Clinical Microbiology and Infection 28 (2022) 825e831

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Clinical Microbiology and Infection

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Original article

Effect of antiseptic bathing with chlorhexidine or octenidine on

central lineeassociated bloodstream infections in intensive care
patients: a cluster-randomized controlled trial
Luisa A. Denkel 1, 2, *, Frank Schwab 1, 2, Jo
€ rg Clausmeyer 1, 2, Michael Behnke 1, 2,
Jennifer Golembus , Solvy Wolke , Petra Gastmeier 1, 2, Christine Geffers 1, 2
1, 2 1, 2

1)
Institute of Hygiene and Environmental Medicine, Charit €tsmedizin Berlin, Corporate Member of Freie Universita
e e Universita €t Berlin, Humboldt-
Universita€t zu Berlin and Berlin Institute of Health, Berlin, Germany
2)
National Reference Center for the Surveillance of Nosocomial Infections, Charit e e Universita€tsmedizin Berlin, Corporate Member of Freie Universita
€t
Berlin, Humboldt-Universita €t zu Berlin and Berlin Institute of Health, Berlin, Germany

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: Our study aimed to compare the effect of daily bathing with chlorhexidine, octenidine, or
Received 29 January 2021 water and soap (routine care ¼ control) on central line (CL)eassociated bloodstream infection (CLABSI)
Received in revised form rates in intensive care units (ICUs).
21 December 2021
Methods: A multicentre cluster-randomized controlled trial was done with a 12-month intervention
Accepted 26 December 2021
Available online 11 January 2022
period from February 1, 2017 to January 31, 2018 (octenidine and routine care group) or from June 1, 2017
to May 31, 2018 (chlorhexidine group). Wards were randomly assigned to one of two decolonization
Editor: L. Scudeller regimes or routine care (control). Intervention included daily bathing with 2% chlorhexidine-
impregnated cloths or 0.08% octenidine wash mitts for 12 months, whereas the control group used
Keywords: water and soap (routine care). The primary outcome was incidence density of CLABSI per 1000 CL days.
Antiseptic bathing Poisson regression and generalized estimating equation models were applied.
Chlorhexidine gluconate Results: A total of 72 ICUs with 76 815 patients (22 897 patients in the chlorhexidine group, 25 127 in the
CLABSI octenidine group, and 28 791 in the routine care group) were included. Incidence densities were 0.90
Octenidine dihydrochloride
CLABSI per 1000 CL days (95% CI 0.67e1.19) in the chlorhexidine group, 1.47 (95% CI 1.17e1.81) in the
Prevention
octenidine group, and 1.17 (95% CI 0.93e1.45) in the routine care group. Adjusted incidence rate ratios of
CLABSI were 0.69 (95% CI 0.37e1.22, p ¼ 0.28) in the chlorhexidine group and 1.22 (95% CI 0.54e2.75,
p ¼ 0.65) in the octenidine group (compared with routine care).
Discussion: Antiseptic bathing with 2% chlorhexidine-impregnated cloths and 0.08% octenidine wash
mitts lacks a significant preventive effect on CLABSI rates in ICUs. However, our trial has a high likelihood
of being underpowered because CLABSI rates in the routine care group were approximately 40% lower
than initially assumed. Luisa A. Denkel, Clin Microbiol Infect 2022;28:825
© 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.

Introduction daily antiseptic bathing with chlorhexidine can significantly reduce

Acquisition of bloodstream infection (BSI) including central
lineeassociated BSI (CLABSI) is one of the most critical complica-
tions for intensive care patients [1]. Several meta-analyses and
large-scale randomized controlled trials have demonstrated that
* Corresponding author: Luisa A. Denkel, Charite  Universita
€tsmedizin Berlin,
Institute of Hygiene and Environmental Medicine, Hindenburgdamm 27, 12203,
Berlin, Germany.
E-mail address: luisa.denkel@charite.de (L.A. Denkel).
BSI and CLABSI in intensive care units (ICUs) [2e5]. However, daily
routine use of chlorhexidine raises concerns about the develop-
ment of tolerance to this antiseptic substance [6e8].
Octenidine dihydrochloride is a cationic antiseptic of the
byspiridine class of chemicals, with activity against gram-positive
and gram-negative bacteria [9]. Octenidine shows high antiseptic
efficacy in vitro [10], is known to be well tolerated, and has had no
resistance described to date [6]. Furthermore, octenidine is cost-
efficient, readily available, and widely used for various medical ap-
plications in Europe [11]. However, clinical studies have not

