Journal of Hospital Infection (2008) 70, 15e20

Available online at www.sciencedirect.com

www.elsevierhealth.com/journals/jhin

Costs of nosocomial Clostridium

difficile-associated diarrhoea
R.-P. Vonberg a,*, C. Reichardt a, M. Behnke b, F. Schwab b,
S. Zindler c, P. Gastmeier a
a
Institute for Medical Microbiology and Hospital Epidemiology,
Medical School Hannover, Hannover, Germany
b
Institute for Hygiene and Environmental Medicine, Charité e University Medicine Berlin,
Berlin, Germany
c
Financial Controlling, Medical School Hannover, Hannover, Germany

Received 27 December 2007; accepted 7 May 2008

Available online 7 July 2008

KEYWORDS Summary Nosocomial Clostridium difficile-associated disease (CDAD) is

Clostridium difficile-
associated disease
(CDAD); Nosocomial;
Costs; Caseecontrol
study
a common infection in hospitals. A matched caseecontrol study was
carried out to determine hospital-wide excess costs due to CDAD. Cases were
assessed by prospective hospital-wide surveillance in a tertiary care univer-
sity hospital in 2006. Nosocomial cases of CDAD (>72 h after admission) were
matched to control patients without CDAD in a ratio 1:3 using the same diag-
nosis-related group in the same year, for a hospital stay at least as long as the
time of risk of the CDAD cases before infection and a Charlson comorbidity
index 1. Data on overall costs per case were provided by the finance depart-
ment. Matching was possible for 45 nosocomial CDAD cases. The difference in
the length of stay showed that CDAD cases stayed significantly longer (me-
dian 7 days; P ¼ 0.006) than their matched controls. The average cost per
CDAD patient was V33,840. The difference in the cost per patient showed
that the cost for CDAD patients was significantly more than for their matched
controls (median V7,147; 95% confidence interval: 4,067e9,276). Nosoco-
mial CDAD is associated with high costs for healthcare systems. Clinicians
should be aware of the financial impact of this disease and the application
of appropriate infection control measures is recommended to reduce spread.
ª 2008 The Hospital Infection Society. Published by Elsevier Ltd. All rights
reserved.

* Corresponding author. Address: Institute for Medical Microbiology and Hospital Epidemiology, Medical School Hannover, Carl-
Neuberg-Strasse 1, D-30625 Hannover, Germany. Tel.: þ0049 511 532 4431; fax: þ0049 511 532 8174.
E-mail address: vonberg.ralf@mh-hannover.de

