A comprehensive review of catheterassociated urinary tract infections: Pathogenesis, risk factors, clinical and laboratory features and contribution to hospital costs, morbidity and mortality

Catheterassociated urinary tract infection (CAUTI) is the most common nosocomial infection in hospitals and nursing homes worldwide with more than one million episodes in the United States alone. Although the morbidity and mortality of catheterassociated urinary tract infections are not as high as for example a deep surgical site infection or a nosocomial pneumonia, CAUTIs are still a cause for concern as they are a major reservoir of resistant pathogens. Numerous studies have documented a high prevalence of resistant pathogens in CAUTI and there is an association between nosocomial CAUTI and other nosocomial infections. The majority of studies aimed at understanding the pathogenesis and complications of CAUTI were done in the 1970s and 1980s before the modern era of infection control and managed care

A comprehensive review of

catheter-associated urinary tract infections:

Pathogenesis, risk factors, clinical and laboratory features and

contribution to hospital costs, morbidity and mortality

Paul A Tambyah, MBBS

A thesis submitted for the degree Doctor of Medicine (M.D.) in the Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore

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Parts of this thesis have been published in the following manuscripts: Copies of the manuscripts are appended in Appendix 1:

International Journal Articles:

1: A prospective study of pathogenesis of catheter-associated urinary tract infections

Tambyah PA, Halvorson KT, Maki DG Mayo Clin Proc 1999;74:131-6

2: Catheter-associated urinary tract infection is rarely symptomatic: a prospective study

of 1,497 catheterized patients.Tambyah PA, Maki DG Arch Intern Med

2000;160:678-82

3: The relationship between pyuria and infection in patients with indwelling urinary

catheters: a prospective study of 761 patients Tambyah PA, Maki DG Arch Intern

Med 2000;160:673-7

4 Engineering out the risk for infection with urinary catheters Maki DG, Tambyah PA

Emerg Infect Dis 2001;7:342-7

5 The direct costs of nosocomial catheter-associated urinary tract infection in the era of

managed care Tambyah PA, Knasinski V, Maki DG Infect Control Hosp Epidemiol

2002;23:27-31

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6 Catheter-associated urinary tract infections: diagnosis and prophylaxis

Tambyah PA Int J Antimicrob Agents 2004;24 Suppl 1:S44-8

7 European and Asian guidelines on management and prevention of

catheter-associated urinary tract infections Tenke P, Kovacs B, Bjerklund Johansen TE,

Matsumoto T, Tambyah PA, Naber KG Int J Antimicrob Agents 2008;31 Suppl

1:S68-78

8 Hooton TM, Bradley SF, Cardenas DD, Colgan R, Geerlings SE, Rice JC, Saint S,

Schaeffer AJ, Tambyah PA, Tenke P, Nicolle LE; Infectious Diseases Society of

America Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious

Diseases Society of America Clin Infect Dis 2010;50:625-63

Book Chapters:

1 Tambyah PA, Maki DG Detection of urinary tract infection in the catheterized

ICU patient In Immunology and Infectious Disease Kluwer Academic

Publishers New York, NY, 2001

2 Tambyah PA, Olszyna DP, Tenke P, Koves B Device associated UTI: Definition, Epidemiology and Risk Factors In “Urogenital Infections”, European Association of Urology (EAU) Arnhem, The Netherlands 2010

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Acknowledgements:

I am most grateful to my supervisor Prof Dennis Maki of the University of Wisconsin –

he is a wonderful role model and a perfect example of a dedicated Infectious Diseases physician, teacher and scientist He led me through all the work that went into this thesis every step of the way including spending early mornings at 6am going over the data at his home in the cold Wisconsin winter to discussions on rounds at midnight in the

hospital I am also grateful to Prof KO Lee of the National University of Singapore who started me off on my career as an academic clinician when I was just a house officer in the Department of Medicine NUS and has continued to be a mentor and guide

I am also grateful to Kathleen Halvorson, Leah Narans and Shelly Fischer for excellent laboratory support and our research nurses, Valerie Knasinski, Jo Thomson, Pam

Owen, Sharon Little, Josh Knox, Ann Kelly, Julie Jurss, Anne Jones, Pat Gwinn, Carol Boone, Rose Bauer and Lani Arrieta for their assistance with collection of data during this study

This thesis would not have been completed without the support and encouragement of

my wife, Dr Siok Tambyah and my parents, Dr & Mrs J A Tambyah This submission is dedicated to my father, Dr John A Tambyah, outstanding clinician, great teacher and a role model for generations of Singaporean physicians and clinician scientists

