]. Senger et al.
[26] had managed to recover resistant E coli isolates
in 76% of patients on cotrimoxazole prophylaxis.
However, E coli strains did not show a signicant
resistance against ciprooxacin. On the other hand,
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nitrofurantoin has been suggested to be considered
as an empirical therapy of lower tract UTI, since
the incidence of nitrofurantoin resistance was not
statistically signicant [69]. Interestingly, it has been
reported that there was no signicant difference in
antibacterial resistance in E coli isolates from either
symptomatic or asymptomatic UTIs patients [69].
Clinical Risk Factors
There is always a high risk for nosocomial infections
among all hospitalized patients. However, certain
patients are at greater risk than others, particularly
young children, elderly and immunocompromised
patients. The risk of acquiring infections in RTRs
depends on many factors including epidemiologic
factors, surgical consequences and the recipients
immunosuppression state [29].
Most postoperative UTIs are related to the use of
an indwelling urinary catheters, which can expose
a hospitalized patient to the possibility of infection
[70]. A strong association was suggested between
postoperative duration of an indwelling urinary cath-
eterization and UTIs, which has been considered as
the most important risk factor for the development
of UTIs [71]. The catheter-associated UTIs were ac-
counted for more than 80% of the most common
nosocomial UTIs [10]. In a retrospective cohort study
in US hospitals, Wald et al. [72] has reported that
a postoperative duration of an indwelling urinary
Figure 2. The Antibiotic resistance
rates of E. coli isolates, the most
common UTI causative agents,
in RTRs, from at least three
representative studies of urinary tract
isolates [18, 89-94] . Where, Amox/
Clav: Amoxicillin/Clavulonic acid.
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catheterization of more than two days was asso-
ciated with an increased likelihood of nosocomial
UTIs. However, in RTRs or in patients underwent
urologic surgery, urinary catheter might be needed
for extended periods. Therefore, catheter-associat-
ed UTIs could be prohibited by the appropriate use
of infection prevention policies according to the
guideline issued in 2009 by the CDC for prevention
of catheter-associated UTIs [73]. Other possible risk
factors of UTIs, which impose some therapeutic dif-
culty in RTRs, were also identied. Prior antibiotic
therapy [59], urinary tract abnormalities [22], diabe-
tes mellitus [48], female gender [74] and advanced
age [15]. However, a recent study by Lim et al. [19]
has not established female gender as an important
risk factor for recurrent UTIs in RTRs, in spite of the
fact that females showed a high incidences in both
nonrecurrent (70.4%) and recurrent (73.9%) UTIs.
Unlike Lim et al. [19], most studies have agreed on
the nding that female gender was the only con-
sistent independent risk factor of UTIs after renal
transplantation. The high risk of UTIs in female pa-
tients is most probably due to distinct anatomical
difference of female genitals. The estimated odd
ratio of the pooled data from some studies was
consistent with studies which reported the female
gender as an independent risk factor of UTI in RTRs
(Figure 3).
Immunosuppressive therapy
The use of immunosuppressive therapy in the post-
operative period in organ transplant recipients is
always necessary to avoid rejection of the donor
organ [75]. However, suppressing the immune sys-
tem functions render patients susceptible for higher
rate of infectious complications [76]. In a recent ret-
rospective observational study which involved 245
RTRs, the infections highest incidence was notice-
able by the sixth month after renal transplantation,
which coincided with the most immune suppressive
effect of the treatment regimen used [29].
Patients typically receive a three-drug immunosup-
pression regimen, which frequently include a combi-
nation of a calcineurin inhibitor, a corticosteroid and
an antiproliferative agent (e.g., azathioprine) [75].
Figure 3. Summary of female gender
risk factor of UTIs in RTRs, expressed as
odd ratio with 95% condence intervals
were computed with Fishers exact test
using Graphpad Prism Version 6 Software
Package.
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Traditionally, corticosteroids were used as the main
regimens in RTRs because of their value in reducing
rejection and enhancing organ survival [77]. How-
ever, it has been recognized that the prolong cor-
ticosteroids therapy was associated with increased
patient morbidity and mortality [78]. Numerous
adverse effects of steroid treatment are widely
recognized including an increased vulnerability to
infection; glucose intolerance; hyperlipidemia; os-
teoporosis; cataracts; myopathy; sodium retention;
weight gain, and impaired growth [79].