0195-6701/$ - see front matter ª 2008 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.jhin.2008.05.004
16
Introduction
About 10e16% of hospitalised patients are asymp-
tomatic carriers of Clostridium difficile (CD).1e3
During or shortly after antimicrobial treatment
these patients are at risk of developing Clostrid-
ium difficile-associated disease (CDAD).4,5 Most
CDAD cases present with mild symptoms only but
sometimes severe complications may occur.6,7
During clinical illness CDAD cases excrete high
numbers of CD spores that show resistance towards
standard disinfection methods.8e11 Thus CD spores
are likely to be transmitted to other patients and
several nosocomial CD outbreaks are documented
in the medical literature.12e14
Recent data indicate that there is a significant
increase in the incidence of nosocomial CDAD
worldwide, and that this infection has an
enormous financial impact on healthcare
systems.15 We performed a matched caseecontrol
study to quantify the hospital-wide excess costs
due to CDAD.
Methods
Setting
Hannover Medical School is a 1420-bed tertiary
care university hospital that cares for 48 000
inpatients each year. The mean length of hospital
stay in our facility is 8.57 days. Prospective
hospital-wide surveillance of CDAD is performed
by members of the infection control staff immedi-
ately after the report of a new CDAD case from the
microbiology laboratory.
Laboratory diagnosis of CDAD
Diarrhoeal stool samples were processed in the
microbiology laboratory of our facility according
to national guidelines as certified by Deutscher
Akkreditierungs Rat (DIN EN ISO 15189). A com-
mercial enzyme immunoassay (EIA) for the de-
tection of the CD toxins A and B was performed
using monoclonal antibodies according to
the manufacturer’s instructions (RidaScreen,
r-biopharm AG, Darmstadt, Germany). Because
proteolytic damage to toxins may easily occur and
lead to false-negative test results, the diarrhoeal
stool was processed within 24 h of sampling. The
cut-off for a positive test result was defined as
0.15 units above the optical density of the nega-
tive control. In addition, anaerobic culture of
clostridia was performed at 36  C for 2 days on
R.-P. Vonberg et al.
schaedler blood agar (Becton Dickinson, Heidel-
berg, Germany), on cycloserine-cefoxitin fructose
agar (CCFA) 7% horse blood agar selective for CD
(Oxoid, Wesel, Germany) and on serum agar for
light microscopy. Thioglycollate broth was used
at 36  C over 4 days for the enrichment of possible
clostridia and then subcultured onto columbia 5%
sheep blood agar (Becton Dickinson) and schae-
dler blood agar if clostridia had not yet been
found. Species identification was performed by
Gram stain, testing for catalase and oxidase
(Merck, Darmstadt, Germany), indole spot testing
(Genzyme Virotech, Rüsselsheim, Germany),
growth on manganese ion agar [nutrient agar
(Oxoid) supplemented with D-glucose and manga-
nese II sulphate monohydrate (Merck)] for the
induction of sporulation, growth on egg lactose
agar (Heipha, Eppelheim, Germany) by Rapid ID
32 A (bioMérieux, Nürtingen, Germany), and by
the CD latex test kit using rabbit antibodies which
bind specifically to CD surface antigens (Oxoid).
Testing for toxins A and B of culture isolates was
then performed by EIA as described.
Inclusion criteria for case patients
All inpatients of Medical School Hannover were
included as CDAD cases if they had either a positive
EIA or a positive culture for toxin-producing CD
from 1 January to 31 December 2006. Patients
were counted more than once as a CDAD case if
their previous episode of symptomatic illness had
resolved for 48 h and a new episode of CDAD
occurred thereafter.16 Nosocomial acquisition of
CDAD was defined as the onset of symptoms after
hospitalisation for at least 72 h.16 When CDAD
occurred, stopping the current antimicrobial
therapy wherever possible or changing to antimi-
crobial agents that also cover CD was recommen-
ded in our facility.16 Additional treatment of
CDAD by metronidazole may have been
commenced. Oral vancomycin was used less often
for CDAD treatment to minimise selection pressure
for vancomycin-resistant enterococci (VRE). The
following demographic and clinical characteristics
of CDAD cases were assessed: age, sex, medical
department, duration of stay before CDAD (time
of risk), length of hospital stay, length of intensive
