Efficacy of chlorhexidine bathing for reducing healthcare associated bloodstream infections: a meta-analysis

Abstract

Background

We performed a meta-analysis of randomized controlled trials (RCTs) to determine if daily bathing with chlorhexidine decreased hospital-acquired BSIs in critically ill patients.

Methods

We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases to identify randomized controlled trials that compared daily bathing with chlorhexidine and a control in critically ill patients.

Results

This meta-analysis included five RCTs. The overall incidence of measured hospital-acquired BSIs was significantly lower in the chlorhexidine group compared to the controls 0.69 (95 % CI 0.55-0.85; P < 0.001; I ^sup 2^ = 57.7 %). Gram-positive-induced (RR = 0.49, 95 % CI 0.41-0.58; P = 0.000; I ^sup 2^ = 0.0 %) bacteremias were significantly less common in the chlorhexidine group. The incidence of MRSA bacteremias (RR 0.63; 95 % CI 0.44-0.91; P = 0.006; I ^sup 2^ = 30.3 %) was significantly lower among patients who received mupirocin in addition to chlorhexidine bathing than among those who did not routinely receive mupirocin.

Conclusions

Daily bathing with chlorhexidine may be effective to reduce the incidence of hospital-acquired BSIs. However, chlorhexidine bathing alone may be of limited utility in reduction of MRSA bacteremia; intranasal mupirocin may also be required. This meta-analysis has several limitations. Future large-scale international multicenter studies are needed.

Choi et al. Ann. Intensive Care (2015) 5:31

DOI 10.1186/s13613-015-0073-9

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Web End = Eun Young Choi1, DongAh Park2, Hyun Jung Kim3,4 and Jinkyeong Park5*

Abstract

Background: We performed a metaanalysis of randomized controlled trials (RCTs) to determine if daily bathing with chlorhexidine decreased hospitalacquired BSIs in critically ill patients.

Methods: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases to iden tify randomized controlled trials that compared daily bathing with chlorhexidine and a control in critically ill patients.

Results: This metaanalysis included ve RCTs. The overall incidence of measured hospitalacquired BSIs was sig nicantly lower in the chlorhexidine group compared to the controls 0.69 (95 % CI 0.550.85; P < 0.001; I2 = 57.7 %).

Grampositiveinduced (RR = 0.49, 95 % CI 0.410.58; P = 0.000; I2 = 0.0 %) bacteremias were signicantly less

common in the chlorhexidine group. The incidence of MRSA bacteremias (RR 0.63; 95 % CI 0.440.91; P = 0.006;

I2 = 30.3 %) was signicantly lower among patients who received mupirocin in addition to chlorhexidine bathing

than among those who did not routinely receive mupirocin.

Conclusions: Daily bathing with chlorhexidine may be eective to reduce the incidence of hospitalacquired BSIs.

However, chlorhexidine bathing alone may be of limited utility in reduction of MRSA bacteremia; intranasal mupirocin may also be required. This metaanalysis has several limitations. Future largescale international multicenter studies are needed.

Keywords: Chlorhexidine, Mupirocin, MRSA, Critically ill, Metaanalysis

Background

Up to 2030 % of patients admitted to intensive care units (ICUs) develop a hospital-acquired infection during their ICU stay [1]. Many of these infections are caused by multidrug-resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), limiting the number of antibiotics available for treatment. These infections prolong the length of stay and increase the costs of care and patient morbidity and mortality [2, 3]. Center for Disease Control and Prevention (CDC) recommends hand washing and isolation for precautions, but these strategies are

not easy to achieve the target. Because a lots of health-care persons should be consistent adherence to strategies and continuously sustain [4].

