A comprehensive review of catheter associated urinary tract infections pathogenesis, risk factors, clinical and laboratory features and contribution to hospital costs, morbidity an

Therefore, the second part of this large prospective observational study of CAUTI was to study risk factors for CAUTI, particularly the impact of non-compliance with recommended precepts

Catheter-associated urinary tract infection (CAUTI) is the most common

nosocomial infection in hospitals and nursing homes worldwide, comprising more than 40% of all institutionally-acquired infections.(Stamm, 1991; Warren 1991; Kunin 1997) Up to 25% of patients requiring a urinary catheter for seven days or longer develop nosocomial bacteriuria or candiduria, with a daily incidence of 5% (Garibaldi et al 1982; Kunin 1997) CAUTI rarely progress to bloodstream infection However, overall, CAUTI is the second most common cause of nosocomial bloodstream infection because of the high frequency of this infection (Maki 1981; Krieger et al 1983; Bryan and Reynolds 1984)

Studies by Platt et al (1982) and Kunin et al (1992) suggest that nosocomial CAUTIs are associated with increased institutional mortality, unrelated to the occurrence of urosepsis Asymptomatic urinary tract infections often precipitate unnecessary antimicrobial therapy CAUTIs comprise perhaps the largest

institutional reservoir of nosocomial antibiotic-resistant pathogens.(Stamm 1991; Jarvis and Martone 1992; Siebert et al 1993; Jarlier et al 1996)

The recognition of the role of the catheter in the pathogenesis of urinary tract infections dates back to the 1950s (Kass 1956) Most of what we know about CAUTI derives from studies done in the early 1970s and 1980s soon after the introduction of infection control programs in the United States and elsewhere

managed care era - increases in technology and the pressure towards early discharge and outpatient management of increasingly sicker patients (Warren 1991; Kunin 1997) Very little is known about the exact pathogenesis,

symptomatology, association with pyuria and mortality as well as economic impact in the modern era This study was undertaken to try to address some of these gaps

2.1 Pathogenesis:

Excluding rare hematogenously-caused pyelonephritis, mainly with S.aureus

(Lee et al 1978; Arpi and Renneberg 1984) the vast majority of microorganisms causing endemic CAUTI are thought to derive from patients’ own perineal flora

or from the hands of healthcare personnel inserting the catheter or manipulating the collection system.(Stamm, 1991; Warren 1991) These organisms are

thought to gain access to the bladder by one of two mechanisms: extraluminally

- early, by direct inoculation at the time of catheter insertion or later, ascending

from the perineum in the mucus film contiguous to the external catheter surface;

or intraluminally, most probably by reflux of organisms gaining access to the

catheter lumen from failure of closed drainage or contamination of collection bag urine The relative contribution of each of the three routes has not been adequately delineated Strategies for prevention, especially technologic

innovations, should be guided by the best understanding of pathogenesis

The first aspect of this large prospective study encompassing 1497 evaluable newly catheterized patients was undertaken to better define the pathogenesis of CAUTI

2.2 Risk factors:

A small number of prospective studies (Garibaldi et al 1974; Shapiro et al 1984;

Platt et al 1986; Johnson et al 1990) examined the risk factors for CAUTI

mainly in the 1970s and 1980s The current era’s strong focus on compliance

with published infection control guidelines, the effect of compliance with the

individual aspects of catheter care has not been adequately examined

Therefore, the second part of this large prospective observational study of

CAUTI was to study risk factors for CAUTI, particularly the impact of

non-compliance with recommended precepts of urinary catheter care on the risk of

CAUTI

2.3 Clinical Features and Symptoms associated with CAUTI

Although there have been recommendations to treat catheter-associated

urinary tract infections only when symptomatic (Warren 1991; National Institute

on Disability and Rehabilitation Research 1992; O’Grady et al 1998), the

symptoms associated with CAUTI have not been clearly defined The third part

of this prospective study of 1497 newly-catheterized hospitalized patients was

undertaken to determine the prevalence of signs and symptoms attributable to

CAUTI and the relative contribution of CAUTI to nosocomial bloodstream

infection

2.4 Association with Pyuria:

Pyuria has been shown to have excellent predictive value for identifying

urinary tract infections in non-catheterized patients (Mabeck 1969,

Stamm et al 1981).Although published guidelines recommend using

pyuria as the criterion for obtaining a urine culture as part of the work-up

of fever in the hospitalized patient (O’Grady et al 1998), the utility of

pyuria to identify bacteriuria or candiduria in short-term catheterized

patients has not been clearly defined previously

The fourth part of this prospective study was to determine the

relationship between pyuria and urinary tract infection in 761 hospitalized

patients with short-term indwelling urinary catheters

2.5 Mortality and Morbidity:

The contribution of CAUTI to hospital mortality has not been clearly defined In

a widely cited study published in 1982, Platt et al reported that nosocomial

CAUTIs were associated with greatly increased in-hospital mortality in

catheterized patients (Platt et al 1982) Subsequently, Kunin et al reported a

strong association between use of urinary catheters and mortality in nursing

home patients (Kunin et al 1992)