care unit (ICU) stay, length of mechanical ventila-
tion, ICD-10 codes, OPS codes [German adaptation
of the International Classification of Procedures in
Medicine (ICPM)], the Charlson comorbidity index,
and the patient’s diagnosis-related group (DRG),
which represents a crucial parameter for
reimbursement by health insurance companies.
Costs of CDAD
Exclusion criteria for case patients
For the calculation of costs we excluded patients
in psychiatry because they do not receive DRG
codes, paediatric patients, and all patients dis-
charged after 31 December 2006 because costs and
charges for patients who remained hospitalised in
2007 were not yet available.
Control patients
Patients without CDAD served as controls for the
calculation of costs and charges due to CD infection.
Controls were matched in a ratio of 1:3 for the same
DRG in 2006, for a hospital stay at least as long as the
time of risk of the CDAD cases before infection, and
for the Charlson comorbidity index 1 as a param-
eter for the severity of underlying disease.17
Acquisition of data on costs
Data on costs for each CDAD case and control
patient were provided from the finance depart-
ment of our hospital. These costs include a general
charge for each day of patient care and some
patient-specific costs, e.g. for certain medical or
surgical procedures and for some expensive drugs.
No differentiation was possible between patient-
specific and non-patient-specific costs.
Statistical analysis
To evaluate the application of matching criteria,
the Wilcoxon test for independent samples and
Fisher’s exact test were used. To evaluate the
difference in length of hospital stay and costs
between matched case and control patients we
calculated the following three parameters for the
matched pairs: the difference in the length of
hospital stay; the difference in costs per patient;
and the difference in costs per patient-day. For all
parameters the median with 95% confidence in-
terval (CI) non-parametric (distribution free) was
calculated. To analyse the parameters we used
non-parametric methods because normal distribu-
tion was rejected by the KolmogoroveSmirnov test.
P < 0.05 or a 95% CI that excludes the zero was con-
sidered significant. Data were analysed by SAS 9.1.
Results
Cases
In the study period a total of 116 CDAD cases was
reported from the microbiology laboratory. None of
17
these had multiple episodes of CDAD. Data on costs
were available for 103 CDAD cases (including 75
nosocomial CDAD cases). The remaining patients
had been discharged within the study period. Cost
calculation could not be performed for patients
who were still hospitalised in the following year.
After matching as described, 45 nosocomial CDAD
cases remained for cost calculation.
Controls
The finance department of our hospital reported
a total of 4702 potential control patients who had
one of the DRGs also present in the CDAD patients.
From these, three control patients were matched to
each single CDAD case as described. The character-
istics of the cases and controls are shown in Table I.
Length of stay
The median hospital stay of CDAD case patients
was 27 days. The difference in the length of stay
showed that CDAD case patients stayed signifi-
cantly longer (median: 7 days; 95% CI: 7e10) than
their matched controls.
Costs
The total cost for the 45 nosocomial CDAD patients
was V2,429,785 (median: V33,840 per CDAD case
patient vs V18,981 per control patient) (Table II).
The difference in the costs per patient showed
that costs for CDAD case patients were signifi-
cantly more than for their matched control
patients (median: V7,147; 95% CI: 4,067e9,276).
Discussion
Nosocomial CDAD is a common complication
associated with the use of antibiotics. The question
of costs due to CDAD has rarely been addressed.
Miller et al. estimated that the overall costs due to
nosocomial CDAD readmissions in 18 Canadian
acute-care hospitals was a minimum of US $85,000
(Can $128,200) per year per facility. However,
they did not calculate costs for the initial hospital
stay, nor did they compare costs for CDAD cases
with control patients without CDAD.18
This study provides data on costs from
a matched caseecontrol study in a tertiary care
hospital. The costs for CDAD cases were increased
by V7,147 (US $10,353) in our study. The median
cost for the 45 CDAD cases was V33,840 (US
$49,022) whereas the median cost for the 135
18 R.-P. Vonberg et al.

