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Clinical presentation, risk

factors and use of antibiotics
in urinary tract infections

virulence of threatening pathogens is normally balanced by host

protective mechanisms. This balance may be disturbed by risk
Sometimes microorganisms enter the urinary tract without
causing problems. This is called asymptomatic bacteriuria and is
no longer regarded as a type of urinary tract infection (UTI),
although treatment is recommended under certain circumstances
like in pregnancy and before invasive urological procedures. The
presence of pathogens in the urine is considered to be a risk
factor for a clinical infection.1,2
Local and systemic symptoms may arise when pathogens
invade the urothelium. The higher up in the urinary tract the
invasion takes place, the more serious is the clinical situation.
The most severe condition is when urinary tract pathogens enter
the blood stream and cause urosepsis.
A doctor who is seeing a patient suspected of having a UTI
must assess clinical diagnosis, available treatment measures and
prognosis. The primary concern is to protect kidney function. A
concern of increasing importance is to protect the environment
against collateral damage from antibiotics.
The aim of this paper is to present recent recommendations on
severity assessment, and use of antibiotics to prevent and treat
urinary tract infections. Severity assessment is based on clinical
presentation, risk factors and antibiotic treatment options.

Truls E Bjerklund Johansen

Rasmus Nilsson
Zafer Tandogdu
Florian Wagenlehner

The European Section for Infections in Urology (EAU) has introduced a new
concept of severity assessment of urinary tract infections (UTI). The assessment is based on clinical presentation, patient risk factors and availability
of effective antibiotics. Instead of the old classification of uncomplicated
and complicated UTI, ESIU suggests to describe risk factors by means of
phenotyping. In this paper we present the new classification and give practical recommendations on antibiotic treatment of the most common community acquired and hospital acquired urinary tract infections.
Antibiotics have been prescribed so extensively that resistant bacteria
have made prophylaxis and treatment of urinary tract infections a more
difficult task.
Prophylaxis during surgical procedures should be prescribed according
to the risk of infective complications. The most important criterion is the
contamination category of the procedure. Basically there are four categories: clean, clean-contaminated, contaminated and dirty, but in urology
the clean-contaminated category is subdivided depending on whether the
urinary tract or the gastrointestinal tract is opened.
International guidelines consider pharmacokinetic and pharmacodynamics features of antibiotics and global resistance data. These recommendations may therefore need local adaptations. Urologists,
microbiologists and infectious disease specialists should meet in every
hospital to adapt their own guidelines according to local resistance data.

Materials and methods

The main reference for the present review is the EAU guidelines
on urinary infections which are being updated on an annual
basis.3 A special update of EAU guidelines was made in 2010 in
collaboration with the ICUD (International Consultation on
Urological Diseases). This update was based on a systematic
review of 3600 references by 123 authors including the systematic literature reviews reported by the international Cochrane
collaboration.4,5 Another important source of information is the
database and publications from the annual Global Prevalence
studies on Infections in Urology (GPIU) that have been run by
ESIU for 10 years in a row.6 We have also considered recent
publications in leading medical journals.

Keywords Antibiotic treatment; clinical presentation; ORENUC; prophylaxis; risk factors; urinary tract infections

Clinical presentation

According to EAU/ESIU definitions a patient is diagnosed as

having a symptomatic UTI if:
 there are clinical symptoms indicative of UTI and
 pathogens can be verified or suspected by culture, microscopy, dipstick or PCR-techniques, or
 the diagnosis or an appropriate therapy of symptomatic
UTI is made by a physician upon clinical evaluation.1,2
A UTI is classified as cystitis (CY), pyelonephritis (PN) and
urosepsis (US). Urethritis (UR) and male accessory gland infections
(male adnexitis or MA, e.g. prostatitis) are usually dealt with
separately, because the clinical presentations are quite different.2
The clinical presentation of the three UTI entities discussed
here (CY, PN, US) are presented in Table 1. A PN is always more
severe than a CY and a US is always more severe than the two
former conditions. In addition, PN can present as a mild and
moderate infection, which usually can be treated by oral antimicrobials in an outpatient setting, and as a severe infection with
systemic reactions like nausea and vomiting, which usually

Microorganisms always threaten to invade the urinary tract.