Hospital-acquired infections are preceded by colonization with pathogenic bacteria, and hospital-acquired bloodstream infections (BSIs) often result from the ingress of skin organisms into the bloodstream along vascular catheters or other breaks in skin integrity [5]. Successful eorts to decolonize patients have reduced the rates of these infections. Chlorhexidine is a water-soluble antiseptic preparation with broad activity against Gram-positive and Gram-negative organisms, facultative anaerobes, aerobes, and yeasts [6]. Recent investigations of whole-body skin decolonization with chlorhexidine in critically ill patients have demonstrated reductions in the rates of VRE, MRSA, and Acinetobacter baumannii colonization, and an overall decrease in the incidence of

*Correspondence: [email protected]

5 Department of Critical Care Medicine in Samsung Medical Center, Sungkyunkwan University School of Medicine, # 50, IrwonDong, Gangnamgu, Seoul, Republic of KoreaFull list of author information is available at the end of the article

2015 Choi et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/

Web End =http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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central catheter-associated BSIs [710]. A previous meta-analysis of non-randomized controlled trials (RCTs) suggested that the practice of daily bathing with chlorhexidine decreased hospital-acquired BSIs [11]. Subsequently, some RCTs of daily bathing with chlorhexidine in the ICU have appeared [1214].

Therefore, we conducted a meta-analysis of RCTs to determine whether daily bathing of critically ill patients with chlorhexidine decreases hospital-acquired BSIs compared to patients who received routine bathing.

Methods andstatistics

The methods for including articles and analysis and reporting the results of meta-analyses are specied a priori in a protocol developed based on recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [15]. An ethics review of systematic reviews and meta-analysis studies, such as this study, was not required per our institutional Health Research Ethics Board.

Literature search strategy

We searched the databases of MEDLINE (1948 to August 2014), EMBASE (1980 to August 2014), and the Cochrane Register of Controlled Trials (CENTRAL) of the Cochrane Library (Issue 8, 2014) using the search lter in the Ovid database (SIGN; http://www.sign.ac.uk

Web End =http://www.sign.ac.uk ). The search terms were critical illness, intensive care units, burn units, coronary care units, respiratory care units, intensive care, ICU, infection control, universal precautions, decontamination, surveillance, screening, antisepsis, decolonization, chlorhexidine, Tubulicid, and Sebidin. We also reviewed the bibliographies of relevant review articles to identify additional publications, and searched an international database (http://www.clinicaltrial.gov

Web End =http://www.clinicaltrial.gov ) to identify relevant ongoing or recently completed clinical trials. The search was performed without restriction with respect to language or year of publication. The last date on which a search was conducted was February 18, 2015.

Selection criteria forstudies

Two authors (JP and EYC) independently evaluated the eligibility of all studies to determine whether they met each inclusion criterion. Disagreements between the two evaluators were resolved by discussion and consensus, and with the opinion of a third reviewer (DAP). The eligibility criteria included all of the following: (a) study design, randomized controlled trials; (b) population, adult (>18years old) critically ill patients in the ICU; (c) intervention, comparison between daily bathing with chlorhexidine and a control (daily bathing with soap and water or non-antimicrobial washcloths); and (d) outcomes. The primary outcome was hospital-acquired BSIs,

dened as bloodstream infections detected more than 48h after admission to the unit. The secondary outcomes were the types of reported microorganisms that caused hospital-acquired BSIs detected more than 48 h after admission to the unit and adverse eects of daily bathing with chlorhexidine. Studies that did not provide quantitative data for the meta-analysis were excluded.

Data extraction andquality assessment

Two authors (JP and EYC) independently extracted the data using a standardized form. Only published data were used. The two extractors assessed the quality of the included trials using Cochrane Collaborations tool, and evaluated the risk of bias in randomized trials, which covers selection, performance, detection, attrition, and reporting bias [16]. High quality was dened as satisfying at least six of the seven criteria. We resolved disagreements about data extraction and quality assessment by consensus or by discussion with a third reviewer (DAP).