We reexamined this association in a prospective analysis of one thousand

catheterized hospitalized patients to determine whether CAUTI is truly an

independent predictor of increased hospital mortality

2.6 Economic Impact:

Retrospective studies quantifying the economic impact of CAUTI were done

mainly in the 1970s and 1980s, (Scheckler 1979; Givens and Wenzel 1980;

Haley et al 1981; Coello et al 1993) before the widespread emergence of

resistant nosocomial uropathogens and also before the advent of managed

care in US hospitals

In the final part of the analysis, we prospectively studied 1497

newly-catheterized hospitalized patients, obtaining daily urine cultures, and quantified

the extra direct costs of hospitalisation incurred in the management of CAUTI in

123 infected patients, and compared the findings with those of earlier studies in

the 1970s and 1980s before the era of managed care

3 METHODS:

3.0 Methods in Common to all six sections:

3.0.1 Patients:

All patients hospitalized at the University of Wisconsin Hospital and Clinics or

the William S Middleton Veterans Administration Medical Center, in Madison,

WI, USA, scheduled to receive an indwelling urethral (Foley) catheter, who

could be successfully catheterized with a 16Fr or 18Fr catheter and were

expected to be catheterized for more than 24 hours were candidates for this

study Patients were excluded if they were under the age of 18 years, pregnant

or had known allergy to silicone After providing informed consent, patients

were randomized to be catheterized with a standard silicone-coated catheter or

a novel silver-hydrogel catheter (both C.R Bard., Inc, Covington, GA, USA)

The two catheters were physically indistinguishable and investigators and the

research team as well as the patients’ healthcare providers were blinded to

each patient’s catheter assignment The study was approved by the institutional

Human Subjects Committee, and written informed consent was obtained from

all patients

3.0.2 Study Procedures:

On entry into the study, demographic and clinical data bearing on risk for

CAUTI identified in previous studies (Garibaldi et al 1974; Shapiro et al 1984;

Platt et al 1986; Johnson et al 1990)were collected, including age, gender,

structural urologic disease, underlying systemic diseases including diabetes

mellitus and cancer, immunosuppressive therapy, hospital service, confinement

in an ICU, recent surgery and the purpose for catheterization A faint line was

made across the catheter-collection tube junction at the outset and inspected

every day permitting continuous assessment of the integrity of closed drainage

(Garibaldi et al 1974) Catheter care was scored daily by trained research

nurses, scoring compliance in each of the following areas (1) integrity of the

tamper-evident line; (2) no other breaks in the closed drainage system; (3)

immobilization of the catheter, taped to the thigh; (4) position of the catheter

tubing below the level of the patient but above the bag, (5) position of the

collection bag, below the level of the patient but off the floor; (6) intact clamp on

the collection bag and (7) protection of the drainage port Each category was

scored (0, non-compliance; 1, no violation noted), and the summed daily score

was averaged for the duration of catheterization, yielding an overall score for

each patient’s catheter, ranging from 0 to 7 Each day, the patient was

questioned regarding discomfort or symptoms associated with the catheter

(pain, sense of urgency or dysuria) and the patient’s record was reviewed for

fever and other data suggesting infection; antimicrobial therapy given was also

recorded

3.0.3 Microbiologic procedures: On entry into the study and daily therafter,

approximately 3 milliliters of urine was aspirated from the sampling port of the

catheter with a sterile syringe, first disinfecting the port with 10% povidone

iodine; a concommittant sample was obtained from the drainage bag with

another sterile syringe, puncturing the drainage tube, after disinfecting the

surface, just above the level of the clamp Each specimen was immediately

brought to the laboratory and cultured using a technique capable of detecting 1

colony-forming unit (CFU) per milliliter, evenly spreading 1 milliliter of undiluted

urine and using serial dilutions on predried sheep-blood agar plates (Stark and

Maki 1984) After aerobic incubation at 37°C for 24 to 48 hours, each colony

type was enumerated and fully identified using standard techniques and criteria

(Balows et al 1992)

3.0.4 Definition of CAUTI: The new appearance of bacteriuria or funguria

>103 CFU/mL in urine aspirated from the collection port was considered to

represent nosocomial CAUTI It has previously been shown that isolation of

>103 CFU/mL is highly predictive of CAUTI; if intercurrent antimicrobial therapy

is not given to the patient, the level of bacteriuria or candiduria uniformly rises to

>105 within 24-48 hours (Stark and Maki 1984)

3.0.5 Definition of nosocomial bloodstream infection: The isolation of a

recognized pathogen from a blood culture, with no evidence that the infection

was present or incubating at the time of hospital admission With

coagulase-negative staphylococci and other skin commensals, at least two positive

cultures were required unless an intravascular device had also been shown by

culture to be infected by the same species (Garner et al 1988)