https://doi.org/10.1016/j.cmi.2021.12.023
1198-743X/© 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
826 L.A. Denkel et al. / Clinical Microbiology and Infection 28 (2022) 825e831
answered the question of whether octenidine might be an adequate
alternative to chlorhexidine for prevention of CLABSI in ICUs [12,13].
We conducted a cluster-randomized controlled trial (cRCT) in 72
adult ICUs in Germany and Austria to analyze the effect of daily
bathing with 2% chlorhexidine-impregnated cloths, 0.08% octeni-
dine wash mitts, or water and soap (routine care ¼ control) on ICU-
associated CLABSI rates.
Patients and methods
Ethics approval
This study was performed in line with the principles of the
Declaration of Helsinki. Approval was granted by the institutional
ethical review board (IRB) of Charite  Universita
€tsmedizin Berlin
(02/06/2016, processing number EA1/093/16). A waiver of written
informed consent was granted by the IRB because the study ful-
filled all criteria of a cluster-randomized controlled trial (cRCT).
Trial design and participants
The CLIP-ID (climate and pathogenseimpact of decolonization)
study was a cRCT conducted in 72 ICUs (clusters) in 68 hospitals in
Germany and Austria. Each ICU represented one cluster and was
randomly assigned to one of three study groups. All analyses were
conducted on the ward (cluster) level.
The trial consisted of a 12-month intervention period from
February 1, 2017 to January 31, 2018 (routine care and octenidine
group) or from June 1, 2017 to May 31, 2018 (chlorhexidine group).
The chlorhexidine group started 4 months later owing to difficulties
in the supply chain.
All ICUs invited were required to be participants of ICU-KISS, the
German nosocomial infections surveillance system for ICU patients.
Details on recruitment and eligibility requirements for ICUs
participating in the CLIP-ID trial can be found in Supplementary
appendix.
Interventions
ICUs were randomly assigned either to routine care (control) or
one of two universal decolonization regimes (with chlorhexidine or
octenidine). ICUs following routine care continued to use their
routine non-antiseptic soap (and water) for daily patient care.
Routine-care bathing was permitted with any non-antiseptic soap
(and water). ICUs following universal decolonization with chlor-
hexidine had routine soap exchanged for 2% chlorhexidine-
impregnated cloths (Sage 2% Chlorhexidine Gluconate Cloths)
below the jawline and nonechlorhexidine-containing disposable
cloths above the jawline. ICUs allocated to universal decolonization
with octenidine had routine soap exchanged for 0.08% octenidine
disposable wash mitts (Octenisan, Schülke). For all study groups,
including the routine care group, standard operating protocols
were provided to harmonize bathing procedures (see supplemen-
tary material). It was recommended that bathing be performed by
trained nurses in all groups. Daily bathing was encouraged in all
groups. Protocols recommended that all interventions including
catheter care be continued according to hygiene plans and standard
operating protocols of each ward. Universal decolonization prod-
ucts were applied according to the respective manufacturer's in-
structions. Consumption of one (if necessary, more) package(s) of
antiseptic products per patient and day was recommended. Details
on the intervention bundles and bathing protocols can be found in
supplementary material. Briefly, in the chlorhexidine group, all
(nontreatment) skin care and prophylactic products were required
to be avoided or compatible with chlorhexidine; superficial
wounds and devices were allowed to be cleansed by chlorhexidine
cloths. Use of chlorhexidine-impregnated cloths was strictly
forbidden above the jawline; bathing above the jawline was per-
formed with chlorhexidine-free cloths provided by the manufac-
turer (Stryker/Sage Products). For universal decolonization with
octenidine, no restrictions were placed on skin care or prophylactic
products, and the face and superficial wounds could be cleansed
with octenidine wash mitts. Cleansing of devices with octenidine
wash mitts was not advised.
On-site implementation of the intervention (routine care or
universal decolonization) was done by the ICU personnel respon-
sible for local quality management. All units received education
material on infection control and daily bathing procedures accord-
ing to their group allocation. Education material included printed
material, downloads, and short videos (3 minutes) on step-by-step
instructions and frequently asked questions on routine care or
antiseptic bathing. Posters were put up on the units, and informa-
tion leaflets were provided to inform patients, patients' legal rep-
resentatives, healthcare staff, and visitors about the participation of
the ward in the trial. On-site training was provided by decoloniza-
tion product manufacturers for use of chlorhexidine-impregnated
cloths or octenidine-impregnated wash mitts. Compliance with
universal decolonization was monitored by charting packages of
decolonization products consumed per month and ward. Random
on-site visits by study personnel in each study group were done to
assess protocol adherence.
Adverse events were managed by the treating physicians and
ICU personnel. Details on documentation, on-site training, standard
operating protocols, information/education material, and all
documentation forms are available in the supplementary material.