Table I Characteristics of cases with nosocomial Clostridium difficile-associated disease (CDAD) and control
patients without disease
Cases (N ¼ 45; 1634 patient-days) Controls (N ¼ 135; 3663 patient-days)
Mean Median Range (IQR) Mean Median Range (IQR)
Age (years) 55.9 56 22e87 (46; 67) 55.5 57 21e86 (45; 70) 0.930a
Days before 19.7 15 3e97 (6; 26) Not applicable e
onset of CDAD
Length of stay 36.3 27 5e117 (18; 47) 27.1 20 3e160 (9; 36) 0.006a
in the hospital
Length of stay on 13.4 3 0e116 (0; 21) 11.6 1 0e127 (0; 17) 0.463a
intensive care unit
Charlson comorbidity 3.8 4 0e8 (2; 5) 3.8 4 0e9 (2; 5) 0.902a
index
Male cases (%) 24 (53.3%) 85 (63.0%) 0.292b
IQR, interquartile range (25th percentile; 75th percentile).
a
Wilcoxon test.
b
Fisher’s exact test.

controls was V18,981 (US $27,497) (Table II). The
difference in the length of stay showed that
CDAD cases stayed significantly longer (median:
27 days; N ¼ 45) than the control patients (median:
20 days, N ¼ 135; P ¼ 0.006) but the difference in
the costs per patient day (median: V56; 95% CI:
e169 to 73) was not significant.
Our findings are in accordance with data from
Spencer and from Wilcox et al. who estimated ex-
tra costs of £4,000 (US $8,130) per CDAD case; with
data from Kyne et al. who determined excess costs
of US $3,669 for one single nosocomial CDAD case;
with data from Kofsky et al. calculating US $3,000
extra costs; and with Spangler et al. who showed
an increase in hospital costs by 38% for nosocomial
CDAD in a DRG-matched caseecontrol study.19e23
Recently Lawrence et al. determined the overall
costs of US $68,036 for a patient with nosocomial
CDAD during his entire hospital stay compared
with US $18,620 for controls without CDAD (3.7-
fold increase; P < 0.001). These data need to be
evaluated with caution. They compared 40 CDAD
cases with 1796 controls but did not match for un-
derlying disease or severity of illness. In their
patient population CDAD patients received anti-
microbial therapy against Gram-positive (100% vs
84%; P ¼ 0.007) and Gram-negative bacteria (98%
vs 85%; P ¼ 0.02) significantly more often. In

Table II Costs and reimbursement for cases with nosocomial Clostridium difficile-associated disease and for
control patients
Cases (N ¼ 45) Controls (N ¼ 135) Median differencea
Median (IQR) mean Median (IQR) mean (95% CI)
Total costs for 2,429,785 6,363,675 NA
the hospital (V)
Costs per patient (V) 33,840 (10,374; 71,345) 53,995 18,981 (6,282; 60,684) 47,138 7,147 (4,067; 9,276)
Costs per 1,110 (676; 1,692) 1,251 1,034 (567; 1,945) 1,392 56 (169; 73)
patient-day (V)
Length of hospital 27 (18; 47) 36 20 (9; 36) 27 8 (7; 10)
stay (days)
Total reimbursement 2,159,922 6,174,213 NA
for the hospital (V)
Average reimbursement 47,998 45,734 NA
per patient (V)
Average financial loss 5,996 1,403 NA
per patient (V)
Average financial loss 165 51 NA
per patient day (V)
IQR, interquartile range (25th percentile; 75th percentile); 95% CI: 95% confidence interval non-parametric (distribution free);
NA, not applicable.
a
Difference between case and control patient by matched pairs.
Costs of CDAD
addition, the CDAD cases required mechanical
ventilation more frequently (85% vs 55%;
P < 0.001) and had a higher percentage of VRE
colonisation or infection (45% vs 16%; P < 0.001).24
Specialties at Medical School Hannover include
solid organ transplantation (heart, lung, liver, and/or
pancreas) and bone marrow transplantation. These
treatments are very expensive. Also, such patients
are often severely immunocompromised, require
antimicrobial treatment and are therefore at high
risk of CDAD acquisition. But even in this ‘expensive’
patient population the differences in the financial
burden between CDAD cases and patients without
CDAD are significant. Since we matched for DRG as
well as for the level of comorbidity, we can exclude
bias due to underlying diseases during the selection
of controls. We also used controls with a hospital stay
at least as long as the ‘time of risk’ for CDAD patients
before their onset of symptoms. As CDAD cases
usually remained in the hospital for several days
after the onset of CDAD, the average length of
hospital stay was longer in CDAD cases than in
controls (36 vs 27 days; Table I). When adjusting costs
per patient day, however, CDAD cases still showed
a more than three-fold increase in the daily financial
loss (V165 vs V51; Table II).
One may also speculate that increased costs for
CDAD may be in part due to infections with a new
hypervirulent CD strain.25 We do not check routinely
for this emerging pathogen and only performed
typing in very severe CDAD cases. The majority of
cases were identified by a positive toxin EIA only.
In this study about 25 cultured strains were typed.
To date this new strain has not been identified in
our hospital. We have observed a marked increase
in the overall incidence of CDAD in our hospital in
recent years, from seven cases in 2002 to 35 cases
in 2004 and 116 cases in 2006.
We conclude from our study that CDAD is associ-
ated with increased costs for hospitals and health-
care systems, mostly deriving from an increased
length of hospital stay. Given the high frequency of
CDAD, efforts should be made to prevent this disease
by using appropriate infection control measures.
Conflict of interest statement
None declared.
Funding sources
None.
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