Towards New Strategies in
Complicated Urinary Tract Infection
C. van Nieuwkoop
Towards New Strategies
in Complicated Urinary
Tract Infection
PROEFSCHRIFT
Ter verkrijging van
de graad van Doctor aan de Universiteit Leiden,
op gezag van de Rector Magnificus Prof. Mr. P.F. van der Heijden,
volgens besluit van het College voor Promoties
te verdedigen op donderdag 17 februari 2011
klokke 16.15 uur
door
Cornelis van Nieuwkoop
geboren te Gouda
in 1972
Promotiecommissie
Promotor:
Prof. Dr. J.T. van Dissel
Co-promotor:
Dr. J.W. van’t Wout
Overige leden:
Prof. Dr. I.M. Hoepelman (Universiteit Utrecht)
Prof. Dr. R.C.M. Pelger (Universiteit Leiden)
Prof. Dr. J.M. Prins (Universiteit van Amsterdam)
The clinical studies discussed in Part I of this Thesis, were ﬁnancially
supported by a grant of the Bronovo Research Foundation.
financial support for the publication of this thesis by franje1 foundation, brahms biomarkers,
astellas pharma bv, janssen-cilag bv, msd bv, viiv healthcare bv, roche nederland bv,
boehringer-ingelheim bv, gilead sciences bv and abbott bv is gratefully acknowledged.
isbn 978-90-9025932-1
printed by mostert & van onderen!, leiden, the netherlands
graphic design jan kleingeld, leiden, the netherlands, www.hakijk.nl
copyright © 2011 by c. van nieuwkoop, the netherlands
Contents
Introduction
7
Part I
Clinical aspects of febrile urinary tract infection
Chapter 1
Prospective cohort study of adults with acute pyelonephritis:
safety of triage towards home based oral antimicrobial treatment.
J Infect 2010;60:114-21.
Chapter 2
Modified pneumonia severity index and CRB-65 identify low-risk patients
with febrile urinary tract infection.
33
Submitted for publication.
Chapter 3
Predicting the need for radiologic imaging in adults with febrile urinary
tract infection.
47
Clin Infect Dis 2010; 51: 1266-72.
Chapter 4
Procalcitonin reflects bacteremia and bacterial load in urosepsis syndrome:
a prospective observational study.
61
Crit Care 2010; 14: R206.
Chapter 5
Risk factors for bacteremia with uropathogen not cultured from urine in
adults with febrile urinary tract infection.
79
Clin Infect Dis 2010;50:e69-72.
Chapter 6
Fluoroquinolone resistant Escherichia coli in community-onset febrile
urinary tract infection: risk factors and outcomes.
87
J Antimicrob Chemother 2010; epub ahead of print.
Chapter 7
Treatment duration of febrile urinary tract infection (FUTIRST trial):
a randomized placebo-controlled multicenter trial comparing short (7 days)
antibiotic treatment with conventional treatment (14 days).
103
BMC Infect Dis 2009;9:131.
19
Part II
Relation between pelvic floor dysfunction and urinary tract infection
Chapter 8
Pelvic floor dysfunction is not a risk factor for febrile urinary tract
infection in adults.
BJU Int 2010; 105:1689-95.
119
Chapter 9.1
9.2
Pelvic floor dysfunction is not related with incidence or outcome of
urinary tract infection.
Submitted for publication.
Part III
Complicated cases of urinary tract infection
Chapter 10
Intravesical gentamicin for recurrent urinary tract infection in
patients with intermittent bladder catherization.
153
Int J Antimicrob Agents 2010; 36:485-95.
Chapter 11
Gather ye buds: fungus formation of the bladder after cesarean section.
165
Am J Obstet Gynecol 2008;199:207.e1-2.
Chapter 12
Chronic bacterial prostatitis and recurrent Enterococcus faecalis
bacteremia successfully treated with moxifloxacin. J Infect 2008;56:155-56.
137
The role of pelvic floor dysfunction in adults with urinary tract infection.
Urology 2010; 76: 1270-71.
147
169
173
General Discussion Nederlandse samenvatting
Dankwoord
Curriculum Vitae
List of publications
Lijst van deelnemende centra
Abbreviations
195
200
201
202
204
207
Introduction
introduction
Introduction
Urinary tract infection (UTI) is the most common bacterial infection leading to substantial morbidity and considerable health care expenditures across all ages 1. Women, the elderly and persons
with underlying illnesses, such as urologic abnormalities or diabetes mellitus, are at increased risk
and many of these persons will develop an UTI at some point in their lives.