3.0.6 Definitions of other infections: The criteria of the National Nosocomial

Infection Study (NNIS) of the US Center for Disease Control and Prevention

were used (Garner et al 1988)

3.1 Methods specific to each section:

3.1.1 Pathogenesis:

Assumptions of analysis for pathogenesis (Section I): The assumptions

made are similar to those based on experimental studies by Kass more than 50

years ago (Kass and Schneiderman 1957) CAUTI appearing within 24 hours

of catheter insertion was considered to represent early extraluminal infection

caused by organisms introduced into the bladder at the time of catheterization

We further assumed that with late extraluminal infections, caused by organisms

ascending from the perineum in the mucus sheath contiguous to the external

surface of the catheter, organisms would appear first in bladder urine collected

from the catheter specimen port, as contrasted with urine from the collection

bag, or initially appear in concentrations at least one log greater than in urine

from the bag With intraluminal CAUTI, caused by organisms gaining access to

the lumen because of failure of closed drainage or contamination of collection

bag urine, organisms would be detected first in the specimen obtained from the

collection bag or initially appear in concentrations at least one log greater in

urine from the bag Patients already infected at the time of insertion of the

catheter were excluded Infections in which there was no differential between

the first appearance of organisms in catheter and collection bag specimens and

no differential in the initial quantitative levels of bacteriuria or candiduria were

classified as indeterminate in origin

3.1.2 Risk factors:

Statistical analysis: Data were analyzed using the statistical analysis package

SPSS for Windows Two analyses were undertaken: univariate analyses of the

association of each variable with CAUTI and multivariable logistic regression to

predict CAUTI outcome In the univariate analysis, Fisher’s Exact Test was

used for categorical variables; for continuous variables, the differences were

compared by Student’s t-test or Mann-Whitney test; all testing was two-sided

For calculation of univariate relative risk ratios and multivariable analyses,

continuous variables were recoded into discrete variables, based on their being

above or below the median value for the population A stepwise procedure was

used for the multivariable logistic analyses: one variable at a time was entered

into the classification equation starting with the predictor variable with the

highest association with CAUTI Variables that showed a statistically significant

contribution to CAUTI were entered into the final model

3.1.3 Clinical Features and Symptoms associated with CAUTI:

Every day, in addition to obtaining a urine culture, the patient was questioned

by a research nurse regarding any discomfort or other symptoms potentially

associated with the catheter: urethral or pelvic pain, sense of urgency or

dysuria Patients’ records were also reviewed for fever and other clinical and

laboratory data suggesting infection Peripheral white blood cell counts were

recorded as they were ordered by the primary team taking care of the patients

3.1.4 Association with Pyuria:

Quantitative urine white blood cell counts were measured daily using a

hemocytometer (Reichert-Jung, Hausser Scientific, Horsham, PA)

(Stamm 1983)

3.1.5 Morbidity and Mortality:

Statistical analysis: Data were analyzed using the statistical analysis package

SPSS for Windows Three analyses were undertaken: univariate analyses of

the association of each variable with mortality, discriminant analysis for

mortality classification and multivariable logistic regression to predict mortality

outcome In the univariate analysis, Fisher’s Exact Test was used for

categorical variables; for continuous variables, the differences were compared

by Student’s t-test; all testing was two-sided For calculation of univariate

relative risk ratios and multivariable analyses, continuous variables were

recoded into discrete variables, based on their being above or below the

median value for the population A stepwise procedure was used for both the

discriminant and multivariable logistic analyses: one variable at a time was

entered into the classification equation starting with the predictor variable with

the highest association with mortality Only variables that showed a statistically

significant contribution to mortality were entered into the final model

3.1.6 Economic Impact:

Analysis of costs: Patients were followed daily to discharge At the time of

discharge, patients’ records were reviewed by a single experienced clinician

and epidemiologic investigator, to determine which of the laboratory

investigations ordered and medications prescribed and potential added length

of stay (LOS), could reasonably be attributed to the patient’s CAUTI The

laboratory costs were then computed together with the drug acquisition costs

and the drug administration costs for each infection

Economic definitions: Hospital costs represent the costs incurred by the

hospital in providing the laboratory service or therapeutic intervention Charges

are the amounts billed to the patients Most hospitals have a cost to charge

ratio which allows for comparisons between costs and charges Again, for

comparison, costs or charges were adjusted for inflation using data from the US

Department of Labor, Bureau of labor statistics (Bureau of Labor Statistics

2000)

4 RESULTS:

4.1 Pathogenesis:

A total of 1497 evaluable newly-catheterized patients had complete data in the

analysis for pathogenesis In this group, there were 235 CAUTI in 224

(15.0%) patients;85% with at least one culture showing >105 CFU/mL in one or

more cultures The incidence of CAUTI was much higher in females (147 of

633, 23.2%) than males (77 of 864, 8.9%; relative risk 1.7, 95% CI 1.6-2.0,

P<0.001) It was also lower with catheters inserted in the operating room

(RR=0.9, 95% CI 0.8-1.0, P=0.02)

