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Consequences of Asymptomatic Bacteriuria in Women With Diabetes Mellitus
Suzanne E. Geerlings, MD, PhD;
Ronald P. Stolk, MD, PhD;
Marielle J. L. Camps, MD;
Patrick M. Netten, MD, PhD;
J. Theo Collet, MD;
Peter M. Schneeberger, MD, PhD;
Andy I. M. Hoepelman, MD, PhD
Arch Intern Med. 2001;161:1421-1427.
ABSTRACT
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Background Women with diabetes mellitus (DM) have asymptomatic bacteriuria (ASB)
more often than women without DM. It is unknown, however, what the consequences
of ASB are in these women.
Objective To compare women with DM with and without ASB for the development of
symptomatic urinary tract infections (UTIs), renal function, and secondary
complications of DM during an 18-month follow-up period.
Methods In this multicenter study we monitored women with DM with and without
ASB for the development of symptomatic UTIs, renal function, and secondary
complications (ie, retinopathy, neuropathy, microvascular, or macrovascular
diseases). Data on the first 18-month follow-up period are presented.
Results At least 1 uncontaminated urine culture was available from 636 women
(258 with type 1 DM and 378 with type 2 DM). The prevalence of ASB at baseline
was 26% (21% for those with type 1 DM and 29% for those with type 2 DM). Follow-up
results were available for 589 (93%) of the 636 women. Of these 589 women,
115 (20%) (14% with type 1 DM and 23% with type 2 DM) developed a symptomatic
UTI. Women with type 2 DM and ASB at baseline had an increased risk of developing
a UTI during the 18-month follow-up (19% without ASB vs 34% with ASB, P = .006). In contrast, there was no difference in the
incidence of symptomatic UTI between women with type 1 DM and ASB and those
without ASB (12% with ASB vs 15% without ASB). However, women with type 1
DM and ASB had a tendency to have a faster decline in renal function than
those without ASB (relative increase in serum creatinine level 4.6% vs 1.5%, P = 0.2).
Conclusion Women with type 2 DM and ASB have an increased risk of developing a
symptomatic UTI than those without ASB.
INTRODUCTION
WOMEN with diabetes mellitus (DM) have asymptomatic bacteriuria (ASB)
more often than women without DM.1-3
In a large multicenter study we recently reported a prevalence of ASB of 26%
in women with DM and of 6% in women without DM.4
Preliminary findings, based on a small patient sample of Harding et al5 showed that women with DM and ASB had a much higher
chance to develop pyelonephritis (and not cystitis) than those without ASB
during a 3-year follow-up period. In a small prospective study of 58 women
without DM but with ASB (1-year follow-up), 18 women (31%) developed a symptomatic
urinary tract infection (UTI).6 In other studies
of patients without DM,7 it was suggested that
ASB can lead to recurrent UTIs8-10
and progressive renal impairment.11-12
It is unknown, however, whether ASB leads to symptomatic UTI and/or a decline
in renal function in patients with DM.2-3
Since DM already is a risk factor for the development of renal function disturbances,
the question arises whether the presence of ASB in patients with DM leads
to a faster decline in renal function.
The aim of the present multicenter study was to compare women with DM
with and without ASB for the development of symptomatic UTIs, renal function,
and secondary complications of DM during an 18-month follow-up period. Since
type 1 DM and type 2 DM are different diseases, we decided to analyze these
2 groups separately and to compare these 2 groups for the aforementioned variables.
PATIENTS, MATERIALS, AND METHODS
PATIENTS
Patients were recruited between October 8, 1996, and September 30, 1997,
from the DM outpatient clinics of the University Hospital, Utrecht (tertiary
care hospital), 3 nonuniversity hospitals (Diakonessenhuis, Utrecht; Bosch
Medicentrum's Hertogenbosch; and Catharina Hospital, Eindhoven, the Netherlands)
and the offices of 7 general practitioners. Patients were asked to participate
(voluntarily) by their treating physician and were enrolled by one of us (S.E.G.).
Inclusion criteria were women with either type 1 DM or type 2 DM who were
aged between 18 and 75 years. Exclusion criteria were as follows: pregnancy,
recent hospitalization or surgery (<4 months), known urinary tract abnormalities,
symptoms of a UTI, or the use of antimicrobial drugs in the previous 14 days.