Definitions UTI refers to an inflammation of the urinary tract in response to the presence of
microbial pathogens. It encompasses a broad range of clinical syndromes associated with one
common finding: a positive urine culture (bacteriuria). Based on clinical symptoms, UTI can be
classified by the site of infection. Dysuria, frequency, urgency, suprapubic pain and/or hematuria
all reflect the presence of bladder infection (cystitis or lower UTI); fever or chills, flank pain, nausea and vomiting reflect kidney infection (pyelonephritis of upper UTI) which is considered an
ascending lower UTI. In men, fever or chills, myalgia, dysuria, pelvic or perineal pain may reflect
infection of the prostate (prostatitis).
For reasons of practicability and differences in clinical approach, UTIs are classified into ‘uncomplicated’ or ‘complicated’ 2, 3. The term ‘uncomplicated’ is usually restricted to non-pregnant women
without underlying functional or anatomical abnormalities of the urinary tract but it remains controversial whether older, postmenopausal women, and women with underlying co-morbidities,
like diabetes mellitus, also belong to this group 4. In adults the following international classification has been used: acute uncomplicated UTI (cystitis), acute uncomplicated pyelonephritis,
complicated UTI (CUTI, cystitis), acute complicated pyelonephritis and in addition, for men there
are several categories of prostatitis 2, 5-7. The term ‘asymptomatic bacteriuria’ is reserved for the
presence of bacteriuria without accompanying symptoms of UTI.
In the Netherlands, we use slightly adapted definitions for the terms ‘uncomplicated’ or ‘complicated’ UTI which indeed itself makes the terminology and classification of UTIs rather complex.
Both the Dutch College of General Practitioners and the Dutch Study Group for Antibiotic Policy
reserve the term ‘uncomplicated’ UTI for UTI in a non-pregnant immunocompetent woman with
no anatomical or functional abnormality of the urinary tract who do not exhibit signs of tissue invasion or systemic infection (e.g. fever, chills, flank pain, nausea, vomiting) 8, 9. UTIs not meeting the
criteria for ‘uncomplicated’ are all considered ‘complicated’. In this respect the term ‘complicated’
either implies the presence of a potentially complicating patient condition (e.g. abnormalities of
the urinary tract, pregnancy or male sex) and/or the presence of extended disease as indicated by
so-called signs of tissue invasion; in particular fever indicates that the infection is not restricted to
the bladder mucosa but has spread locally or systemically (e.g. pyelonephritis and urosepsis).
Pathogenesis The pathogenesis of UTI is complex and related to the interplay between a host
and a pathogen invading the urinary tract. Several mainly local factors may influence the susceptibility of the host whereas pathogen factors comprise various virulence properties. Furthermore
9
figure 1
Pathogenesis of Urinary Tract infection (UTI) (adopted from 11 and 12 ).
Factors enhancing
susceptibility
Factors enhancing
exposure and
transmission
Factors enhancing
bladder invasion
Factors enhancing
bacterial growth
and/or affecting
immune response
Immunity
Susceptible Host
10
Periurethral
colonization
(E. coli)
Asymptomatic
bacteriuria
Symptomatic UTI
Host response
Bacterial virulence characteristics
different behavioural and environmental factors determine the chance of periurethral uropathogen colonization that usually precedes the invasion of the urinary tract 10 (Figure 1).
Several host factors have been identified as risk factors for UTI. Most factors in some way or another facilitate periurethral colonization or entry of uropathogens into the bladder. These include
functional or anatomical abnormalities of the urinary tract, like pelvic floor dysfunction, benign
prostatic hyperplasia and cystocele, and behavioural characteristics, such as sexual activity and
bladder catherization 12, 13.
Uropathogens possess diverse properties that may enable them to overcome the local host defense
of the urinary tract. In particular such properties have been studied and characterized for Escherichia
coli as the most common uropathogen. Several virulence factors of E. coli have been identified that
contribute to its ability to adhere to, colonize or invade host cells and tissues in such a way that it
leads to the pathologic changes that are clinically recognized as symptoms of UTI. Examples of
such virulence factors are adhesions, siderophores, toxins, polysaccharides and proteases 14, 15.