Outcomes
This cRCT is based on data provided by ICU-KISS [14,15]. Initially,
the trial was planned for the primary outcome of nosocomial pri-
mary BSI (PBSI). In November 2016, the primary outcome of PBSI
was changed to CLABSI to adjust PBSI for the most important risk
factor for BSI: presence of a central line (CL). CLABSI (with any
pathogen) associated with stay in a participating ICU standardized
by CL-days was defined as the new primary outcome. Detailed
definitions of PBSI, including nosocomial CLABSI and device use
rates, can be found in the supplementary material and the ICU-KISS
protocol [15]. Device use rates were defined as number of patient
days with device present divided by number of patient days.
Sample size
Initially, sample size calculation was done for PBSI but was
changed to CLABSI before the intervention started. We powered the
trial for the outcome of nosocomial CLABSI. Further details can be
found in supplementary appendix.
Randomization and masking
Cluster-randomization with wards as clusters was done. Details
are described in supplementary material. Patients, study personnel
(excluding the statistician), and health care personnel (physicians,
nurses, infection control practitioners) were aware of the assigned
bathing strategy. The statistician was blinded, and surveillance of
CLABSI was performed independently from the study.
Statistical analysis
Incidence of CLABSI was defined as the number of newly ac-
quired CLABSI per 100 patients (admissions) during the study
 L.A. Denkel et al. / Clinical Microbiology and Infection 28 (2022) 825e831
period (12 months). Incidence density of CLABSI was defined as the
number of patients with newly acquired CLABSI per 1000 CL days.
For all incidence rates, exact Poisson 95% confidence intervals (CIs)
were calculated. In the descriptive analysis, numbers with per-
centages and (monthly) pooled means and/or medians with inter-
quartile ranges were calculated. The p values were based on c2,
Wilcoxon rank sum or Kruskal Wallis test.
Differences in incidence densities were tested by unadjusted
Poisson regression models. For each outcome, the trial effect was
measured by crude incidence rate ratios that calculated whether
the incidence densities of CLABSI differed significantly between the
intervention groups (chlorhexidine and octenidine group) and the
routine care (control) group.
Primary analyses
The primary analysis was a comparison of the incidence den-
sities of CLABSI with any pathogen between the intervention
groups (chlorhexidine and octenidine group) and the routine care
(control) group in the intervention period. All analyses were con-
ducted on ward (unit) level.
In the multivariable analyses, we compared the outcomes be-
tween the intervention groups (chlorhexidine or octenidine) and
the control group (routine care). We used generalized estimating
equation (GEE) models based on monthly ward-level aggregated
data, with negative binomial distribution and accounting for clus-
tering effects [16]. The GEE offset variable was the logarithmized
number of CL days. The ward-level parameters of rate of mechan-
ical ventilation and patient length of stay in the current month
were determined as possible confounders and considered in all
models. All parameters added one degree of freedom to the model.
The pooled mean for length of stay was calculated as the number of
patient days of units divided by the number of patients of units. The
pooled mean of the mechanical ventilation rate was calculated as
the number of ventilation (via tubus or tracheostoma) days of units
divided by the number of patient days of units (multiplied by 100).
Fig. 1. Flowchart for the intervention period.
827
Subgroup analyses
We performed additional analyses (crude and multivariable) for
the following subgroups: CLABSI with gram-positive bacteria,
CLABSI with coagulase-negative staphylococci (CoNS), CLABSI with
gram-negative bacteria, CLABSI with any pathogen excluding CoNS,
and CLABSI with gram-positive bacteria excluding CoNS.
Sensitivity analyses
We did sensitivity analyses to test the robustness of our data by
excluding the drop out ward in the chlorhexidine group from all
analyses.
All analyses were performed using SPSS 25 (IBM SPSS statistics,
Somer, NY, USA) and SAS 9.3 (SAS Institute, Cary, NC, USA).
Results
The flowchart of recruitment is depicted in Fig. 1. A detailed
description of the recruitment process can be found in the sup-
plementary appendix. In total, 72 ICUs implemented the assigned
intervention. One ICU assigned to decolonization with chlorhexi-
dine withdrew after the intervention started. This unit was
included in the main analysis but excluded from sensitivity
analysis.
There were 76 815 patients included in the trial (Fig. 1, Table 1).
During the intervention period, 108 920 packages of chlorhexidine-
impregnated cloths and 103 561 packages of octenidine wash mitts
were consumed. This represents a consumption of 1.3 packages of
chlorhexidine-impregnated cloths (containing six cloths per pack-
age) and 1.1 packages of octenidine wash mitts (containing 10 wash
mitts) per patient day. Ward characteristics did not differ between
the groups (Table 1 and Table S1). The number of events per trial
outcome and their associated rates per 100 patients or 1000 CL days
during the intervention period (12 months) per group are shown in
Table 1.
828 L.A. Denkel et al. / Clinical Microbiology and Infection 28 (2022) 825e831