Although the use of corticosteroids has been a
mainstay for the management of acute organ re-
jection, there had been a rational tendency to em-
ploy steroid-sparing immunosuppression protocols
to minimize adverse effects [78]. Since the intro-
duction of immunosuppressive therapy in the early
1980s, a new approach has been established that
allowed either early withdrawal of steroids or spar-
ing steroids altogether. Some studies have demon-
strated that newer steroid-free immunosuppression
regimes were associated with lower incidence of
Figure 4. Summary of A) CsA, B) MMF (p=0.0222), C) TAC, and D) ATG Induction therapy (p=0.0365) risk factor of UTIs
in RTRs, expressed as odd ratio with 95% condence intervals were computed with Fishers exact test using Graphpad
Prism version 6 software package. Where, CsA: Cyclosporine A; MMF: Mycophenolate mofetil; TAC: Tacrolimus; ATG,
antithymocyte globulin.
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infectious complications and equivalent organ sur-
vival rates [80]. However, removal of corticosteroids
has not been always free of acute rejection risk.
Some studies have indicated that steroid-free pro-
tocols were associated with a signicant increase in
the rate of the incidence of acute rejection episodes
[2, 81]. Thus, the main challenge nowadays is to
identify the renal transplant candidates who may
benet from steroid-free regimens without increas-
ing the risk of acute rejection. Peculiarly, a study by
Alangaden et al. [28] has reported that the use of
newer immunosuppressive agents was associated
with a number of changes in the epidemiology of
infections in transplant recipients. Enterococci have
become the predominant pathogen responsible
for UTIs. Therefore, further studies are required to
establish the impact of steroid avoidance in these
protocols before drawing a rm conclusion.
Although many published studies have reported that
immunosuppressive drugs, including cyclosporin A,
azathioprine, mycophenolate mofetil, tacrolimus,
and induction regimens (antithymocyte globulin),
do not show any signicant risk factor for UTIs in
RTRs. The estimated odd ratio of the pooled data
(Figure 4) shows an ambiguous signicant value in
both mycophenolate mofetil (p=0.0222) and anti-
thymocyte globulin (p=0.0365).
On the other hand, Golebiewska et al. [21] has
indicated that the increased proliferation of cyto-
megalovirus (CMV) in UTIs patients was due to the
reactivation of latent CMV by proinammatory cy-
tokines. Moreover, many reports have demonstrat-
ed that CMV increases the net immunosuppression
status after organ transplantation by undermining
the immune responses, which predispose the pa-
tient to different infections [21, 82]. However, only
few studies have reported a signicant effect of
CMV on UTIs in RTRs. The estimated odd ratio of
the pooled data again shows a signicant value due
to CMV infection (see Figure 5).
Figure 5. Summary of
cytomegalovirus (CMV) risk factor
of UTIs in RTRs, expressed as odd
ratio with 95% condence intervals
were computed with Fishers exact
test using Graphpad Prism version 6
softwargepackages.
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Other Risk Factors
Additional risk factors were also recognized in hos-
pitalized patients that increase the opportunity of
acquiring infections. For example, prolonged hos-
pital stay, underlying disease severity, nutritional
deciencies, and failure of health care workers to
follow good hygiene practices [83]. Nevertheless,
some factors which are critically important in RTRs
such as bladder dysfunction or residual urine were
not considered as predisposing factors of recurrent
UTIs [25]. However, recent reports have found that
vesicoureteric reux (VUR), presence of ureteric
stents and urological malformations are represented
as risk factors of recurrent UTIs in RTRs throughout
the post-transplantation period [4, 84].
On the other hand, it has been reported that organ
transplant recipients are at a high risk of hyperuri-
cemia [85]. Hyperuricaemia has been suggested to
be an early sign of acute cellular rejection in RTRs
[86] or it could be attributed to the use of immuno-
suppressant cyclosporine and/or to the impairment
of renal functions. Hyperuricaemia is a challenging
clinical problem that adversely affects organ trans-
plant patients quality of life, which underlines the
importance of prompt treatment of hyperuricemia
[85]. However, treatment of hyperuricemia and/or
gout in RTRs has always been difcult due to the
risk of adverse effects and possible drug interactions
with the immunosuppressive regimen [87]. Allopuri-
nol has a serious interaction with azathioprine, but
not with mycophenylate mofetil, which might result
in bone marrow suppression. Moreover, uricosuric
medications, such as probenecid, are ineffective in
patients with kidney malady [85]. However, the rate
of having hyperuricemia and gout was signicantly
lower in patients receiving tacrolimus [88]. There-
fore the improper choice of immunosuppressants
could make organ transplant recipients vulnerable
to develop gout, which imposes additional risk in
RTRs.