Statistical analysis

The clinical outcomes in our analysis can be categorized as binary or continuous data. BSIs were quantied as patient-days. One patient-day represents a unit of time during which the services of the institution or facility are used by a patient. Relative risk (RR) and 95% condence interval (CI) were used as the summary eect for a binary outcome, and the standardized mean dierence and 95% CI were used as the summary eect of a continuous outcome. Data were pooled using the MantelHaenszel method. We reported results according to a xed-eects model in the absence of signicant heterogeneity, and to a random-eects model [17] in the presence of signi-cant heterogeneity. We used the random-eects model because it accounts for variation among studies, in addition to sampling error within studies [16]. The appropriateness of pooling data across studies was assessed using Cochranes 2 test and the I2 test for heterogeneity, which measure the inconsistency across the study results and describe the proportion of the total variation in the study estimates that is due to heterogeneity, rather than sampling error. Statistically signicant heterogeneity was considered to be present when P<0.10 and I2>50% [18]. We checked the publication bias as subgroup analysis based on dierences in design, type of control, the number of study sample, concomitant using drug, and so on. We followed the guidelines of the Cochrane Handbook for meta-analysis of randomized controlled studies, and PRISMA criteria were used to evaluate research methodology (Fig.1). Two-sided P values less than 0.05 were considered statistically signicant. Meta-analyses, forest plots, and publication bias analyses were produced using Stata SE 13.1 for Mac (Stata Corp, TX, USA) [19]. We

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Fig. 1 Flowdiagram of the selection criteria. Flow chart explaining the selection of eligible studies included in the metaanalysis

pre-specied the subgroup analysis according to more similar interventions or control groups.

Results

Literature search andstudy selection

Figure1 shows the ow diagram used for study selection. We identied 18,843 citations from electronic databases, and selected 34 potentially relevant publications for a full text assessment. Of these 34 articles, 30 were excluded from this meta-analysis for the following reasons: 18 trials were not randomized controlled trials; 8 trials were only abstracts; and 3 trials [2022] measured other outcome variables. Two trials were duplicates; we included

the most recent trial only [23]. Additionally, we found one study through hand searching under writing a manuscript. Consequently, we included ve studies in the nal analysis [1214, 24, 25].

Characteristics ofthe included studies

All of the trials were prospective, randomized trials, and three of them were crossover trials. One trial was post hoc analyzed after the completion of randomized control. The characteristics of the studies are presented in Table1. Four studies used cloths impregnated with 2% chlorhexidine (the equivalent of 500mg chlorhexidine per cloth) (Sage Products) for decolonization, and a non-antiseptic

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Multicenter, pragmatic cluster

randomized, crossover, con

trolled study

LocationSingle center, USA7 hospitals, USA43 hospitals, USA3 hospitals, FranceSingle center, USA

Study siteTwo 11bed medical ICUsEight ICUs, one BMT unit74 ICUsMedical ICUs5 adult ICUs

Study periodJun 8 to Dec 20, 2005 and Jan

5 to Jun 21, 2006

Daily bathing with 2 % chlorhex

idineimpregnated cloth

Daily bathing with disposable

nonantimicrobial cloths

Contact precautions according

to the usual practice of each

unit

During the chlorhexidine bath

ing period

Clusterrandomized trialMulticenter, placebocon

StudyBleasdale etal. [24]Climo etal. [12]Huang etal. [13]Camus etal. [25]Noto etal. [16]

Study designProspective, 2arm, crossoverMulticenter, clusterran

Aug 2007 to Feb 2009Apr 8, 2010 to Sep 30, 2011Apr 1996 to Jun 1999Jul 2012 to Jul 2013

trolled, randomized, double

blind study

Daily bathing with 4 % chlo

rhexidine soap and daily

intranasal mupirocin

Daily bathing with nonantisep

tic liquid soap

Standard precautions accord

ing to the French recommen

dation

Between the randomization

and the termination date

of study treatments plus an

additional 48 h

Daily bathing with 2 % chlo

rhexidineimpregnated cloth

and twicedaily intranasal

mupirocin

Screening and isolation for

MRSA colonization

Contact precautionsContact precaution policies,

based on the Centers for Dis

ease Control and Prevention

From the third day after ICU

admission through the sec

ond day after ICU discharge

BMTbone marrow transplantation, HCAIhealthcare associated infection, MICUmedical intensive care unit, MRSAmethicillin resistant S. aureus