Table 1
Characteristics of wards (study population) and outcomes, including comparison of intervention groups to routine care (control) during the intervention period (12 months),
according to the study group (crude analysis, structured by primary and subgroup analyses)

Parameter Description Study group

Chlorhexidine Octenidine Routine care (control)

Patients n 22 897 25 127 28 791

Patient days n 85 135 90 820 103 356
CL days n 54 305 58 656 70 068
ICU n 24 24 24
ICU months n 288 288 288
Type of ICU
Surgical* n (%) 4 (16.7%) 5 (20.8%) 6 (25.0%)
Medical-surgical <400 beds* n (%) 13 (54.2%) 12 (50.0%) 12 (50.0%)
Medical-surgical 400 beds* n (%) 5 (20.8%) 4 (16.7%) 4 (16.7%)
Medical* n (%) 2 (8.3%) 3 (12.5%) 2 (8.3%)
Size of ICU (beds)* Median (IQR) 12.0 (9.5e14.0) 13.5 (10.0e16.0) 12.5 (9.5e17.5)
Type of hospital
Primary/secondary level of care or specialized hospital* n (%) 17 (70.8%) 12 (50.0%) 15 (62.5%)
Tertiary care hospital* n (%) 7 (29.2%) 12 (50.0%) 9 (37.5%)
Size of hospital (beds)* Median (IQR) 349 (249e666) 390 (268e632) 322 (244e588)

Primary analyses

CLABSI with any pathogen n 49 86 82

Incidence Incidence per 100 patients (95% CI) 0.21 (0.14e0.28) 0.34 (0.25e0.42) 0.29 (0.21e0.35)
during intervention period
Incidence compared to routine care (crude analysis) RR (95% CI), p-value 0.73 (0.51e1.03), 0.112 1.20 (0.88e1.62), 0.233 1 ¼ reference
Incidence density (ID) ID per 1000 CL days (95% CI) 0.90 (0.67e1.19) 1.47 (1.17e1.81) 1.17 (0.93e1.45)
ID compared to routine care (crude analysis) IRR (95% CI), p-value 0.77 (0.54e1.10), 0.150 1.25 (0.93e1.70), 0.144 1 ¼ reference

Subgroup analyses

CLABSI with gram-positive bacteria n 28 72 55

ID ID per 1000 CL days (95% CI) 0.52 (0.34e0.75) 1.23 (0.96e1.55) 0.79 (0.59e1.02)
ID compared to routine care (crude analysis) IRR (95% CI), p-value 0.66 (0.42e1.04), 0.070 1.56 (1.10e2.22), 0.013 1 ¼ reference