I am also grateful to the University and the Research office of the School of Medicine for their patience with this delayed submission

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A note on this submission:

The work that is contained in this thesis submission was done during the years 1996 to

1999 while I was a clinical and research fellow at the University of Wisconsin Hospitals and Clinics under the supervision of Prof Dennis Maki The writing was done primarily in Wisconsin and back home in Singapore from 1999 to 2002 while I was on the staff of the National University Hospital and subsequently on the faculty of the National

University of Singapore

The submission of this thesis was delayed because of the pressures of clinical,

research and teaching work brought on by a number of things including the SARS

outbreak of 2003 and the avian influenza pandemic concerns of 2005

I deeply appreciate the patience of the University in allowing this delayed submission of work that is now a decade old

In response to the suggestions of the examiners, a brief addendum has been added to bring the work up to date by including the latest developments in the field

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Table of Contents:

3 Methods:

3.0.5 Definition of nosocomial bloodstream infection 9 3.0.6 Definitions of other nosocomial infections 10

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5 Discussion:

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Summary:

Catheter-associated urinary tract infection (CAUTI) is the most common nosocomial infection in hospitals and nursing homes world-wide with more than one million

episodes in the United States alone Although the morbidity and mortality of catheter-associated urinary tract infections are not as high as for example a deep surgical site infection or a nosocomial pneumonia, CAUTIs are still a cause for concern as they are a major reservoir of resistant pathogens Numerous studies have documented a high prevalence of resistant pathogens in CAUTI and there is an association between

nosocomial CAUTI and other nosocomial infections The majority of studies aimed at understanding the pathogenesis and complications of CAUTI were done in the 1970s and 1980s before the modern era of infection control and managed care As such, there are still a number of unanswered questions including the relative pathogenesis of the different microorganisms causing CAUTI, the risk factors for CAUTI in the modern era, the symptomatology of CAUTI, the association of CAUTI with pyuria and morbidity and mortality as well as the costs associated with CAUTI in the era of managed care

As part of two large randomized trials of novel coated urinary catheters, we undertook a prospective observational study of 1,497 newly catheterized patients hospitalized at the University of Wisconsin Hopspitals and Clinics to attempt to answer some of these questions Every patient who was catheterized in the hospital was eligible to participate

in the study Consenting patients were questioned daily on symptoms associated with urinary tract infections, had daily clinical parameters measured and two sets of urine

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cultures done daily with a technique capable of detecting even one colony forming unit

of uropathogens Patients were followed daily to discharge and the data collected were analysed using standard microbiologic and statistical methods

Pathogenesis:

The entry of a urinary catheter bypasses the normal host defences at the meatus and allows the entry of pathogens into the bladder The presence of a foreign body also allows for the formation of a biofilm, which is a conduit for pathogens to multiply and cause infection It has been postulated that there are two main routes for CAUTI Firstly, the extraluminal route: this could be either early at the time of catheter insertion due to inadequate antisepsis or contamination, or late due to colonisation of the meatus and the ascent of microorganisms from the perineum along the surface of the catheter The second pathway for microorganisms to enter the bladder is the intraluminal route This

is from breaks in the closed drainage system that occurs through irrigation of the

bladder without proper asepsis Alternatively, and perhaps more commonly, the

collection-bag urine becomes contaminated through healthcare workers not washing hands when going from bag to bag emptying urine or when changing bags The

assumption was that if the organism ascended into the bladder by the intraluminal route from the bag, it would appear first in a culture from the bag On the other hand, if the microorganism came along the surface of the catheter from the perineum, it would be detected in the catheter sample before it was detected in the bag Overall, two thirds of infections were caused by organisms ascending along the surface of the catheter This was more marked for staphylococci and enterococci as well as yeasts which are

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common commensals of the perineum For Gram-negative organisms such as

Pseudomonas, Enterobacter or Acinetobacter, the intraluminal route from the

collection-bag was more important

Risk factors

At least four prospective studies in previous decades have conducted multivariate

analysis of the risk factors associated with CAUTI with daily urine cultures to detect all CAUTIs in large numbers of patients Our results in the modern era were remarkably consistent The most important risk factors have been prolonged catheterization and being female Other risk factors identified have included catheterization outside the sterile environment of the operating room, being on a urology service, other infections, diabetes, malnutrition and renal failure Interestingly, most of the infection control

interventions were found to have a minimal impact on the incidence of CAUTI with one exception—if the drainage tube was allowed to be above the level of the patient; that was a major risk factor for infection Antibiotics were in general protective, but the risk of selecting for antibiotic-resistant organisms precludes this as a control strategy