domized, nonblinded

crossover trial

Daily bathing with 2 %

chlorhexidineimpregnated

cloth

Daily bathing with nonantimi

crobial washcloths

and the intervention period

chlorhexidineimpregnated

cloth

Table 1 Characteristics ofthe included studies

InterventionDaily bathing with 2 %

ComparatorDaily bathing with soap and

water

The period under observationMICU stayBetween the control period

Number of patients

Intervention391397026,0242594852

Comparator445384223,4802564488

Number of patientdays

Intervention221024,902101,603396320,720.5

Comparator221924,98388,222427619,201.5

Other HCAI preventionThe MICU catheter insertion

policy

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groups washed with non-antimicrobial soap to treat hospital-acquired BSI. A subgroup analysis classied by the concentration of chlorhexidine revealed no signicant dierence in hospital-acquired BSI. The pooled RR was 0.82 (95% CI 0.730.92; P<0.001; I2=32.5%)

between 2 % chlorhexidine groups. The pooled RR for reported hospital-acquired BSI was 0.82 (95% CI 0.730.92; P<0.001; I2=32.5%) when a study performed as post hoc analysis in the 1990s was excluded. The pooled

RR for reported hospital-acquired BSI was 0.77 (95% CI 0.650.91; P=0.002; I2=27.1%) when a largest study was excluded.

Of all hospital-acquired BSIs, central catheter-related BSIs were dened as BSIs noted in patients for whom at least one central venous catheter was placed within 48h before detection of the infection. Two studies presented quantitative data [12, 14]; 30 central catheter-related BSI events developed in the chlorhexidine group over 14,824 catheter-days, compared to 65 in the control arm over 14,297 catheter-days. Fixed-eects modeling yielded an RR of 0.44 (95% CI 0.280.67; P<0.001; I2=0.0%).

Secondary outcomesMicroorganisms were isolated frombloodstream infections

In total, 475 microorganisms for 132,678 patient-days in the chlorhexidine group and 543 microorganisms for 119,600 patient-days in the control group were isolated in BSIs (RR 0.73, 95% CI 0.570.93; P=0.001, I2=51.1%).

Four of the ve trials in this meta-analysis reported the isolation of Gram-positive pathogens. Overall BSIs caused by Gram-positive pathogens involved 251 events in 132,678 patient-days with chlorhexidine compared to 351 events for 119,600 patient-days in the controls.Figure 3 summarizes the Gram-positive pathogens isolated. The summary eect of Gram-positive pathogens had a pooled RR of 0.59 (95% CI 0.440.79; P<0.001;I2=46.0%) in a random-eects model. Subgroup analysis yielded more homogeneous results for Gram-positive pathogen-related BSIs. Subgroup analysis of mupirocin use in conjunction with chlorhexidine bathing yielded

Table 2 Risk ofbias assessment forthe randomized controlled studies included inthis meta-analysis

Study Bleasdale etal. [24] Climo etal. [12] Huang etal. [13] Camus etal. [25] Noto etal. [16]

Adequate sequence generation? Low Unclear Low Unclear Low Allocation concealment? Low Low Low Low Low Blinding of participants and personnel? High High Unclear Low High Blinding of outcome assessment? Low High Low Low Low Incomplete outcome data addressed? Low Low Low Low Low Free of selective reporting? Low Low Low Low Low Free of potential bias relevant industrial funding? High High Low High Low

liquid soap was applied as a comparator; and one trial compared 4 % chlorhexidine (Hibiscrub; AstraZeneca, Rueil-Malmaison, France) and non-antiseptic liquid soap. The study size ranged from 2210 to 10,603 patient-days. All of the studies examined adults. A funnel plot for publication bias could not be performed because there were too few trials to analyze with the Egger test.

Risk ofbias inthe included studies

Our assessments of each risk of bias item for each randomized controlled study are summarized in Table 2. Three [1214] of ve trials were quasi-experimental, with limited to no assessment of potential confounding factors. Four studies were cluster-randomized trials. We assessed these studies as being at low risk of allocation concealment. We assessed the study as being high risk of having a funding-related item when there were grants or support from a company. However, when public funding was used, we assessed the studies as low-risk.