CLABSI with CoNS n 11 43 26

ID ID per 1000 CL days (95% CI) 0.20 (0.10e0.36) 0.73 (0.53e0.98) 0.37 (0.24e0.564)
ID compared to routine care (crude analysis) IRR (95% CI) p-value 0.55 (0.27e1.10), 0.092 1.96 (1.21e3.22), 0.006 1 ¼ reference

CLABSI with gram-negative bacteria n 12 12 22

ID ID per 1000 CL days (95% CI) 0.22 (0.11e0.39) 0.21 (0.11e0.36) 0.31 (0.20e0.48)
ID compared to routine care IRR (95% CI), p-value 0.70 (0.35e1.42), 0.328 0.65 (0.32e1.32), 0.233 1 ¼ reference

CLABSI with any pathogen excluding CoNS n 38 43 56

ID ID per 1000 CL days (95% CI) 0.70 (0.49e0.96) 0.73 (0.53e0.99) 0.80 (0.60e1.04)
ID compared to routine care (crude analysis) IRR (95% CI), p-value 0.88 (0.58e1.32), 0.531 0.92 (0.62e1.36), 0.673 1 ¼ reference

CLABSI with gram-positive bacteria excluding CoNS N 17 29 29

ID ID per 1000 CL days (95% CI) 0.31 (0.18e0.50) 0.49 (0.33e0.71) 0.41 (0.28e0.50)
ID compared to routine care (crude analysis) IRR (95% CI), p-value 0.76 (0.42e1.38), 0.365 1.19 (0.71e2.00), 0.501 1 ¼ reference

CLABSI with MDRO

MRSA n 0 2 0
VRE n 1 3 7
MDR GNO n 3 0 1

CLABSI, central lineeassociated bloodstream infection; CL, central line; CoNS, coagulase-negative staphylococci; ID, incidence densities per 1000 CL days; IRR, crude incidence
rate ratio calculated by Poisson regression; ICU, intensive care unit; IQR, interquartile range; MDR GNO, multi-drug-resistant gram-negative organisms; MDRO, multi-drug-
resistant organisms; MRSA, methicillin resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococci.
* P-values are not shown because there were no significant differences between the three study groups.

Primary analyses Subgroup analyses

For CLABSI with any pathogen, incidence densities were 0.90
CLABSI per 1000 CL days (95% CI 0.67e1.19) in the chlorhexidine
group, 1.47 (95% CI 1.17e1.81) in the octenidine group, and 1.17 (95%
CI 0.93e1.45) in the routine care group (Table 1, Fig. 2(A)). In the
crude analysis, no significant differences were detected when
comparing the chlorhexidine and octenidine group with routine
care (Table 1). The same was true for adjusted incidence rate ratios
of CLABSI with any pathogen when applying GEE models to
compare the intervention groups with routine care (Table 2).
For CLABSI with gram-positive bacteria, incidence densities are
visualized in Fig. 2(B). The crude incidence rate ratios were 0.66
(95% CI 0.42e1.04, p ¼ 0.07) in the chlorhexidine group and 1.56
(95% CI 1.10e2.22, p ¼ 0.01) in the octenidine group compared with
routine care (Table 1). Similar observations were made for CLABSI
with CoNS (Table 1). However, in the multivariable analyses, no
significant differences were detected between intervention groups
and routine care (Table 2). In all study groups, two thirds of CLABSI
were caused by gram-positive bacteria including CoNS (Table 1).
 L.A. Denkel et al. / Clinical Microbiology and Infection 28 (2022) 825e831 829