Approximately 75% of the eligible women participated. There were no differences
in age or in the type and duration of DM between nonparticipating patients
and the final study group. The present study had the approval of the medical
ethical committee of all hospitals and all patients gave written informed
consent. All patients were interviewed at baseline and their medical histories
were obtained from the hospital records using a standardized questionnaire,
including age, type and duration of DM, secondary complications of DM, medication(s),
and the number of UTIs in the previous year. The following laboratory values
were also obtained: glycosylated hemoglobin A1c, serum creatinine,
albumin, glucose, leukocytes, and urinary pH. At least 1 uncontaminated urine
culture was available from 636 women (265 from university hospitals, 347 from
nonuniversity hospitals, and 24 from offices of general practitioners). Of
these women 258 had type 1 DM and 378 had type 2 DM. The prevalence of ASB
at baseline was 26% (21% in those with type 1 DM and 29% in those with type
2 DM).
All patients were given a standard form with a return envelope and asked
to mail the form to one of us (S.E.G.) if they developed a symptomatic UTI
or used antimicrobial agents for any reason during the 18 months after inclusion
in the study. Furthermore, all patients came to the same treating physician
every 3 months after inclusion, who asked the patient if she had developed
a symptomatic UTI or had taken antimicrobial agents in the time between inclusion
and these outpatient clinic visits. The development of secondary complications
(ie, retinopathy, neuropathy, or macrovascular diseases) during the study
period was also recorded by the treating physician. When data discrepancies
were noted, the patient and the general practitioner of the patient were telephoned
to resolve these conflicting findings. Antimicrobial therapy was usually prescribed
by a general practitioner after diagnosing a UTI in symptomatic women by using
urinary diagnostic tests (urine culture or microscopic analysis or leukocyte
esterase on dipstick testing). Finally, one of us (S.E.G.) telephoned all
of the patients (or the general practitioner of the patient when the patient
had moved) for whom follow-up data were incomplete. The glycosylated hemoglobulin
A1c, serum creatinine, and urinary albumin values were determined
at baseline and at the end of the follow-up period.
URINE CULTURE
Two screening methods were used simultaneously at the University Hospital
Utrecht and the St Joseph Hospital: first, a Uricult Dipslide (Orion Diagnostica,
Espoo, Finland) was dipped in freshly voided midstream urine; and second,
a direct preparation was made, meaning that urine was put on a slide and viewed
at x40 magnification. If at least 105 colony-forming units/mL
grew on the Dipslide or 5 leukocytes or more or 10 microorganisms or more
were seen on the slide, the urine sample (stored in the refrigerator) was
plated onto blood agar and MacConkey plates, and the results were read after
24 hours. Causative microorganisms were identified using an automated identification
system (Vitek; BioMérieux, Den Bosch, the Netherlands). All urine samples
were plated in the Bosch Medicentrum and the Diakonessenhuis using quantitative
loops. No results were noted if the plate yielded 3 or more different microorganisms,
and the urine was regarded as contaminated. For the definition of a positive
culture, see the "Definitions" section. The patients and the patients' physicians
were blinded for the culture results.
DEFINITIONS
Asymptomatic bacteriuria was defined as the presence of at least 105 colony-forming units/mL of 1 or 2 of the same microorganisms in a
culture of clean-voided midstream urine from a patient without a fever or
symptoms of a UTI.13
Following the 1985 World Heatlh Organization criteria, we defined DM
as a fasting glucose concentration of at least 7.8 mmol/L (140 mg/dL), or
a 2-hour glucose concentration of at least 11.1 mmol/L (200 mg/dL), or the
use of glucose-lowering medication (tablets or insulin).14
Type 1 DM was defined as the absolute deficiency of insulin secretion15 and according to the data of the treating physician,
measured as the absence of C-peptide, and type 2 DM was the combination of
resistance to insulin action and an inadequate compensatory insulin secretory
response.15
Albumin excretion was measured in 24-hour urine samples and defined
as normoalbuminuria when albumin excretion was less than 30 mg/24 h, microalbuminuria
when albumin excretion was 30 to 300 mg/24 h, and macroalbuminuria when albumin
excretion was 300 mg/24 h or more.