Primary outcome: allcause hospitalacquired BSIs

The primary outcome was the overall incidence of measured hospital-acquired BSI; 587 BSI events developed in the chlorhexidine group over 151,879 patient-days, compared to 670 in the control arm over 140,320 patient-days. Fixed-eects modeling yielded an RR of 0.82 (95% CI 0.730.91; P<0.001; I2=20.6%). Figure2 summarizes the primary outcome.

Exploring the heterogeneity

Subgroup analyses of the potential eect of the concomitant use of mupirocin were performed to determine the eects on measured and reported hospital-acquired BSI. Subgroup analysis at the results for hospital-acquired BSI was more homogeneous. Subgroup analysis featuring the concomitant use of intranasal mupirocin yielded a pooled RR of 0.59 (95 % CI 0.510.68; P < 0.001; I2 = 0.0 %). Subgroup analysis classied by the type of control group determined that the pooled RR was 0.68 (95% CI 0.550.85; P=0.001; I2=0.0%) between the

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Fig. 2 The overall incidence of hospitalacquired bloodstream infections. Each eect size is shown with its condence interval (CI) as solid triangle. The overall eect and CI are shown as a diamond with a dotted line indicating its location. Vertical solid line at 1 indicates no treatment eect. MH MantelHaenszel weighted xed eects, D + L randomeects estimate

a pooled RR of 0.69 (95 % CI 0.570.83; P = 0.001; I2=21.6%). There were signicantly fewer MRSA-related

BSIs with chlorhexidine than in the controls (pooled RR 0.64; 95 % CI 0.470.88; P = 0.006; I2 = 0.0 %; Fig. 4). In subgroup analysis by mupirocin use, MRSA-related

BSIs were signicantly fewer in the group featuring concomitant use of intranasal mupirocin and chlorhexidine bathing the chlorhexidine bathing compared to chlorhexidine bathing alone (pooled RR 0.63; 95% CI 0.440.91; P=0.013; I2=30.0%).

Three of the ve trials indicated the isolation of Gram-negative pathogens. The infections caused by Gram-negative pathogens involved 132 of 32,204 patient-days with chlorhexidine compared to 111 of 29,441 patient-days in the controls. The summary eect of Gram-negative pathogens was a pooled RR of 1.09 (95% CI 0.851.40; P=0.51; I2=0.00%) in the xed-eects model.

Three of the ve trials isolated fungal pathogens. There were 73 fungal infections for 32,204 patient-days with chlorhexidine compared to 70 for 29,441 patient-days in the controls. The summary eect of fungal infection

was a pooled RR of 0.83 (95 % CI 0.421.62; P = 0.56; I2=52.1%) in the random-eects model.

Adverse eects: skin rash

Four of the ve studies included in this meta-analysis reported chlorhexidine-related skin rashes as an adverse eect of chlorhexidine. In total, 92 events in the chlorhexidine group developed over 132,678 patient-days compared to 136 events in the control arm over 119,600 patient-days. A random-eects model resulted in an RR of 1.20 (95% CI 0.433.31; P=0.73; I2=56.3%).

Discussion

In this meta-analysis of ve randomized controlled trials, we found that daily bathing with chlorhexidine reduced the development of hospital-acquired BSIs more eectively with the concomitant use of intranasal mupirocin. BSIs caused by Gram-positive cocci in critically ill patients also decreased signicantly. However, chlorhexidine bathing had a limited eect on reducing BSIs caused by MRSA. MRSA-BSIs were signicantly fewer

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Fig. 3 Grampositive bacteria isolated from bloodstream infections. Each eect size is shown with its condence interval (CI) as solid triangle. The overall eect and CI are shown as a diamond with a dotted line indicating its location. Vertical solid line at 1 indicates no treatment eect. MH Man telHaenszel weighted xed eects, D + L randomeects estimate

in only subgroups in the concomitant use of intranasal mupirocin. And, chlorhexidine bathing would be helpful to reduce the incidence of Gram-negative bacteremia and fungemia. The overall incidence of adverse events such as skin rashes was similar between daily bathing with chlorhexidine and the control.