Billions of them are coming out of the anal opening near by. The

Truls E Bjerklund Johansen MD PhD is Professor, Department of Urology,

Oslo University Hospital, Oslo, Norway. Conflicts of interest: none
Rasmus Nilsson MD is a urologist at Telemark Hospital, Skien, Norway.
Conflicts of interest: none declared.
Zafer Tandogdu MD holds an EAU scholarship at Newcastle University,
Medical School, Northern Institute for Cancer Research (NICR),
Newcastle upon Tyne, UK. Conflicts of interest: none declared.
Florian Wagenlehner MD is Professor at the Department of Urology,
University of Giessen, Giessen, Germany. Conflicts of interest: none



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Clinical presentation of cystitis (CY), pyelonephritis (PN) and urosepsis (US) and grading of severity2

Clinical diagnosis

Clinical symptoms

Grade of severity




Mild and moderate pyelonephritis


Severe pyelonephritis


Urosepsis (simple)a


Severe urosepsisa


Uroseptic shocka

Dysuria, frequency, urgency, suprapubic pain;

sometimes unspecific symptoms
Fever, flank pain, CVA tenderness; sometimes
unspecific symptoms with or without
symptoms of CY
As PN-2, but in addition nausea and vomiting
with or without symptoms of CY
(>2 SIRS criteria must be met for US-4
Temperature > 38  C or < 36  C
Heart rate > 90 beats min
Respiratory rate > 20 breaths/min or
PaCO2 < 32 mmHg (<4.3 kPa)
WBC > 12,000 cells/mm3 or < 4,000 cells/mm3
10% immature (band) forms
With or without symptoms of CY or PN
As US-4, but in addition associated with organ
dysfunction, hypoperfusion or hypotension.
Hypoperfusion and perfusion abnormalities
may include but are not limited to lactic
acidosis, oliguria or an acute alteration of
mental status
AS US-4 or US-5, but in addition with
hypotension despite adequate fluid
resuscitation along with the presence of
perfusion abnormalities that may include, but
are not limited to, lactic acidosis, oliguria, or
an acute alteration in mental status. Patients
who are on inotropic or vasopressor agents
may not be hypotensive at the time that
perfusion abnormalities are measured.


Note: Hypotension due to urosepsis is defined as a systolic blood pressure of <90 mmHg or a reduction of >40 mmHg from baseline in the absence of other causes of
Urosepsis is defined as sepsis originating from the urogenital tract.
CVA, costovertebral angle; SIRS, systemic inflammatory response syndrome; WBC, white blood cell.

Table 1

new concept of phenotyping to better describe the different

groups of risk factors of UTI.1e3 Risk factors related to UTI will
modify the patients prognosis. The diagnostic work-up in patients with UTI is about detecting risk factors that need to be
considered or eliminated to achieve treatment aims.
ESIU has suggested to phenotype risk factors in UTI by means
of the so-called ORENUC system (Table 2). The system has six
main categories. Each category is referred to by a letter. All letters
together make up the name ORENUC. Table 2 presents examples
of risk factors in each category. The list of risk factors in this
table is not complete.
Phenotyping of risk factors is also relevant before a surgical
procedure, like for example a prostate biopsy. A history of UTI
during the recent 6 months and asymptomatic bacteriuria are
important category U risk factors, while having had an
indwelling catheter is a category C risk factor.

needs initial parenteral therapy and hospitalization. For urosepsis the severity grading of sepsis in general use is: sepsis,
severe sepsis and septic shock. Recently the ESIU suggested
ascribing each of the clinical presentations a severity grade in
Arabic letters.1 The clinical presentation is always the most
important prognostic criterion.

Risk factors
Many categories of risk factors are described in literature on UTI,
such as risk factors for getting UTI, risk factors for recurrences,
risk factors for serious complications, risk factors for kidney
failure, etc. Long and often overlapping lists of risk factors have
been described within a concept of UTIs being either uncomplicated or complicated.7,8 The ESIU found this old concept
not sufficiently reflecting the clinical needs, and introduced a



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Host risk factors in urinary tract infections categorized according to the ORENUC system1,2