Lower UTI (cystitis) was defined as the report of the presence of dysuria,
frequency, urgency, stranguria, and/or abdominal discomfort. Upper UTI (pyelonephritis)
was defined as the above reports and/or the presence of flank and/or lower
back pain and fever (temperature >38.3°C).16
A history of recurrent UTI (UTI-prone) was defined as a history of at least
3 symptomatic UTIs in the year before study enrollment. The relative increase
in the levels of serum creatinine, albumin, and glycosylated hemoglobulin
was defined as the difference between the values after 18 months and the baseline
values divided by the baseline values multiplied by 100.
STATISTICAL ANALYSIS
Absolute and relative values between baseline and follow-up were compared
between patients with DM with and without ASB, using the t test for continuous variables, the Mann-Whitney test for categorial
variables, and the  2 test for dichotomous variables. Asymptomatic
bacteriuria as a risk factor for the incidence of a UTI was investigated using
a Cox proportional hazards analysis, in which patients were censored when
antimicrobial therapy was started for any reason, which resulted in a hazard
ratio as the approximation of the relative risks. No other controlling variables,
aside from time, were used. We found that age was not a risk factor for the
development of UTI or relative increase of serum creatinine level in this
patient group. Therefore, the analyses were not age-adjusted. All analyses
were performed on the entire study population and on women with type 1 DM
and type 2 DM separately. P<.05 was considered
statistically significant.
RESULTS
STUDY POPULATION
Follow-up results were available for 589 women (93% of the study population).
Reasons for inadequate follow-up included the following: impossibility to
reach the patient (n = 41), known death (n = 4: 2 of cardiovascular causes,
1 of breast carcinoma, and 1 of pneumonia), renal-pancreas transplantation
(n = 1), and patient refusal (n = 1). Clinical characteristics (ie, age, the
percentage of women with type 1 DM, and the percentage of women with ASB at
baseline) between patients with and those without follow-up did not differ
significantly (P>.60). Patients included from the
offices of general practitioners were comparable with the other women with
type 2 DM (mean age, 62.3 years; mean duration of DM, 6.8 years; and mean
baseline serum creatinine level, 84 µmol/L [0.95 mg/dL]; 25% of them
developed a symptomatic UTI during the follow-up period). We did perform the
analyses after excluding these 24 patients, and the results remained essentially
the same. The descriptive characteristics of all women, those with type 1
DM, and those with type 2 DM are listed separately in Table 1. The mean age of all (with and without ASB and with and
without UTI) women with type 1 DM was lower than of all women with type 2
DM (Table 1). Age was a risk factor
for having ASB,4 but not for the development
of symptomatic UTIs (mean age, 51.3 years for all women without UTI and 54.5
years for all women with UTI).
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Table 1. Characteristics of the 589 Women Who Were Followed Up for
18 Months*
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PATIENTS WITH AND WITHOUT ASB
Women with ASB developed UTIs (P = .02) and
received antimicrobial therapy for them more often (P
= .01) during the 18-month follow-up period than women without ASB at the
moment of inclusion. After developing the first symptomatic UTI, no differences
were seen in the number of UTIs between women with and those without ASB at
baseline (P = .40). In contrast to women with type
2 DM (P = .006), no difference in the incidence of
symptomatic UTI was found between women with type 1 DM with and without ASB
(P = 0.8) (Table
2).
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Table 2. Follow-up Characteristics of 589 Women With Type 1 and Type
2 Diabetes Mellitus (DM)*
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It can be expected that women who receive antimicrobial therapy for
reasons other than a UTI may be less prone to a UTI. Because of this, a second
analysis was conducted (Cox proportional hazards model) in which women were
included in the follow-up only until the start of antimicrobial therapy for
any reason. The Cox proportional hazards analysis was used to adjust for differences
in the follow-up time between patients, and to use only the follow-up period
during which the women did not use antimicrobial therapy. The presence of
ASB at baseline increased the risk of UTI incidence in women with type 2 DM
(relative risk = 1.91; 95% confidence interval, 1.21-3.01; P = .005; Figure 1 B), but
disappeared for women with type 1 DM (relative risk = 0.75; 95% confidence
interval, 0.29-1.96; P = .60, Figure 1 A). The figure indicates that the increased risk of UTI
is continued during the follow-up period and starts immediately after the
inclusion of the patients.