Our data were consistent with those in the meta-analysis reported by OHoro etal. [11] or Derde etal. [26] which indicated efficacy of daily bathing with chlorhexidine in order to decrease hospital-acquired BSIs. OHoro et al. included only 1 RCT [24] and 11 observational studies. They pooled the studies together regardless of study design. We included ve RCTs and removed observational trials. As the previous report, chlorhexidine bathing reduced the development of hospital-acquired BSIs caused by Gram-positive cocci. In recent evidence [11, 26] (not from RCTs) also reported that chlorhexidine bathing eectively prevented MRSA BSIs in critically ill patients. These studies did not distinguish whether eects came from chlorhexidine alone or combination of mupirocin and chlorhexidine. Our results showed some limitations about chlorhexidine bathing alone. In enrolled studies in our meta-analysis, the combination group had studies with higher quality and

larger than chlorhexidine alone group. One study in combination group completed more than 15years ago (1996 1999), several practices that may impact catheter-related BSIs have changed signicantly during those years. Prevention of MRSA seems to require a combination of chlorhexidine and mupirocin. In our results, daily bathing with chlorhexidine did not aect BSI caused by Gram-negative bacteria or fungi. This may be because Gram-negative BSIs often originate from the lung or digestive tract, and are therefore not impacted by the chlorhexidine skin wash.

Our meta-analysis had some limitations. First, it involved a small number of studies, and the ve RCTs in this meta-analysis had various study designs: one of ve trials was a 22 factorial design [25] with other interventions (topical polymyxin and tobramycin) and post hoc analysis. Three trials [1214] of ve trials were crossover or cluster random designs. It may be considerably smaller number of RCT studies when it is assumed that a cluster enrollment. Infection rates are dierent in each ICU. The infection related interventions could be aected by the infection state neighbor patients. Maybe even given these limitations are infection-related design seems to be a cluster randomized controlled trials possess a greater

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Fig. 4 Methicillin resistant S. aureus isolated from bloodstream infections. Each eect size is shown with its condence interval (CI) as solid triangle. The overall eect and CI are shown as a diamond with a dotted line indicating its location. Vertical solid line at 1 indicates no treatment eect. MH MantelHaenszel weighted xed eects, D + L randomeects estimate

advantage. We tried to overcome these limitations according to various study design with multiple sensitivity-test. However, our results were continuously constant.

Second, most of the studies enrolled in this meta-analysis were not high quality due to the open-label study design. Additionally, three of the ve studies could not guarantee blinded studies. The studies for infection were strikingly inuenced by adherence to infection control. It was possible to overestimate the intervention eects. Therefore, caution is needed when interpreting the results. Third, the microorganisms reported were very dierent. One study [25] reported only S. aureus bloodstream infections. For fungi, two studies [13, 24] reported only Candida, one study [12] reported Candida and others, and the other did not report fungi. The results for Gram-negative bacteria came from three of the ve trials. This might contribute to a lack of condence in the results. Fourth, none of studies reported the baseline patient characteristics. We only estimated the similarity between studies or groups based on a low I2 value. Fifth, one [25] of the ve studies used 4 % Hibiscrub soap instead of 2% chlorhexidine cloths. The chlorhexidine of

the soap might have been diluted; lower concentrations of chlorhexidine exert bacteriostatic eects, thus being less eective than chlorhexidine-impregnated cloth bath. To overcome this problem, we performed a subgroup analysis by chlorhexidine concentration, and found no signicant dierence in hospital-acquired BSIs, including those caused by Gram-positive bacteria or MRSA. Sixth, four of the ve studies were performed in the United States and the other was performed in France; thus, the regional environment in the United States could have aected these results. A multinational RCT on this topic is necessary to overcome these limitations.

In conclusion, daily bathing with chlorhexidine was associated with reductions in the rates of measured hospital-acquired BSI without signicant complications in critically ill patients. Daily bathing with chlorhexidine decreased the incidence of Gram-positive bacteremia regardless of mupirocin use. However, chlorhexidine-only bathing may not be entirely eective to decrease MRSA-related hospital-acquired BSIs. We should consider to emergence of resistance when daily chlorhexidine bathing in the ICUs was implemented [27]. Further

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multinational, multicenter RCTs are required to overcome the limitations of the meta-analysis.