Category of risk factor

Examples of risk factors


NO known risk factor

Risk factors for Recurrent UTI, but no risk of
more severe outcome

Extra-urogenital risk factors with risk of more

severe outcome

Nephropathic diseases with risk of more

severe outcome

Urological risk factors with risk of more severe

outcome, which can be resolved during

Permanent urinary Catheter and non

resolvable urological risk factors with risk of
more severe outcome

Otherwise healthy premenopausal women

Sexual behaviour (frequency, spermicide),
Hormonal deficiency in postmenopause
Secretor type of certain blood groups
Well-controlled diabetes mellitus
Prematurity, newborn
Male gender
Badly controlled diabetes mellitus
Relevant immunosuppression (not well
Relevant renal insufficiency (not well defined)
Polycystic nephropathy
Interstitial nephritis (e.g. due to analgetics)
Ureteral obstruction due to a ureteral stone
Well controlled neurogenic bladder
Transient short-term external urinary catheter
Asymptomatic bacteriuria
Long-term external urinary catheter
Non resolvable urinary obstruction
Badly controlled neurogenic bladder

Table 2

complication can be found in existing databases. Table 3

shows the risk of infective complications related to one of
the most common urological procedures, prostate biopsy.3,11,12
Patient-related risk factors as described in the ORENUC system
will modify the procedure-related risk of infection in a given
patient. All factors need to be addressed when risk assessment is
done before a surgical procedure.

The risk of developing infective complications after surgical

procedures is usually described in a separate system known as
Contamination categories (Box 1). The most important factors for
assessment of contamination category have been the age of the
surgical wound, if bodily tracts are opening during surgery,
spillage of its contents, and signs of infection or devitalized tissue.9
The concept of contamination categories was developed during World War II in order to evaluate prognosis and risk of
infection after injuries. Since then large databases have been
built that give the infection rate in each category and confirm the
validity of the classification principle also in modern surgery.10
However, modern urological surgery differs significantly from
war injuries and open surgery. Therefore the ESIU recently worked
out their own definitions of contamination categories in urology.
The categories are still based on characteristics of the surgical field,
but a new criterion has been added according to which bodily tract
that is entered or opened and the duration of the procedure.
All surgical procedures may be ascribed a contamination
category. Once the category is defined, the risk of infective

Antibiotic stewardship
The overall aim of antibiotic treatment in UTI is to restore a normal
balance between pathogens and the host. This either means getting rid of the pathogens, or causing the pathogens to withdraw to
their habitats outside the urinary tract, or even inside urothelial
cells. Not all pathogens will receive a lethal dose of antibiotics and
some may survive. While resting in their trenches some pathogens
are even capable of developing resistance mechanisms to classes
of antibiotics such as betalactams and spread to other hosts. This is
what collateral damage is about. With a generation time of only 20
minutes new genes are multiplied at high speed thus making
pathogens appear as intelligent creatures. As long as the number of
available antibiotics is limited and resistance increases, our chance
of giving effective prophylaxis and treatment is steadily being
reduced. This is why antibiotic stewardship is important.13
Over the past ten years we have seen a rise in multiresistant
pathogens such as extended spectrum betalactamase producing
strains (ESBL), vancomycin resistant strains and methicillin
resistant staphylococci (MRSA). Recently the first omniresistant
bacteria NDM-1, was described in urine cultures in UK.14 Within
a short time the pathogen spread to most European countries.

Classical definitions of surgical field contamination



Box 1



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Biopsy routes, contamination categories and risk of infection without prophylaxis in prostate biopsies3,11
Biopsy route

Contamination category







Key criteria

Sterile urine
No history UTI/UGI
Sterile urine
History of UTI/UGI
Sterile urine
Bacteriuria Urethral catheter

Risk of infection

UGI, urogenital infection (i.e. prostatitis); UTI, urinary tract infection.