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A, Cumulative incidence of symptomatic urinary tract infection (UTI)
during an 18-month follow-up period (x-axis) of women with type 1 DM with
(upper curve) and without (lower curve) asymptomatic bacteriuria (ASB) at
baseline (relative risk = 0.75; 95% confidence interval, 0.29-1.96; P = .60). No patients had UTI symptoms at baseline. Patients were withdrawn
from further follow-up at the moment of UTI incidence or when antimicrobial
treatment was given for any reason. B, Cumulative incidence of symptomatic
UTI during an 18-month follow-up period (x-axis) of women with type 2 DM with
(lower curve) and without (upper curve) ASB at baseline (relative risk = 1.91;
95% confidence interval, 1.21-3.01; P = .005).
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Women with type 1 DM with ASB had a greater relative increase in serum
creatinine level than those without ASB (4.6% vs 1.5%, P = .20) (Table 2). No
differences were demonstrated in renal function development between women
with type 2 DM with and without ASB (6.6% vs 6.1%, P
= .90) (Table 2). Because the
development of microvascular and macrovascular complications may be responsible
for a decrease in renal function, we also analyzed the occurrence of these
complications. Neither the risk of microvascular and macrovascular complications
nor the development of microalbuminuria was increased in women with or without
ASB (P>.40) (Table
2).
FOLLOW-UP RESULTS
Of the total study population (n = 589) (type 1 DM and type 2 DM together),
115 women (20%) (34 women [14%] with type 1 DM and 81 women [23%] with type
2 DM) developed at least 1 symptomatic UTI, and 96 women (83%) (30 women [88%]
with type 1 DM and 66 women [81%] with type 2 DM) of them were given antimicrobial
therapy. The mean number of symptomatic UTIs was 1.9 per patient: 66 patients
developed 1 UTI, 28 patients developed 2 UTIs, 8 patients developed 3 UTIs,
and 12 patients developed 4 or more UTIs. Five of the patients with more than
2 UTIs may have had a relapse, because they developed the next UTI within
2 weeks of the first UTI. The first UTI during follow-up was used in all analyses.
The cystitis-pyelonephritis ratio was 37:1. The mean duration between study
inclusion and development of a UTI was 7 months.
Age was not a risk factor for the development of UTI in the entire study
group and separately in women with type 1 DM or type 2 DM. Age was also not
a risk factor for a faster renal function decline. Women with type 1 DM and
ASB had a greater relative increase in serum creatinine level than those with
type 1 DM without ASB (4.6% vs 1.5%, P = .20) (Table 2).
Other events during the 18-month follow-up period included the following:
antimicrobial therapy for other reasons (54 women [25%] with type 1 DM and
67 women [21%] with type 2 DM), development of retinopathy (12 women [5%]
with type 1 DM and 9 women [3%] with type 2 DM), peripheral neuropathy (7
women [3%] with type 1 DM and 15 women [4%] with type 2 DM), and occurrence
of macrovascular disease (1 woman [1%] with type 1 DM and 10 women [3%] with
type 2 DM).
COMMENT
We compared the development of symptomatic UTIs, renal function, and
secondary complications in women with DM and ASB with those in women with
DM without ASB during an 18-month follow-up period. We found that women with
type 2 DM and ASB have a greater chance of developing a symptomatic UTI than
women with type 2 DM without ASB. Other risk factors for the presence of ASB
at baseline or for the development of a symptomatic UTI during follow-up have
been described in separate articles.4, 17
To our knowledge, this is the largest follow-up study of women with DM with
and without ASB. Others showed no differences in the incidence of UTI development
between 53 patients with DM with ASB and 54 patients with DM without ASB during
a follow-up period of 14 years.18 However,
that study was small and only the development of pyelonephritis (and not cystitis)
was investigated. Regardless, like Semetkowska et al,18
we diagnosed pyelonephritis in a few women (3 women, all without ASB at the
moment of study enrollment).