Authors contributions

EYC: data acquisition, drafted and revised the manuscript. DAP: interpreted the data and results of the analyses. HJK: interpreted the data and results of the analyses, serial revision. JP: generating the study concept and design, data acquisition and analysis, interpreted the data and results of the analyses, drafted and revised the manuscript, supervised the study. All authors read and approved the nal manuscript.

Take Home message

Daily bathing with chlorhexidine may be eective to reduce the incidence of hospitalacquired BSIs. Chlorhexidine bathing alone may be of limited utility in reduction of MRSA bacteremia; intranasal mupirocin may also be required. Further multinational, multicenter RCTs are required to overcome several limitations of this metaanalysis performed with 5 RCTs which had high risk of blinding bias.

Author details

1 Department of Pulmonary and Critical Care Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea. 2 Office of Health Technology Evaluation, National EvidenceBased Healthcare Collaborating Agency, Seoul, Republic of Korea. 3 Institute for Evidencebased Medicine, The Korean Branch of Australasian Cochrane Center, Seoul, Republic of Korea. 4 Depart ment of Preventive Medicine, College of Medicine, Korea University, Seoul, Republic of Korea. 5 Department of Critical Care Medicine in Samsung Medical Center, Sungkyunkwan University School of Medicine, # 50, IrwonDong, Gangnamgu, Seoul, Republic of Korea.

Compliance with ethical guidelines

Competing interests

The authors declare that they have no competing interests.

Received: 22 July 2015 Accepted: 21 September 2015

References

1. Richards MJ, Edwards JR, Culver DH, Gaynes RP. Nosocomial infections in combined medicalsurgical intensive care units in the United States. Infect Control Hosp Epidemiol. 2000;21(8):5105. doi:http://dx.doi.org/10.1086/501795

Web End =10.1086/501795 .

2. Grundmann H, AiresdeSousa M, Boyce J, Tiemersma E. Emergence and resurgence of meticillinresistant Staphylococcus aureus as a publichealth threat. Lancet. 2006;368(9538):87485.

3. Kreman T, Hu J, Pottinger J, Herwaldt LA. Survey of longtermcare facili ties in Iowa for policies and practices regarding residents with methicillin resistant Staphylococcus aureus or vancomycinresistant enterococci. Infect Control Hosp Epidemiol. 2005;26(10):8115. doi:http://dx.doi.org/10.1086/502498

Web End =10.1086/502498 .

4. Siegel JD, Rhinehart E, Jackson M, Chiarello L. 2007 Guideline for isolation precautions: preventing transmission of infectious agents in health care settings. Am J Infect Control. 2007;35(10 Suppl 2):S65164. doi:http://dx.doi.org/10.1016/j.ajic.2007.10.007

Web End =10.1016/j. http://dx.doi.org/10.1016/j.ajic.2007.10.007

Web End =ajic.2007.10.007 .

5. Davis KA, Stewart JJ, Crouch HK, Florez CE, Hospenthal DR. Methicillin resistant Staphylococcus aureus (MRSA) nares colonization at hospital admission and its eect on subsequent MRSA infection. Clin Infect Dis. 2004;39(6):77682. doi:http://dx.doi.org/10.1086/422997

Web End =10.1086/422997 .

6. Weinstein RA, Milstone AM, Passaretti CL, Perl TM. Chlorhexidine: expand ing the armamentarium for infection control and prevention. Clin Infect Dis. 2008;46(2):27481. doi:http://dx.doi.org/10.1086/524736

Web End =10.1086/524736 .

7. Derde LP, Cooper BS, Goossens H, MalhotraKumar S, Willems RJ, Gniad kowski M, et al. Interventions to reduce colonisation and transmission of antimicrobialresistant bacteria in intensive care units: an inter rupted time series study and cluster randomised trial. Lancet Infect Dis. 2014;14(1):319. doi:http://dx.doi.org/10.1016/s1473-3099(13)70295-0

Web End =10.1016/s14733099(13)702950 .