Table 3

normalization of reflux, the children are outpatients and there

are no foreign bodies present. What seems to be an inconsistence
of principles as to antibiotic use in children and in perioperative
prophylaxis reflects the relative lack of high level evidence in this

Knowledge about the clinical course of urinary tract infections

with multiresistant or omniresistant pathogens is still limited, but
the perspectives give reasons for concern.
Urologists should be aware of the antibiotic prescription policy for community acquired UTIs as this may enhance the
development of resistant strains that may be brought into hospitals. Today up to 100% of patients in a urology ward may be
receiving antibiotics for prophylaxis or treatment. This means
that urology departments are high-risk zones for development of
resistant uropathogens.
If effective antibiotics are not available, natural host defence is
the only protection against spread of infection. Risk factors will
make spread of infection more likely.
In many developing countries there is poor availability of
antibiotics, and in some regions even in Europe today available
antibiotics are no longer effective because of high resistance
rates. Therefore the ESIU recommended that availability of
effective antibiotics should be included in the assessment of
severity and prognosis for a case of UTI, and suggested a three
letter scale, aec, describing the different combinations of pathogen susceptibility and availability of effective antibiotics.1 This
concept is however, not fully developed.

Short-term perioperative prophylaxis

Hospital acquired urinary tract infections are seen in about 11%
of patients in urology departments.6 When this occurs after
surgical procedures it is because pathogens are resistant to the
antibiotics used for prophylaxis. EAU guidelines are based on
evidence from pharmacokinetic, pharmacodynamic and international studies of pathogens and resistance. However, the GPIU
studies have shown that urologists do not always adhere to the
EAU guidelines recommendations.17 As a rule the urologist
should sit down with the local microbiologist and infectious
disease specialist to work out prophylaxis regimens based on
local culture results of hospital acquired UTI and regional results
of community acquired UTI. Designing prophylactic regimens is
a dynamic process and the regimens should be changed with a
few years interval. The most potent antibiotics such as aminoglycosides and carbapenems should be reserved for treatment.
Perioperative prophylaxis is a short-term administration
ensuring adequate serum levels at the time of maximal exposure
to possible pathogens. Sometimes administration may be prolonged for up to three days. However, antibiotics are not recommended for prophylaxis in patients waiting for catheter
removal, for example after radical prostatectomy or cystectomy.
The risk of infective complications following urological surgery may be foreseen by the contamination category of the procedure. Prophylaxis is not generally recommended in clean
procedures where the risk of infective complications is less than
5%,3 but individual risk factors may modify the overall risk and
justify prophylaxis also in clean procedures.
The antibiotics most commonly recommended for prophylaxis
in endourological procedures are trimethoprim sulphametoxazol,
second generation cephalosporins, aminopenicillin plus a betalactamase inhibitor and fluoroquinolones. For open surgical procedures the most commonly recommended antibiotics are
trimethoprim sulphametoxazol, second or third generation cephalosporins, aminopenicillin plus a betalactamase inhibitor and
metronidazole.3 Amikacin is frequently used in Asia, while second and third generation cephalosporins are often used in South

Use of antibiotics in urology

Antibiotics are prescribed in three different situations in urology:
 suspected UTI
 UTI with an identified pathogen.
Suspected UTI is the main reason for prescribing antibiotics in
urology accounting for 50% of cases, while the two other groups
account for about 25% each.15 Prophylaxis may be given as longterm administration to prevent recurrent UTI like in children and
as short-term administration to prevent infective complications
after surgical procedures.
Long-term prophylaxis in children
There is evidence to support long-term administration of oral
antibiotics in children at risk of kidney damage.3,16 The concept
of prophylaxis in children with recurrent UTI is different from the
concept of perioperative prophylaxis. Important characteristics
are that the patients are children, the situation we try to prevent
is end-stage kidney disease, the urinary tract is undergoing
physiological development during prophylaxis including



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America and Africa.17 For details on contamination categories and

recommended prophylactic regimens the reader is referred to the
Guidelines of the European Association of Urology.3
Antibiotic prophylaxis in prostate biopsies represents a special
challenge in terms of which antibiotic to use, especially in repeat
biopsies, and the timing of administration in outpatient procedures.18 Most guidelines recommend fluoroquinolones for
prophylaxis in prostate biopsies, but the increase of fluoroquinolone resistance has raised the question of appropriateness of the current recommendation.3 As a rule extended courses
is not recommended after prostate biopsies. Doing culture tests of
rectal swabs may help developing a better tailored prophylaxis.