It has been demonstrated, in a large prospective study of 796 young
women with DM, by Hooton et al,19 that the
presence of symptomatic bacteriuria is associated with a history of recurrent
UTIs. Stamm et al20 described the natural history
of uncomplicated UTI in 51 women without DM who had recurrent UTI (UTI-prone)
during a mean follow-up period of 9.3 years. They diagnosed 770 episodes of
bacteriuria (205 [27%] of these episodes were asymptomatic) and an average
infection rate of 2.6 per patient-year.20 However,
11 (22%) of these women had minor abnormalities visualized on their intravenous
pyelograms. Therefore, they are not representative for all healthy women with
recurrent UTI. In our women with DM who had a UTI, we found a mean incidence
rate of 1.3 symptomatic UTIs per patient-year. Only a few (21%) of our women,
however, had a history of recurrent UTI. Because it has been demonstrated19, 21 that a history of recurrent UTI is
an important risk factor for the development of a UTI, this may explain why
we found a lower incidence rate than Stamm et al.20
It is hypothesized that ASB may develop into symptomatic UTI and cause
renal function disturbances. A study of 104 patients with DM (95 females)
and bacteriuria, who were followed up for a mean period of 44 months after
therapy, showed significantly more events of persistent bacteriuria in women
with microvascular complications (proteinuria or retinopathy), but no differences
in renal function (measured by serum urea nitrogen level) between the 2 groups
at the end of the follow-up period. However, a higher percentage of patients
with persistent bacteriuria did have abnormal pyelograms compared with patients
without such infections.22 Despite the fact
that a pyelogram is not the most adequate way to measure renal function, this
finding may indicate that bacteriuria can lead to renal function disturbances.
The same phenomenon was found in a 5-year follow-up study of ASB in schoolgirls
without DM.11 In that study minimal renal damage
was demonstrated in patients with ASB compared with nonbacteriuric controls.
Furthermore, schoolgirls with ASB had a higher chance of developing asymptomatic
and symptomatic bacteriuria when they became pregnant.11
In concordance with these studies, we found that ASB predisposes to the development
of a UTI. Furthermore, we did not find an increase in the absolute serum creatinine
level during the 18-month follow-up period. Nevertheless, we could demonstrate
a tendency to renal deterioration by measuring the relative increase of serum
creatinine level in women with type 1 DM, which was higher in women with ASB
than in those without ASB (4.6% vs 1.5%, P = .20).
Because no differences were found in the development of secondary complications
between these groups, the deterioration in renal function may be the result
of the ASB and not due to the development of microangiopathy. In contrast,
Freedman23 reviewed retrospective and prospective
studies and found that UTI in the absence of other predisposing factors does
not lead to renal damage. Therefore, since ASB in combination with microangiopathy
may possibly be harmful to the kidney, longer follow-up studies are needed
to investigate whether renal function deteriorates in women with DM and ASB.
We found that ASB leads to symptomatic UTI in women with type 2 DM,
but not in women with type 1 DM. Since symptoms of a UTI are considered as
a sign of inflammation of the urinary tract, it could be that women with type
1 DM have a less adequate inflammatory response (and as a result fewer symptoms)
than women with type 2 DM. Our data show that women with DM and ASB have lower
urinary cytokine concentrations and leukocytes than women without DM with
ASB. Furthermore, we found that women with type 1 DM had a lower secretion
of proinflammatory cytokines after monocyte stimulation compared with women
with type 2 DM or control subjects.24 This
inadequate host response possibly plays a role in the absence of UTI incidence
in women with type 1 DM. However, women with type 1 DM might clear their bacteria
without symptoms more easily than women with type 2 DM. This phenomenon of
bacterial clearance without clinical symptoms was demonstrated in a Polish
study25 where 20 (51%) of the 39 women with
DM and ASB cleared their bacteria without developing symptoms during an 18-month
follow-up period.
The strength of our study is that it is a multicenter study with, to
our knowledge, the largest group of patients with DM, ever described. The
most important limitation of this study is that we did not culture the urine
sample the moment that the patient developed symptoms of a UTI. However, the
Dutch guidelines advise to diagnose a UTI with sediment microscopy or nitrite
test,26 which was performed in 83% of the cases.
Moreover, the diagnosis of a UTI, based on symptoms in the absence of a urine
culture, has also been used in the analyses of the previous mentioned large
prospective study of Hooton et al.19 Other
limitations are that we measured the renal function by serum creatinine level,
which is a commonly used and practical, however not very precise, way to detect
renal deterioration. Furthermore, we do not know if the nonsignificant faster
decline in renal function in women with type 1 DM and ASB is the cause or
the result of the ASB. In other words: Are women with DM and a faster decline
in renal function more susceptible to develop ASB (as another diabetic complication)
or is the decline in renal function the result of the presence of bacteria?