Finally, the host immune response plays an important role in keeping the urinary tract to be sterile.
Alterations in the host defense mechanisms may thus contribute to the susceptibility to UTI. The
innate immune system of the urinary tract is diverse and includes many components like toll-like
receptors, chemokines, antimicrobial peptides and interleukins 16, 17. Recently it has been shown
that variations in this innate immune system may have a genetic basis which provides evidence of
an inherited host susceptibility to UTI 18-20.
Management The clinical approach of an acute uncomplicated UTI is straightforward and consists of a short course of oral antimicrobials on an outpatient basis. There is no need for additional
microbiological tests or radiologic imaging of the urinary tract. In contrast, there is less conformity
on the clinical approach for CUTI and acute (un)complicated pyelonephritis, reflecting the fact
introduction
that these conditions represent a broad spectrum of clinical syndromes. In particular this holds for
pyelonephritis for which different definitions have been used in clinical trials 21. As fever in UTI is
considered to be the most sensitive sign of pyelonephritis, it makes sense to classify UTI patients
according to the presence or absence of fever 8, 9, 21, 22. From a clinical point of view, fever in UTI
only indicates tissue inflammation of the urinary tract and the ensuing host response 8, 9. From a
scientific point of view, it is of interest to know whether this involves the kidney, bladder, prostate,
lymph nodes of the pelvis, blood circulation or a combination of those, but an exact anatomical
distinction on clinical grounds can often not be made. To date, many practical issues of febrile
UTI have not yet been fully addressed. Thus, facing a patient with febrile UTI, the attending physician is lacking clear evidence-based guidelines, and questions upon its management decisions
remain. Does this patient need to be referred to the hospital and subsequently to be hospitalized?
What is the risk of complications for this individual patient? What is the optimal empiric antibiotic
therapy? What is the risk of antibiotic resistance of the causative uropathogen in this patient? What
is the optimal duration of therapy and how should it be administered? Are blood cultures indicated
and what is the clinical relevance of detecting bacteremia? Is there a need for radiologic survey to
detect potential underlying abnormalities of the urinary tract? Are laboratory biomarkers of any
value in answering these questions?
To address these questions we set up a prospective observational multicenter cohort study including consecutive adults presenting with febrile UTI either at primary care or at regional emergency
departments (Figure 2).
The aim of this study was to assess clinical predictors for the different clinical and microbiological outcomes. Patients with febrile UTI usually present with a mild illness in primary care but
may rapidly develop a life-threatening condition, progressing into septic shock and multiple organ
failure. The overall mortality of patients with febrile UTI admitted to hospital amounts to about
7-8% 23, 24. Given the spectrum of clinical presentation, disease severity and outcome, the clinically
well-recognizable syndrome of febrile UTI is a good candidate for the development of a clinical
scoring system of disease severity. It is also suitable to characterize new biomarkers of disease that
figure 1
Participating sites of prospective observational study on adults with febrile urinary tract infection.
Hoofddorp
the Netherlands
Leiden
the Hague
Leiderdorp
Gouda
Hospital
Primary Health Care Center
11
12
will allow not only a timely diagnosis of UTI and the etiologic microbial agent (and/or antibiotic
resistance), but also allow early identification of those patients who will progress into more severe
stages of the host inflammatory response, e.g., sepsis and septic shock with multiple organ failure. For patients with pneumonia, the risk of complications contributing to an adverse outcome,
i.e., death, can reliably be estimated by means of a set of clinical criteria. If the estimated risk for
complications is low, a patient may be treated at home with oral antibiotics; in high risk patients
hospital admission is advised. For UTI, being the second most frequent cause of fever in adults
presenting at emergency departments after pneumonia 25-27, a set of clinical criteria have not been
established. Thus, the general practitioner and emergency room specialist will decide to refer and
hospitalize a patient or not guided by the perception of the patient’s illness 8. In this study, besides
deriving and validating a clinical scoring system of disease severity, we aimed to survey for diseaserelated biomarkers of both human host response and microbial agent, in blood and urine samples
of clinically and microbiologically well characterized individuals with fever due to UTI. To obtain
these data, the participating patients were thoroughly followed clinically including the monitoring
of blood and urine samples over time (Table 1).