pyelonephritis an oral therapy of 10e14 days is usually

 A fluoroquinolone for 7e10 days can be recommended as
first-line therapy if the resistance rate of E. coli is still
below 10%. If the fluoroquinolone dosage is increased, the
treatment can probably be reduced to 5 days. However,
increasing rates of fluoroquinolone resistant E. coli already
found in the community area in some parts of the world
restrict the empiric use of fluoroquinolones.
 A third generation oral cephalosporin (e.g. cefpodoxime
proxetil or ceftibuten) may be an alternative. However,
available studies demonstrated only equivalent clinical, but
not microbiological, efficacy compared with ciprofloxacin.
Because of increasing E. coli resistance rates above 10%,
cotrimoxazole is not suitable for empiric therapy in most areas,
but can be used as test conform therapy when susceptibility of
the pathogen is already known. Amoxiclav is not recommended
as a drug of first choice for empiric oral therapy of acute pyelonephritis. It is, however, recommended when susceptibility
testing shows a susceptible Grampositive organism.
In communities with high rates of fluoroquinolone resistant
and ESBL producing E. coli (>10%), an initial empiric therapy
with an aminoglycoside or a carbapenem has to be considered
until susceptibility testing demonstrates that oral drugs can also
be used. Hospital admission should be considered if risk factors
cannot be ruled out by available diagnostics and/or the patient
has clinical signs and symptoms of sepsis. After improvement,
the patient can be switched to an oral regimen using one of the
abovementioned antibacterials, if active against the infecting
organism, to complete the 1e2 week course of therapy.19
Patients with severe pyelonephritis who cannot take oral
medication because of systemic symptoms like nausea and vomiting, have to be treated initially with one of the following parenteral antibiotics depending on the local resistance rates of E. coli:
 a parenteral fluoroquinolone, in communities with resistance rates of E. coli to fluoroquinolones <10%
 a third generation cephalosporin, in communities with
resistance rates of ESBL producing E. coli <10%
 an aminopenicillin plus a betalactamase inhibitor in case
of a known susceptible Gram-positive pathogen
 an aminoglycoside or a carbapenem in communities with
resistance rates to fluoroquinolones
 and/or ESBL producing E. coli >10%.
In women whose pyelonephritis symptoms do not improve
within 3 days, or that resolve and then recur within 2 weeks, a
repeat urine culture, antimicrobial susceptibility testing and an
appropriate investigation, such as renal ultrasound, computertomography or scan, should be performed. In the patient with no
urological abnormality, it should be assumed that the infecting
organism is not susceptible to the agent originally used and an
alternative tailored therapy should be considered based on culture results. For those patients who have a symptomatic relapse
with the same pathogen as the initial infecting strain, diagnosis of
uncomplicated pyelonephritis should be reconsidered and further
diagnostic steps are necessary.3

Suspected UTI
Suspected UTI always means that treatment is started on an
empirical basis, and usually the situation has to be reassessed
once the identity and susceptibility of the pathogen is known.
According to both US and European guidelines it is acceptable to
diagnose UTI by patient history and clinical examination only
and to initiate treatment on this basis, which should be tailored
as soon as urine culture results are available.
In the majority of community acquired UTI the identity and
susceptibility of the pathogen is unknown at the time when
treatment is started. Primary care physicians must however,
acquaint themselves with local resistance figures because only
drugs with a general resistance in the population of <20% are
recommended as first-line therapy. In terms of hospital acquired
UTI we advocate waiting for evidence from urinalysis and culture
if clinically suitable, otherwise empirical treatment for suspected
UTI is considered. All general recommendations have to be
modified by patient related risk factors.
Community acquired cystitis without known risk factors: according to known susceptibility patterns, the following antibiotics
can be considered the drugs of first choice in many countries,
where available:
 fosfomycin trometamol 3 g as a single dose
 pivmecillinam 400 mg bid for 3 days and
 nitrofurantoin macrocrystal 100 mg bid for 5 days.
Cotrimoxazole 160/800 mg bid for 3 days or trimethoprim
200 mg for 5 days should only be considered as the first choice in
areas with known resistance rates of Escherichia coli below 20%.
Alternative antibiotics are ciprofloxacin 250 mg bid, ciprofloxacin ER 500 mg qd, levofloxacin 250 mg qd, norfloxacin 400 mg
bid and ofloxacin 200 mg bid, each as a 3-day course. However,
collateral effects have to be considered.
Symptomatology may be sufficient for routine follow-up. In
treated patients where symptoms do not resolve and in patients
with early relapse (<2 weeks) urine culture and antimicrobial
susceptibility testing should be performed for guidance of
Community acquired acute pyelonephritis without known
risk factors: due to lack of suitable surveillance studies the
spectrum and susceptibility patterns of uropathogens causing
uncomplicated cystitis has to be used as guide for empiric therapy in a given country. However, Staphylococcus saprophyticus is
to be less considered in acute pyelonephritis as compared to
acute cystitis. In mild and moderate cases of acute uncomplicated