The probable mechanism of infection could be determined for 173 (69.2%) of

the 250 infecting organisms For these cases, 115 (66%) were

extraluminally-acquired, 30 (17%) detected within 24 hours and considered to have originated

from organisms introduced at catheter insertion and 85 (49%) gaining access

later, extraluminally; 58 (34%) derived from intraluminal contamination of the

collection system (Table 1.1)

As shown in Table 1.2, comparing CAUTIs by the mechanism of infection, there

were no significant differences in features of patients or their catheters,

including catheter care violations in the extraluminal, intraluminal and

indeterminate groups, and except for the early extraluminal group, there were

no differences in duration of catheterization prior to onset of infection Catheter

disconnections occurred during less than 10% of all catheter-days in each

group The intensity of antibiotic use also did not differ between the groups

However, there were significantly fewer early extraluminal infections with

catheters inserted in the operating room

Of the 235 CAUTIs, 220 (94%) were unimicrobial and 15(6%) were

polymicrobial, most commonly with enterococci and gram-negative bacilli; 29

infections (12%) were caused by Escherichia coli, 69(28%) by Klebsiella spp,

Enterobacter spp, Citrobacter spp, Pseudomonas aeruginosa or other resistant

nosocomial gram-negative bacilli, 84(34%) by enterococci and staphylococci

and 68(27%) by Candida spp.(Table 3) The distribution of pathogenetic routes

of infection differed significantly for the major groups of infecting organisms For

the determinable cases (Table 1.3), CAUTI caused by gram-positive cocci

enterococci and staphylococci or yeasts were far more likely to be

extraluminally acquired (extraluminal:intraluminal,2.9) whereas gram-negative

bacilli caused infection by both routes equally (extraluminal:intraluminal, 1.2)

4.2 Risk factors:

In order not to confound matters with the two different catheters, analysis for

risk factors was confined to patients catheterized with the novel silver hydrogel

catheter

A total of 850 evaluable newly-catheterized patients had complete data

available for risk factor analysis A total of 158 (18.6%) of the patients

developed CAUTI The novel silver hydrogel catheter was associated with a

significant reduction in CAUTI compared with controlled catheters (21.2 vs 15.4

infections per 100 catheters, relative risk 0.74, 95% CI 0.67-1.00, P=0.039),

especially CAUTIs caused by gram-positive cocci (RR 0.31, P<0.001); the

magnitude of risk reduction was similar on the multivariable model but did not

quite achieve statistical significance (OR 0.7, 95%CI0.5-1.0,P=0.08)

Only seven factors were independently predictive of an increased risk of CAUTI

(Table 2.1): extended catheterization (OR 5.2, P<0.001), female gender (OR

3.7, P<0.001), a urologic stent (OR 2.5, P<0.008), other active infections (OR

2.4, P<0.001), malnutrition (OR 2.4, P<0.001), insulin-requiring diabetes (OR

2.2, P=0.002), and drainage tube position (O.R.2.1,P=0.03) Antimicrobial

therapy (OR 0.1,P<0.001) conferred protection against CAUTI (Table 2.1)

Violations of closed drainage and lack of compliance with other precepts of

catheter care monitored were relatively frequent (one or more days in 50% of

the study population) but were not associated with an increased risk of CAUTI

(Table 2.2)

4.3 Clinical Features and Symptoms of CAUTI

4.3.1 Clinical Presentation

A total of 1497 evaluable newly-catheterized patients had complete data on

symptoms associated with CAUTI There were 235 CAUTI in 224 (14.9%)

patients (11 patients had two infections while catheterized); 85% showed >105

CFU/mL in one or more cultures and most showed active infection in serial

cultures for more than three days (mean duration of bacteriuria or candiduria,

4.0 ± 3.9 days) Only 123 (52%) of 235 CAUTIs were diagnosed by the

patients’ physicians using the hospital laboratory; thus, only about half of the

CAUTIs were treated The microbial profile of infections that were not detected

was similar to those that were detected during hospitalization and, usually,

treated

Overall, less than 10% of the 235 episodes of CAUTI were associated with

subjective symptoms referrable to the urinary tract, pain, urgency or dysuria

To more precisely analyze the effect of CAUTI on patients' symptoms, a subset

of 1034 patients, who did not have another, potentially confounding site of

infection besides the urinary tract, was analyzed; 89 had developed CAUTI with

>103 CFU/mL In this large subset (Table 3.2), there were no significant

differences between patients with and without CAUTI in subjective symptoms

commonly associated with urinary tract infections; most were afebrile There

were also no significant differences between the two groups in mean peripheral

leukocyte counts, although there were significant elevations in urine white blood