In this thesis part of the results of this study are discussed with a focus on clinical predictors. The
analysis of the stored blood and urine samples is currently in progress and the results of that will
appear later. The aim of these more laboratory derived studies will be on microbiological, diagnostic, prognostic, pathophysiologic, immunogenetic and immunologic aspects of febrile UTI. This
will include the proteomic analysis of urine samples of which the methodology has recently been
described 28. Furthermore a genomic analysis of stored DNA of the participating patients will be
done to further elucidate aspects of genetic host susceptibility, responses of the innate immune
system of the urinary tract as measured in human urine during febrile UTI and the evaluation of
antimicrobial resistance mechanisms by using stored uropathogens.
Table 1.
Flowchart of assessments in patients with febrile urinary tract infection.
Evaluation
0
Enrolment
x
Demography
x
Clinical data
Adverse events
Days after enrolment
3-4
24-32
84-92
x
x
x
x
x
x
x
x
x
x
x
Survival
Blood culture
x
Urine culture
x
x
Plasma sample
x
x
x
Urine sample
x
x
x
Contact – in person
x
x
x
Contact – by phone
x
introduction
Outline of the Thesis
The focus of this thesis in on different clinical aspects of febrile UTI, examined in a large prospective observational multicenter cohort study, and on clinical observations in individuals with very
complicated UTIs.
Part I addresses different aspects of unresolved issues in the clinical management of febrile UTI.
Chapter 1 evaluates the safety of triage towards home based oral antimicrobial treatment of febrile UTI or acute pyelonephritis, as guided by the Dutch College of General Practitioners guideline on management of UTIs 8, 29. In addition this study discusses the adherence to this guideline
and risk factors for adverse outcome.
The study in Chapter 2 evaluated the predictive value of clinical severity assessments used in
community-acquired pneumonia in predicting clinical outcome of adults with febrile UTI. The
aim of this study was to differentiate patients into low and high risk febrile UTI that may be helpful
in guiding physicians to decide upon hospitalization.
Chapter 3 focuses on adults with febrile UTI presenting at emergency departments. The majority
of such patients are specifically referred by their general practitioner and thus they do have a higher
risk for complications or underlying conditions 25, 29. In this respect radiologic imaging of the
urinary tract will frequently be performed. This study presents a clinical prediction rule predicting
outcome of radiologic imaging.
The studies presented in Chapter 4 and Chapter 5 both focus on the presence of bacteremia
in adults with febrile UTI. Chapter 4 displays risk factors for bacteremia and the predictive
diagnostic value of the biomarker procalcitonine. Chapter 5 describes the diagnostic value of
blood cultures over urine cultures 30.
As antimicrobial resistance is emerging, the aim of the case-control study in Chapter 6 was to
assess risk factors of E. coli resistance to fluoroquinolones 31. This included not only host-related
risk factors but also potential environmental risk factors as contact with animals and health care
workers.
Chapter 7 describes a protocol of a randomized placebo-controlled non-inferiority multicenter
trial on treatment duration of febrile UTI 32. This study is currently enrolling patients and the results will await another year. Included is an evidence-based review of trials examining treatment
duration of febrile UTI or acute pyelonephritis.
Part II evaluates the relation between UTI and pelvic floor dysfunction; that is a general term for
functional clinical problems affecting the urinary, rectal and/or sexual function and considered to
be a risk factor for UTI 12, 33-35.
Chapter 8 and Chapter 9 describe the results of two case-control studies evaluating risk factors
for febrile UTI and pelvic floor dysfunction. In particular, the relation between pelvic floor dysfunction and incidence and outcome of febrile UTI has been addressed.
13
Part III discusses complicated clinical cases of UTI requiring unconventional methods of treatment.
In Chapter 10, two patients with a neurogenic bladder are described who have practiced intermittent bladder catherization and developed recurrent UTI with a multiresistent E. coli. Antibiotic
treatment options were very limited and finally they were treated with gentamicin intravesically.
In addition, the results of a systematic review on intravesical treatment with aminoglycosides are
presented.
Chapter 11 describes a patient who participated in the observational study and had extensive fungal disease of the bladder 36. Embolization of uterine artery after complicated cesarean section may
have contributed to this kind of complicated UTI.
Finally, Chapter 12 describes a renal transplant patient who suffered recurrent bacteremic Enterococcus faecalis UTI in the context of chronic bacterial prostatitis. Antibiotic agents to treat E. faecalis do
poorly penetrate the prostate; thus limiting the treatment options for such a complicated UTI 37-39.
14
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introduction
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15
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16
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