Antibiotic treatment of HAUTI and urosepsis: the goal of

antibiotic therapy of hospital acquired UTIs (HAUTI) is not only
to cure the patient but also to contain the spread of infection and


2014 Elsevier Ltd. All rights reserved.


 Urologists prescribe a huge amount of antibiotics, 50% for

prophylaxis, 25% for suspected UTI and 25% for
confirmed infections with known pathogens.
 The best way to develop prophylactic regimens is for the
urologist, microbiologist and infectious disease specialist
to work together. Increasing resistance among urinary tract
pathogens necessitates prudent use of antibiotics.
 Fluoroquinolones still hold a key position in prophylaxis
and treatment of urinary tract infections, but care must be
taken because of world-wide increase of resistant uropathogens and to avoid overuse causing further collateral
damage to the patients.
 Special attention should be paid to avoid infective complications after prostate biopsies. Rectal swabs before
intervention may help developing a better tailored prophylaxis.

prevent the emergence of resistant mutants. Susceptibility testing

should be carried out in any case of HAUTI, and if possible the
results should be awaited before treatment. However, in severe
infections an initial empiric therapy must be instigated immediately after microbiological sampling. Susceptibility testing can
serve in these cases to narrow the antibiotic coverage. Provisional microbiological findings can lead to early stratification of
pathogens and allow a more tailored empiric antibiotic therapy.
Prudent use of antimicrobials may also help to reduce the selection of resistant pathogens to a minimum.
Antibiotics with an enlarged antibacterial spectrum are
necessary for initial empiric treatment. The empiric parenteral
treatment could start with:
 a cephalosporin group 3a
 a fluoroquinolone with good renal excretion or
 an aminopenicillin in combination with a betalactamase
If clinical improvement fails after two to three days, treatment
should be switched to:
 a pseudomonas active acylaminopenicilline/betalactamase-inhibitor
 a group 3b cephalosporin or
 a carbapenem.
Other reasons for treatment failure, such as persistent risk
factors, other infections or noninfectious sources, should also be
taken into account and be re-evaluated. Regional variations in
resistance must also be considered for empiric treatment. The use
of parenteral antibiotics is determined by the general condition of
the patient (e.g. nausea, vomiting) and the severity of the
infection; oral antibiotics can be continued as soon as the clinical
situation has improved. After the results of the susceptibility
testing have arrived, the antibiotic treatment should be aligned
accordingly. Treatment duration should continue for at least
three to five days beyond defervescence, depending on the
removal of the risk factor. However, this recommendation does
not hold true for the treatment of pyelonephritis with abscess
formation or chronic bacterial prostatitis, which should usually
continue for several weeks.19,20
HAUTIs are frequently complicated by the presence of a biofilm in which pathogens adhere to anatomical structures of the
urinary tract - stones, foreign materials or necrotic tissue - and
are embedded in organic (exopolysaccharide) and anorganic
(phosphate) material. Therefore it is necessary to elevate antibiotic concentrations by 10- to 100-fold in order to inhibit or kill
the pathogens. Such increased antibiotic concentrations are often
not clinically achievable. Fluoroquinolones and macrolides (only
effective against Gram-positive bacteria) exhibit a specific effect
on the biofilm formation, which, however, is usually not sufficient to eradicate the pathogens. Therefore, antimicrobial therapy in complicated UTIs may only kill the bacteria dissolved
from the biofilm (planktonic form) and thus inhibit spread of the
infectious process. An accompanying urological therapy must
aim to remove the biofilm.21

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 Severity scoring in UTI is based on clinical presentation,
risk factors and availability of effective antibiotics. Risk
factors may be classified by the ORENUC system.



2014 Elsevier Ltd. All rights reserved.


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The authors wish to acknowledge with thanks Drs Peter Tenke, Mete
Cek and Kurt Naber for their critical review of this article during its


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