cell counts in patients with CAUTI compared to uninfected catheterized

patients; the largest differences were seen in patients infected with

gram-negative bacilli

4.3.2 Bloodstream Infection:

During the study, 79 (5.3%) nosocomial bloodstream infections were identified

in the study population, 67 primary bloodstream infections 38 originating from

an intravascular device and 12 secondary bloodstream infections There were

only four concordant bloodstream infections with the same organism isolated

from a catheterized urine specimen and subsequent blood cultures: two with

gram-negative bacilli: Klebsiella pneumoniae and Enterobacter cloacae, one

with coagulase-negative Staphylococcus and one with Candida lusitaniae In

the latter two cases, an infected central venous catheter could not be excluded

as the source of the patient’s bloodstream infection, because the infecting

organism was also recovered in large numbers from a semi-quantitative culture

of a central venous catheter; in one case with K.pneumoniae, the patient had a

concordant ventilator-associated pneumonia In only a single case, with

Enterobacter cloacae, did a nosocomial bloodstream infection appear

unequivocally to have derived from a CAUTI; interestingly, this patient had no

symptoms, whatsoever, referrable to the urinary tract

4.4 Association with Pyuria:

A total of 1035 evaluable newly-catheterized patients had complete data on

urinary leukocyte counts To accurately assess the significance of pyuria in

patients with indwelling urinary catheter, we excluded kidney or

kidney-pancreas transplant patients, who we have found show a burst of sterile

leukocyturia immediately post-transplantation, and analyzed 761 catheterized

patients of whom 82 (11%) developed 95 nosocomial CAUTIs

The incidence of CAUTI was much higher in females (50 of 236, 21.1%) than

males (32 of 443, 7.2%; relative risk 2.9, 95% C.I 2.1-4.2, P<0.001) Of the 95

CAUTIs , 89 (94%) were unimicrobial and 6 (6%) were polymicrobial, most

commonly with enterococci and gram-negative bacilli; 14 infections (14%) were

caused by Escherichia coli, 27(27%) by Klebsiella spp, Enterobacter spp,

Citrobacter spp, Pseudomonas aeruginosa or other resistant nosocomial

gram-negative bacilli, 27 (27%) by enterococci or staphylococci and 31(31%) by

Candida spp These organisms were detected from the first day onwards of

catheterization Only 50 (53%) out of 95 CAUTIs were detected by the primary

team taking care of the patients; more than half of the CAUTIs were not treated

As can be seen in Table 4.1, except for gender and duration of catheterization,

patients with and without CAUTI were quite similar, including severity of illness,

as measured by APACHE II score although this might not be as sensitive for

non-ICU patients Moreover, most patients were asymptomatic, including those

with CAUTI, and mean peripheral white blood cell counts were similar in

patients with and without CAUTI

The mean urine white blood cell count in patients with CAUTI during active

infection was significantly higher than in uninfected patients, (Table 4.2, 71 per

mm3 vs 4 per mm3, P=0.006) Pyuria was most strongly associated with

infection caused by gram-negative bacilli (mean urine white-cell count, 121 per

mm3 vs 4 per mm3, P=0.03) In contrast, CAUTI caused by coagulase-negative

staphylococci and enterococci (39 per mm3 vs 4 per mm3, P=0.25) or yeasts (

25 per mm3 vs 4 per mm3, P=0.15) produced far less pyuria

Although the maximum level of pyuria was considerably higher than the mean

during the period of catheterization, both in patients with and without CAUTI,

the discrimination between uninfected and infected patients using maximum

urine white blood cell counts was no better than using mean values (Table 4.2)

Urine white blood cell counts on the day of onset of bacteriuria or candiduria

>103 CFU per mL were only modestly elevated and were not useful for

prediction of CAUTI (Table 4.2) The absolute level of bacteriuria or candiduria

did not correlate with the level of pyuria except at very high microbial

concentrations, >108 CFU per mL (Figure1)

The sensitivity of pyuria >10 white blood cells per mm3 in a fresh urine

specimen (which corresponds roughly to >5 per high power field in microscopic

examination of the urine sediment24) for the diagnosis of CAUTI with >105 CFU

per mL was only 37%; specificity was 90% and positive predictive value, 36%

(Table 4.3)

4.5 Mortality associated with CAUTI:

Complete mortality and morbidity data were available from 1664

newly-catheterized patients participating in the two trials of the silver hydrogel and

nitrofurazone impregnated catheters Two hundred and eleven patients

acquired a CAUTI (12.7%) during the study period, 85% with at least one

culture showing >105 CFU/mL The incidence of CAUTI was much higher in

females (146 of 704, 20.8 %) than males (65 of 960 , 6.8%; relative risk [RR]

3.1, 95% CI 2.3-4.1, P<0.001) Four hundred and ninety patients (29.5%) had

another active infection while catheterized; most commonly lower respiratory

tract infection (212), community-acquired urinary tract infection (122),

intra-abdominal infection (57), primary bacteremia (46) or skin or soft tissue infection