Nevertheless, when it is true that ASB contributes to the development of diabetic
nephropathy, this would have important consequences. Diabetes mellitus now
accounts for 35% of all new cases of end-stage renal disease in the United
States, and persons with DM make up the fastest growing group of renal dialysis
and transplant recipients.27-28
Therefore, longer follow-up studies and also better renal function determinations
(as ongoing in our center) are needed to give a definite answer to this question.
CONCLUSIONS
Women with type 2 DM and ASB had an increased risk of developing a symptomatic
UTI compared with those without ASB. Furthermore, ASB was associated with
a tendency to renal function decline in women with type 1 DM during the 18-month
follow-up period, but we cannot conclude that ASB is associated with the progression
of renal disease in women with type 1 DM.
AUTHOR INFORMATION
| The Diabetes Mellitus Women Asymptomic Bacteriuria Utrecht (DWABU) Study Group
Authors and Physicians
University Hospital, Utrecht: E. W. M. T. ter
Braak, M. C. Castro Cabezas, P. S. van Dam, T. W. van Haeften, J. B. L. Hoekstra,
P. C. Ligtenberg-Oldenburg, H. W. de Valk, H. E. Westerveld, P. M. J. Zelissen. Catharina Hospital, Eindhoven: B. Bravenboer. Diakonessenhuis, Utrecht: J. B. L. Hoekstra, W. M. N. Hustinx. Bosch Medicentrum's Hertogenbosch: K. P. Bouter. The general practitioners from Utrecht: C. L. M. Appelman,
C. P. Bouter, W. H. Eizenga, Y. W. M.Gresnigt, W. van der Kraan, and M. E.
Numans. The general practitioner from Amsterdam:
G. Ijff. The Students From University Hospital, Utrecht: M. Bellaar, M. Kuipers, and R. Jansen. The medical
microbiologist From University Hospital, Utrecht: J. Verhoef. St Joseph Hospital Laboratory, Veldhoven: A. R. Jansz. Diakonessenhuis Laboratory, Utrecht: R. J. A. Diepersloot.
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Accepted for publication December 4, 2000.
This study was supported by a grant (Project No. 95.123) from the Dutch
Diabetes Fund, Amersfoort, the Netherlands.
Presented as a poster (poster session 53.L, number 604) at the 39th
Interscience Conference on Antimicrobial Agents Chemotherapy, San Francisco,
Calif, September 26-29, 1999.
We thank M. Rozenberg-Arska, MD, medical microbiologist, University
Hospital, Utrecht, the Netherlands, for translating the Polish-language articles.
Drs Geerlings, Camps, Netten, and Collet recruited and provided the
follow-up for the study patients. Dr Schneeberger provided microbiological
advice. Dr Geerlings collected data. Drs Geerlings and Stolk performed data
analysis. Dr Hoepelman initiated and supervised the project. Drs Geerlings,
Stolk, and Hoepelman wrote the manuscript. All authors actively participated
in the study (eg, during study meetings and by issuing advice).
Corresponding author: Andy I. M. Hoepelman, MD, PhD, Department of
Internal Medicine, Division of Infectious Diseases and AIDS, Eijkman Winkler
Laboratory for Medical Microbiology, University Hospital, Utrecht, PO Box
85500, F 02.126, 3508 GA Utrecht, the Netherlands, (e-mail:
I.M.Hoepelman{at}digd.azu.nl).
From the Department of Internal Medicine (Drs Geerlings, Collet, and
Hoepelman), Division of Infectious Diseases and AIDS (Drs Geerlings and Hoepelman),
the Julius Center for Patient Oriented Research (Dr Stolk), and the Eijkman
Winkler Laboratory for Medical Microbiology (Dr Hoepelman), University Hospital,
Utrecht; Department of Internal Medicine, Catharina Hospital, Eindhoven (Dr
Camps); Department of Internal Medicine (Dr Netten) and the Laboratory of
Medical Microbiology (Dr Schneeberger), Bosch Medicentrum's Hertogenbosch,
the Netherlands.
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