Symptoms

Although many guidelines make the distinction between “symptomatic CAUTI” and asymptomatic bacteriuria in the management of CAUTI, we were unable to demonstrate

a difference in presence of fever or symptoms related to the urinary tract in catheterized patients with and without CAUTI, The catheter can itself be the source of symptoms as

we found that the proportion of catheterized patients without CAUTI with symptoms was

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similar to those with CAUTI Part of the reason for the absence of symptoms of urethral irritation such as dysuria or supra-pubic pain is believed to be that the catheter itself prevents contact of inflammatory cells in urine and large numbers of microorganisms with the urethral mucosa The presence of the urinary catheter in situ also allows for decompression of the bladder, thus preventing the development of symptoms related to bladder distension or reflux Symptoms cannot be relied on to distinguish “asymptomatic bacteriuria” from urinary tract infections in patients with indwelling urinary catheters

Pyuria

Pyuria is widely used as a criterion for diagnosing urinary tract infections in

non-catheterized patients However, we found pyuria to be most useful in predicting CAUTI

in patients with UTI due to Gram-negative pathogens while CAUTI caused by large numbers of yeasts and enterococci or staphylococci were less significantly associated with pyuria This is thought to be due to less urinary tract inflammation elicited by these organisms Pyuria alone cannot be used as the criteria for obtaining a urine culture in a catheterized patient It has been argued that if a catheterized patient develops signs of sepsis that cannot be linked to another source, such as nosocomial pneumonia, surgical site infection, or vascular catheter-related bloodstream infection, a urine culture should

be obtained even if the patient does not have demonstrable pyuria

Morbidity and mortality:

Earlier studies had shown an association between catheter associated urinary tract infections and mortality in both hospitalized patients as well as in nursing home

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residents independent of age or underlying medical conditions We examined this

relationship in a multivariable model that took into account other active nosocomial infections and found that when these were taken into account, CAUTI did not emerge as

a significant risk factor for mortality in our large and vulnerable patient cohort This supports our hypothesis that while CAUTI per se might not be a major cause of

inflammation, mortality or morbidity, they are important reservoirs of resistant pathogens which can go on to cause bloodstream infections or surgical site infections with their attendant well documented increased mortality and morbidity

Economic impact:

There have been a limited number of retrospective case control studies examining the economic impact of CAUTI but again, most of these date from before the managed care era in American Healthcare Our prospective study which examined each individual case of CAUTI and determined which investigations and medications were associated with CAUTI showed that each CAUTI cost an approximate USD $500 and prolonged the average length of stay by a day While this might not seem like a significant impact, the sheer volume of CAUTI ensures that efforts to reduce these infections are likely to be cost-effective

Conclusion:

We have advanced our understanding of CAUTI by appreciating the differences in pathogenesis between the different microorganisms and also the reality that definitions used in non-catheterized patients cannot be automatically applied to patients with

indwelling urinary catheters Efforts to reduce CAUTI should be targeted at the different

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pathogenetic routes There are clearly many challenges that face researchers and clinicians working in the field of CAUTI Foremost among these must be the prevention

of these infections Effective interventions to prevent CAUTI will doubtless help to

reduce the reservoir of resistant pathogens in the intensive care units, wards and long-term care facilities This will be a critical step in the battle against antibiotic resistance worldwide

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List of Tables:

Table 1.1: Pathogenesis: Mechanisms of infection in 235

catheter-associated urinary tract infections

51 Table 1.2 Features of patients and catheters with CAUTI by the four

mechanisms of infection

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Table 1.3 Mechanisms of CAUTI for groups of infecting

microorganisms

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Table 2.1 Risk factors: Frequency of compliance with recommended

precepts of catheter care and their impact on the risk of CAUTI by univariate analysis

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Table 2.2: Multivariable stepwise regression model of risk factors

predictive for CAUTI

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Table 3.1 Symptoms associated with CAUTI: Epidemiologic

characteristics of 224 patients with 235 nosocomial CAUTIs identified

in a prospective study of clinical features of 1497 catheterized patients

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Table 3.2 Symptoms referrable to the urinary tract, fever, leukocytosis

and quantitative pyuria in a subset of 1034 hospitalized patients with

urinary catheters and no identified infections, other than CAUTI in 89.*

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Table 4.1: Association with Pyuria: Epidemiologic characteristics of 82

patients with nosocomial CAUTI among 761 catheterized patients

prospectively studied

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Table 4.2: Urine white blood cell counts in hospitalized

catheterized patients

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