(53) One hundred and two study patients died during hospitalization (24 with

CAUTI, 78 without) Whereas catheter type (medicated vs control) was a

significant predictor of the occurrence of nosocomial CAUTI during

catheterization in both trials, it had no association with hospital mortality (RR

1.1, 95% CI 0.8-1.6,P=0.70)

Eight variables showed a significant association with mortality in univariate

analyses (Table 5.1): admission to a medical service (relative risk [RR], 9.7)

presence of other active infections (RR 7.0), catheters inserted by nurses (RR

4.7) APACHE II score (RR 4.4), duration of catheterization (RR 2.6), CAUTI

(RR 2.2), increasing age (2.2) and elevated baseline serum creatinine (RR 1.7)

However, stepwise multivariable logistic regression modeling (Table 5.2)

showed the presence of other active infections (Odds ratio [OR] 3.0, 95% CI

1.8-5.2, P<0.001), admission to a medical service (OR 2.8, 95% CI 1.7-4.6,

P=0.0001), APACHE II score (OR 2.6, 95% CI 1.5-4.4, P=0.0004), age (OR

1.9, 95% CI 1.2-3.1, P=0.008) and duration of catheterization (OR1.7, 95% CI

1.0-2.8, P=0.045) were significantly associated with mortality The model

correctly classified 93.5% of the study population A logistic model incorporating

only other active infections and CAUTI, showed that whereas CAUTI was

strongly associated with other active infections (P<0.001), it was not a

significant predictor of mortality (OR 1.33, 95% C.I 0.80-2.20,P=0.28)

4.6 Costs associated with CAUTI:

A total of 1497 evaluable newly-catheterized patients had complete data

available for the cost analysis Two hundred and twenty-four patients (14.9%)

developed CAUTI during the study; 85% showed >105 CFU/mL in one or more

cultures and most showed active infection in serial cultures for more than three

days (mean duration of bacteriuria or candiduria, 4.1 ± 3.9 days) More than

90% of the CAUTI were completely asymptomatic and only 123(52%) were

diagnosed by the patient’s physicians using the hospital laboratory

The 123 CAUTI diagnosed by the hospital laboratory were judged to have been

responsible for an additional $20,662 in extra costs for diagnostic tests and

$35,872 in extra medication costs; an average of $589 (median, $356) per

CAUTI (Table 6.1) CAUTI caused by E.coli cost considerably less than

infections caused by other gram-negative bacilli ($363.3 ± 228.2 vs $690.4 ±

783.7, P=0.02) or yeasts ($821.2 ± 2169.9) There were less striking differences

in the costs of CAUTI caused by staphylococci or enterococci ($387.1 ± 434.8)

There were only four concordant bloodstream infections with the same

organism isolated from a catheterized urine specimen and subsequent blood

cultures as described above In only a single case, with Enterobacter cloacae,

did a nosocomial bloodstream infection appear unequivocally to have derived

from a CAUTI; this patient had no symptoms, whatsoever, referrable to the

urinary tract; this was the only infected patient in this study in which an

extended hospital LOS was judged to be attributable to a nosocomial CAUTI

5 D ISCUSSION :

5.1 Pathogenesis of CAUTI:

In this part of the study, using daily paired quantitative urine cultures from the

catheter sampling port and the drainage bag to determine the probable route by

which microorganisms gain access to the catheterized urinary tract, it was

possible to identify the probable mechanism of infection in 69% of 250 distinct

organisms causing 235 CAUTIs The largest proportion of infections were

extraluminally- derived (Table 1.1), a finding consonant with studies using

periurethral cultures or rectal cultures at catheter insertion to ascertain

pathogenesis (Garibaldi et al 1980;Daifuku and Stamm 1984) corroborating the

assumptions of our analysis

While intraluminally-derived infections accounted for the smallest proportion of

determinable cases (Table 1.1), this number is not insignificant, given the

universal emphasis on closed catheter drainage for prevention of CAUTI

(Stamm, 1991; Warren 1991; Kunin 1997,) Open catheter urinary drainage, in

use for centuries, carries an almost universal risk of bacteriuria (Kass 1956;

Guzman et al1991) and, perhaps, a substantial risk of associated

bacteremia.(Guzman et al1991) Closed catheter drainage is universally

regarded as the most important measure for the prevention of nosocomial

CAUTI (Duke 1928) and can delay the onset of catheter-associated bacteriuria

to more than 30 days.(Kunin and McCormack 1966) It has been assumed that

with adoption of closed catheter drainage that the intraluminal route of infection

would diminish and that extraluminally-acquired infections would predominate,

which our study suggests has occurred

In reality, totally closed drainage is probably unattainable Our overall rate of

CAUTI, 15 infections per 100 catheters, is at the low end of seven prior but

similar prospective studies of CAUTI in other centers in which daily urine

cultures were done to accurately determine the true incidence of infection

(Stamm 1991) The number of catheter care violations noted in our

intraluminal-acquired CAUTI group, which would increase the incidence of infection by this

route, did not differ significantly from the other pathogenesis groups, suggesting