Incidence densities of CLABSI with any pathogen excluding
CoNS per study group are shown in Fig. S1. For CLABSI with gram-
negative bacteria, CLABSI with any pathogen excluding CoNS and
CLABSI with gram-positive bacteria excluding CoNS, crude and
adjusted incidence rate ratios showed no significant differences
between the intervention groups and routine care (Tables 1 and 2).
All results were stable after exclusion of the drop out ward (data not
shown).
Adverse events (all mild) occurred in 81 patients (0.35%) treated
with chlorhexidine and 12 patients (0.04%) treated with octenidine.
Discussion
Our cRCT found no significant differences in CLABSI rates be-
tween the intervention groups (chlorhexidine and octenidine
group) and the routine care group during the intervention period.
Chlorhexidine-impregnated cloths and octenidine wash mitts were
very well tolerated by patients.
The significant preventive effect of chlorhexidine on CLABSI
rates found in previous studies could not be confirmed by our trial
[3,17e20]. However, negligible effects of chlorhexidine bathing
have been observed before (e.g. by a cluster randomized cross over
trial with low CLABSI rates at baseline) [21]. Furthermore, we could
not confirm the promising results of previous clinical studies on
octenidine [12,13].
This is the first multicentre cRCT examining two different anti-
septic bathing regimes, chlorhexidine and octenidine, to prevent
CLABSI in ICUs. However, our work has some limitations. First, there
is a high likelihood that our study was underpowered to find a 40%
reduction in CLABSI rates with antiseptic bathing. Sample size
calculations based on ICU-KISS data at that time assumed an inci-
dence of 0.5 CLABSI per 100 patients as the mean during the study
period. However, in the routine care group of this trial, the inci-
dence of CLABSI accounted for only 60% of the incidence initially
assumed (0.3 CLABSI per 100 patients). Considering the lower
incidence of CLABSI observed, a sample size of 44.316 patients per
study group and 132.949 patients in total would have been required
to show a 40% reduction. Second, the intracluster correlation co-
efficient to account for greater similarity of data within wards than
between wards was applied from patient-based models and might
have been underestimated (at 0.0003) for our trial [22]. Third, only
the statistician was blinded. Because the effectiveness of antiseptic
bathing should be tested under real-life conditions, patients, health
care staff, and study personnel (excluding the statistician) were
aware of the study allocation. However, study outcomes were
assessed within the course of ICU-KISS independently from the

Fig. 2. Incidence densities of CLABSI with any pathogen (A) and CLABSI with gram-positive bacteria (B) by study group. Monthly pooled means (bold lines) and pooled means (thin
lines) during the intervention period were depicted for each study group: chlorhexidine (blue dashed lines); octenidine (red dashed lines); and routine care group (control, green
solid lines). CLABSI, central line associated bloodstream infections; CL, central line; PM, pooled means.
830 L.A. Denkel et al. / Clinical Microbiology and Infection 28 (2022) 825e831

Table 2
aIRR of intervention groups versus routine care (control) group during intervention period for the outcomes of CLABSI with any pathogen, CLABSI with gram-positive bacteria,
CLABSI with CoNS, CLABSI with gram-negative bacteria, CLABSI with any pathogen excluding CoNS, and CLABSI with gram-positive bacteria excluding CoNS

Outcome Covariates/Category aIRR 95% CI p-value p-value (Type III)

Primary analysis

CLABSI with any pathogen

Routine care (control) 1 ¼ reference

Chlorhexidine 0.69 0.37e1.29 0.249 0.277
Octenidine 1.22 0.54e2.75 0.628 0.649
Mechanical ventilation use (per 1%) 1.01 0.99e1.02 0.374 0.409
Length of stay (per 1 day) 1.03 0.96e1.11 0.431 0.464

Subgroup analyses

CLABSI with gram-positive bacteria

Routine care (control) 1 ¼ reference

Chlorhexidine 0.58 0.29e1.13 0.110 0.129
Octenidine 1.46 0.61e3.51 0.394 0.472
Mechanical ventilation use (per 1%) 1.00 0.99e1.01 0.962 0.964
Length of stay (per 1 day) 1.05 0.97e1.13 0.244 0.248

CLABSI with CoNS

Routine care (control) 1 ¼ reference

Chlorhexidine 0.45 0.17e1.22 0.118 0.132
Octenidine 1.99 0.61e6.44 0.253 0.400
Mechanical ventilation use (per 1%) 1.01 1.00e1.03 0.110 0.151

CLABSI with gram-negative bacteria

Routine care (control) 1 ¼ reference

Chlorhexidine 0.61 0.22e1.72 0.349 0.403
Octenidine 0.68 0.25e1.86 0.450 0.495
Mechanical ventilation use (per 1%) 1.01 0.99e1.03 0.424 0.438
Length of stay (per 1 day) 1.05 0.94e1.17 0.382 0.448