Discussion and
recommendations
Although renal transplantation had saved many
patients lives with end-stage renal disease, post-
transplantation infections are considered common
causes of morbidity and mortality among RTRs. It
is alarming that infections have been considered the
second cause of fatality in RTRs after cardiovascular
complications [89]. In spite of the fact that UTIs are
the most common infections in RTRs, there are limit-
ed treatment guidelines on antibacterial prophylaxis
for UTIs in this population. This may be due to the
shortage of published data that examine antibacte-
rial susceptibility in renal pathogens among RTRs.
However, in the face of lack of strong evidence to
support the use of antibacterial prophylaxis to pre-
vent recurrence of UTI, it continues to be a very
common medical practice nowadays [6]. Although
mortality rate after renal transplantation has been
fairly diminished to less than 5% [29], infection-
related complications still pose a serious challenge
that attenuate organ survival opportunity. The use
of antibacterial prophylaxis is still considered indis-
pensable in order to achieve successful outcomes
following renal transplantation and overcome infec-
tion impediments.
The following critically important issues, in the au-
thors opinion, should be of concern by health prac-
titioners for the well-being of RTRs to avoid the
avertable lethal consequences and to minimize risk
factors for UTIs:
Investigating regularly the UTIs caustic patho-
gens, antibacterial susceptibility and the local pat-
tern of resistance to optimize the initial empiric
antibacterial selection and update the treatment
protocols.
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Choosing narrow spectrum antibacterial accord-
ing to antibacterial sensitivities, to minimize the
opportunity of invasive fungal or parasitic infec-
tions.
Selecting the correct balanced therapy of the
immunosuppressant agents and the use of anti-
microbial prophylactic regimens that will signi-
cantly reduce the incidence of early opportunistic
infections.
Avoiding unnecessary prolonged urethral cath-
eterization in RTRs since it has been found that
long catheterization was frequently associated
with high rate of UTIs which could increase mor-
tality or at least delay discharges to home.
Recognizing promptly the occurrence of serious
infections that require meticulous management
of immunosuppressive therapy
Encouraging living kidney donations, since most
investigators have reported that UTIs risk was con-
siderably higher in RTR of grafts from deceased
donors. However, this requires a thorough medi-
cal examination of living-related donors to reduce
the incidence of UTIs in recipients of kidneys from
these donors.
Development of potent therapeutic strategies, in
light of the decreased efcacy of existing anti-
bacterial regimes, for better management of in-
fections.
Commitment regimens to the use of hand sani-
tizers as lack of general hygiene is considered a
serious threat of nosocomial infections.
Health care practitioners should be alert for dif-
ferent risk factors that participate in the occur-
rence of UTIs which can undermine the function
and survival of transplanted organ in cri tically ill
patients.
Finally, it is essential to conduct larger prospective
studies involving multiple centers to evaluate the
microbiology and treatment of post-transplanta-
tion infections hopefully to develop guidelines for
monitoring and preventing organ transplant as-
sociated infections.
Conclusions
In summary, the high infection rate associated with
the use of immunosuppressive agents currently used
necessitates the use of antibacterial prophylaxis. The
UTI-related mortality and morbidity in the rst year
post-transplantation can be substantially reduced
by elegant integration of antibacterial prophylactic
regimens in the therapy practice early after renal
transplantations. However, the optimal antibacterial
therapy duration to prevent recurrent UTIs in RTRs
remains uncertain.
However, despite routine antibacterial therapy, re-
current UTIs remain common; besides, there was
not enough evidence to support the benecial ef-
fect of prophylactic antibacterial drugs other than
reducing the risk of bacterial sepsis. Therefore, it is
essential to establish a long-term prospective obser-
vational study with a sample sufcient to determine
evidence to support the potential benets and risks
associated with the long-term antibacterial prophy-
laxis in RTRs. Such study is indispensable to deter-
mine the optimal duration of antibacterial therapy
for recurrent UTIs in RTRs.
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