that there may well be an irreducible minimum rate of intraluminal CAUTI, given

current technology (without safe and effective valves) and achievable levels of

catheter care (Sanderson 1995) This study illustrates that even with excellent

adherence to accepted principles of catheter care, (overall catheter care score

for the study population 5.8 out of 7, Table 1.2), as long as there remains the

need to periodically drain urine from the collection bag, there will still be ample

opportunities for organisms to gain intraluminal access and ascend into the

bladder

Although Platt et al (1983) showed that use of a catheter with a sealed,

pre-connected catheter-drainage tube junction was associated with a lower

incidence of CAUTI as well as hospital mortality in a large randomized trial,

other investigators have not been able to confirm these findings (Classen et al

1991;Huth et al 1992) In theory, instillation of an antiseptic into the collection

bag or continuous, irrigation of the bladder with an antimicrobial solution should

reduce the risk of CAUTI, but randomized trials of these strategies have been

almost universally disappointing ( Maizels and Schaeffer 1980 ; Gillespie et al

1983 ; Warren et al 1978 ; Thomson et al 1984 ; Ball et al 1987; Classen et al

1991)

This is the first study of the pathogenesis of CAUTI which examined infections

appearing within the first 24 hours after catheter insertion (Table 1.1), which we

believe represent extraluminal introduction of organisms into the bladder at the

time of catheter insertion, probably stemming from failure of periurethral

disinfection or from touch contamination by the person inserting the catheter

Sterile gloves and a long-sleeved surgical gown, as contrasted with the use of

non-sterile gloves alone has been shown to significantly reduce the risk of

central venous catheter-related bacteremia (Mermel et al 1991; Raad et

al1994) Nevertheless, whether the use of maximal sterile barriers would reduce

the incidence of early CAUTI is uncertain; a small randomized trial did not show

differences.(Carapeti et al 1996) Our finding that patients catheterized in the

operating room had a lower incidence of early infections (Table 1 2) suggests

that augmented barrier precautions at insertion may be helpful

The largest proportion (49%) of CAUTIs in which the mechanism could be

determined were late extraluminally-introduced infections, a route long

considered to be the predominant mechanism of microbial entry into the urinary

tract by mass transport in the mucus film adherent to the catheter surface

(Kass and Schneiderman 1957) What is surprising from our data is the finding

that the relative importance of this route was comparable in men and women, in

contrast to the findings of earlier investigators Daifuku and Stamm (1984)

found that of 18 women with CAUTI, 12 had antecedent peri-urethral

colonization and 14, antecedent rectal colonization; only 5 of 17 men had

antecedent rectal or peri-urethral colonization with the infecting microorganism

These investigators concluded that the routes of CAUTI were predominantly

extraluminal in females and intraluminal in males, but did not attempt to confirm

intraluminally-derived infections microbiologically Garibaldi et al (1980)found

that antecedent peri-urethral colonization was a risk factor for CAUTI both in

males and females (8% of colonized males and 22% of colonized females

developed CAUTI vs 2% of non-colonized males and 12% of non-colonized

females) Our data indicate that the extraluminal route is very important in both

men and women It stands to reason that males with heavy meatal

colonization are also at risk However, in males the frequency (Garibaldi et al

1980) and probably the density of meatal colonization is lower and the distance

urethral contaminants must traverse to get to the bladder is greater, thus

accounting for the lower absolute risk of CAUTI in males as compared with

females

Unfortunately, strategies to prevent CAUTI by the extraluminal route, using

antiseptic urethral lubricants (Butler and Kunin 1968; Kunin and Finkelberg

1971; Schiotz 1996), daily meatal cleansing (Burke et al 1983)or topical

antibiotic ointments (Warren et al 1978; Burke et al 1981; Classen et al 1991)

have been disappointing

It has been suggested that the infected catheterized urinary tract harbors

organisms both within the urine itself (“planktonic growth”) as well as in a biofilm

on the surface of the catheter.(Stamm 1991) Our data suggest that enterococci,

staphylococci and yeasts, which have a propensity to form surface

biofilms,(Nickel et al 1994) most often gain access to the bladder by the

extraluminal route whereas gram-negative bacilli are more likely to gain access

intraluminally This hypothesis is supported by our finding that a novel catheter

impregnated with nitrofurazone, which elutes into the lumen of the catheter,

significantly reduced the frequency of infections caused by gram-negative bacilli

but had much less benefit for prevention of infections caused by yeasts,

staphylococci or enterococci.(Maki et al 1997) Moreover, we had also shown

that a novel silver-hydrogel coated catheter, which inhibits microbial adherence

to the external catheter surface, exhibits a significant and durable effect in

preventing CAUTI caused by extraluminally-introduced enterococci,

staphylococci and yeasts but showed no benefit for prevention of infection

caused by gram-negative bacilli, which most often were intraluminally-acquired

(Maki et al 1998)