CLABSI with any pathogen excluding CoNS

Routine care (control) 1 ¼ reference

Chlorhexidine 0.85 0.35e2.04 0.707 0.722
Octenidine 0.83 0.35e1.98 0.671 0.693
Mechanical ventilation use (per 1%) 1.00 0.99e1.02 0.755 0.759
Length of stay (per 1 day) 1.02 0.94e1.11 0.655 0.668

CLABSI with gram-positive bacteria excluding CoNS

Routine care (control) 1 ¼ reference

Chlorhexidine 0.74 0.25e2.20 0.592 0.622
Octenidine 0.96 0.36e2.58 0.934 0.935
Mechanical ventilation use (per 1%) 0.99 0.97e1.01 0.373 0.407
Length of stay (per 1 day) 1.05 0.95e1.16 0.377 0.366

All analyses were adjusted for mechanical ventilation use and length of stay. aIRR, adjusted incidence rate ratios; CLABSI, central line associated bloodstream infection; CoNS,
coagulase-negative staphylococci.

study. Fourth, we did not collect individual patient data but only
aggregated data at the ICU level. Thus, potential confounders
including age, sex, comorbidities, central line insertion site, and
individual central line care were not assessed and could not be
considered in statistical analyses. However, the rate of mechanical
ventilation, which represents an important surrogate of disease
severity, was considered in our analysis and did not differ among
the study groups. Fifth, although consumption and daily use of
antiseptic bathing was documented by health care staff and addi-
tional occasional visits by study personnel on the wards were
conducted, the quality of chlorhexidine and octenidine application
to the skin and adherence to the study protocols were not assessed.
However, the high consumption of antiseptic products (1.3 pack-
ages of chlorhexidine-impregnated cloths and 1.1 packages of
octenidine wash mitts per patient day) suggests good compliance.
Furthermore, owing to delivery difficulties by the manufacturer, the
intervention period in the chlorhexidine group started 4 months
later than in the octenidine and routine care group. However,
intervention periods in all groups lasted 12 months; thus, possible
seasonal fluctuations were covered. The primary outcome was
changed from PBSI to CLABSI before the intervention started. We
consider the potential bias that might be caused by using CLABSI
instead of PBSI to be negligible because 97% (n ¼ 217) of 221 PBSI
observed in our trial were associated with CL.
Conclusion
In general, antiseptic bathing with 2% chlorhexidine-
impregnated cloths and 0.08% octenidine wash mitts did not pre-
vent CLABSI in ICUs. Thus, ICU patients might not benefit from these
interventions in settings with low CLABSI rates. However, our trial
has a high likelihood of being underpowered because the incidence
of CLABSI in the routine care group accounted for only 60% of the
incidence initially assumed. Further clinical studies, especially with
octenidine-containing products, are needed for evidence-based
recommendations.
Transparency declaration
The authors declare that they have no conflicts of interest. The
German Ministry of Education and Research (funder) and com-
panies sponsoring products and the investigation of tolerance of
 L.A. Denkel et al. / Clinical Microbiology and Infection 28 (2022) 825e831
chlorhexidine and octenidine by an independent laboratory (Sage
Products/Stryker, Schülke) had no role in study design, data
collection and analysis, data interpretation, the decision to publish,
or the preparation of the manuscript.
The CLIP-ID study was financially supported within the scope of
the InfectControl consortium by the German Federal Ministry of
Education and Research (03ZZ0807A). The (antiseptic) products for
the interventions and the investigation of tolerances of chlorhexi-
dine and octenidine by an independent laboratory were sponsored
by the manufacturers of chlorhexidine-impregnated cloths (Sage
Products/Stryker) and octenidine wash mitts (Schülke). This trial is
registered with the German register for clinical trials (18/08/2016,
number DRKS00010475).
Author contributions
PG and CG supervised, were responsible for the conception of
the study, and handled the funding acquisition. FS, MB, JC, LAD, PG,
CG, SW, and JG were responsible for the methodology. FS, LAD, and
CG handled the formal analysis and investigation. LAD wrote the
original draft preparation. FS, MB, JC, LAD, PG, CG, SW, and JG did
the reviewing and editing. PG was in charge of resources.
Acknowledgements
We thank the physicians, nurses, health care staff, and infection
control practitioners from all participating ICU-KISS units for the
collaboration and their great effort in conducting this trial. We
thank Sage Products/Stryker and Schülke for their support.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.cmi.2021.12.023.
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