5.2 Risk factors:

In the first study to prospectively evaluate risk factors for nosocomial CAUTI,

Garibaldi et al (1974) reported 95 CAUTIs in 405 hospitalized patients who

were studied daily Significant risk factors for CAUTI by univariate analysis

included female gender, severity of underlying illness and lack of antibiotics in

the first four days of catheterization Catheter care violations – most notably,

breaks in closed drainage – were identified in 121 (29.9%) of 405 catheterized

patients but were not shown to increase the risk of CAUTI

Since that report, four groups have reported prospective studies of risk

factors for CAUTI in patients cultured daily, using multivariate analysis: Shapiro

et al, (1984) Platt et al, (1986) Johnson et al (1990) and Riley et al.(1995)

Factors found to be associated with an increased risk of CAUTI in one or more

of these studies included prolonged catheterization, female gender, renal

insufficiency, colonisation of urine in the catheter bag, catheter insertion outside

of the operating room,orthopedic or urology service, diabetes, advanced age,

and lack of monitoring of urinary output using a urinometer; and “catheter care

violations” In all of the studies, antimicrobial therapy was associated with a

reduced risk of infection A comparison of the results of the different studies is

at Table 7.1

In our study, as in the previous studies, female gender (OR,3.7), duration

of catheterization (OR,5.2), and exposure to systemic antimicrobial therapy

(OR,0.1 ) were found to be associated with significantly increased or decreased

risk of CAUTI The increased risk in women has long been recognized and can

be ascribed to the shorter female urethra and it’s proximity to the anus and

rectum which are heavily colonized with both uropathogenic and

non-uropathogenic E.coli In a prospective study in which catheterized studies were

cultured daily using a technique capable of detection of very low level

bacteriuria (1 CFU per milliliter), (Stark and Maki 1984) it was found that

isolation of any microorganisms from a specimen aspirated from the lumen of

the catheter, even 3 - 4 per milliliter, was highly predictive of CAUTI: if

intercurrent antimicrobial therapy was not given to the patient, the level of

bacteriuria or candiduria uniformly rose to >105 CFU per mL within 24 - 48

hours, pointing out the extraordinary vulnerability of the catheterized urinary

tract to infection, once any microorganisms gained access to the lumen of the

catheter It seems self-evident that the longer a patient has a urinary catheter

in place, the greater the likelihood of microorganisms gaining access to the

lumen of the catheter With regard to the effect of systemic antimicrobials in

catheterized patients, which has been found in most studies, (Garibaldi et al

1974; Platt et al 1986; Shapiro et al 1984; Johnson et al 1990) including ours,

exposure to antimicrobials clearly keeps the rate of CAUTI lower than it would

otherwise be, but unfortunately selects for the resistant organisms that produce

most nosocomial CAUTIs and comprise the largest reservoir of multi-resistant

nosocomial pathogens in hospitals and nursing homes (Jarlier et al 1992,

Jarvis and Martone 1996) As such, the prophylactic use of antibiotics

specifically for prevention of CAUTI cannot be endorsed

Prior studies (Garibaldi et al 1974; Platt et al 1986; Shapiro et al 1984;

Johnson et al 1990) did not adequately examine the role of host factors in

vulnerability, beyond severity of illness by McCabe-Jackson criteria, advanced

age, chronic renal failure, or diabetes mellitus Using a more quantitative and

widely accepted scoring system for severity of illness (APACHE II) (Knaus et al

1985), we did not find severity of illness to be predictive of CAUTI; however,

diabetes mellitus (OR,2.2) and malnutrition (OR,2.4), as assessed by serum

albumin level, were each independently associated with a significantly

increased risk of CAUTI It is possible that the APACHE score might not be that

relevant for non-ICU patients

An important risk factor found in this study, not examined in previous

studies, is other active nosocomial infections While an association between

CAUTI with candida and invasive nosocomial infections in intensive care unit

patients has been reported (Pittet et al, 1994) our study is the first to

prospectively examine this relationship with a range of microorganisms

Whereas only a small proportion of CAUTIs found in this study were caused by

the same organism identified in other nosocomial infections in the same

patient, this study shows that patients who already have other nosocomial

infections are at significantly increased risk for CAUTI, independent of length of

stay, duration of catheterization or other potential confounding factors It has

recently been shown that risk factors for CAUTI caused by different

multi-resistant organisms, specifically methicillin-multi-resistant Staphylococcus aureus,

vancomycin-resistant enterococci, extended-spectrum

beta-lactamase-producing gram-negative bacilli, Clostridium difficile or Candida are common

between these diverse groups of resistant organisms (Safdar and Maki 2002)

Since most studies (Garibaldi et al 1974, Shapiro et al 1984; Platt et al 1986;

Johnson et al 1990) have shown that the majority of patients developing CAUTI

have received systemic antimicrobial therapy prior to or even up through the

onset of CAUTI, it may not be surprising that there appears to be a strong

association between susceptibility to CAUTI and other active nosocomial

infections