8. Evans HL, Dellit TH, Chan J, Nathens AB, Maier RV, Cuschieri J. EFfect of chlorhexidine wholebody bathing on hospitalacquired infections

among trauma patients. Arch Surg. 2010;145(3):2406. doi:http://dx.doi.org/10.1001/archsurg.2010.5

Web End =10.1001/ http://dx.doi.org/10.1001/archsurg.2010.5

Web End =archsurg.2010.5 .9. Dixon JM, Carver RL. Daily chlorohexidine gluconate bathing with impregnated cloths results in statistically signicant reduction in central lineassociated bloodstream infections. Am J Infect Control. 2010;38(10):81721.

10. Montecalvo MA, McKenna D, Yarrish R, Mack L, Maguire G, HaasJ, et al. Chlorhexidine bathing to reduce central venous catheter associated bloodstream infection: impact and sustainability. Am J Med. 2012;125(5):50511.

11. OHoro JC, Silva GLM, MunozPrice LS, Safdar N. The efficacy of daily bathing with chlorhexidine for reducing healthcareassociated bloodstream infections: a metaanalysis. Infect Control Hosp Epidemiol. 2012;33(3):25767.

12. Climo MW, Yokoe DS, Warren DK, Perl TM, Bolon M, Herwaldt LA, et al. Eect of daily chlorhexidine bathing on hospitalacquired infection. N Engl J Med. 2013;368(6):53342.

13. Huang SS, Septimus E, Kleinman K, Moody J, Hickok J, Avery TR, et al. Targeted versus universal decolonization to prevent ICU infection. N Eng J Med. 2013;368(24):225565. doi:http://dx.doi.org/10.1056/NEJMoa1207290

Web End =10.1056/NEJMoa1207290 .

14. Noto MJ, Domenico HJ, Byrne DW, Talbot T, Rice TW, Bernard GR, et al. Chlorhexidine bathing and health careassociated infections: a randomized clinical trial. JAMA. 2015;313(4):36978. doi:http://dx.doi.org/10.1001/jama.2014.18400

Web End =10.1001/ http://dx.doi.org/10.1001/jama.2014.18400

Web End =jama.2014.18400 .

15. Moher D, Liberati A, Tetzla J, Altman DG. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. Ann Intern Med. 2009;151(4):2649.

16. Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Col laboration, 2011. http://www.cochrane-handbook.org

Web End =http://www.cochranehandbook.org

17. DerSimonian R, Laird N. Metaanalysis in clinical trials. Control Clin Trials. 1986;7(3):17788.

18. Higgins J, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in metaanalyses. BMJ. 2003;327(7414):55760.

19. Harris R, Bradburn M, Deeks J, Harbord R, Altman D, Sterne J. Metan: xed and randomeects metaanalysis. Stata J. 2008;8(1):328.

20. Popovich KJ, Lyles R, Hayes R, Hota B, Trick W, Weinstein RA, et al. Relation of chlorhexidine gluconate skin concentration to microbial density on skin of critically ill patients bathed daily with chlorhexidine gluconate. Infect Control Hosp Epidemiol. 2012;33(9):889.

21. Sangal V, Girvan EK, Jadhav S, Lawes T, Robb A, Vali L, et al. Impactsof a longterm programme of active surveillance and chlorhexidine baths on the clinical and molecular epidemiology of meticillinresistant Staphylococcus aureus (MRSA) in an intensive care unit in Scotland. Int J Antimicrob Agents. 2012;40(4):32331.

22. MendozaOlazarn S, CamachoOrtiz A, MartnezResndez MF, Llaca Daz JM, PrezRodrguez E, GarzaGonzlez E. Inuence of wholebody washing of critically ill patients with chlorhexidine on Acinetobacter baumannii isolates. Am J Infect Control. 2014;42(8):8748. doi:http://dx.doi.org/10.1016/j.ajic.2014.04.009

Web End =10.1016/j. http://dx.doi.org/10.1016/j.ajic.2014.04.009

Web End =ajic.2014.04.009 .

23. Camus C, Bellissant E, Sebille V, Perrotin D, Garo B, Legras A, et al. Preven tion of acquired infections in intubated patients with the combination of two decontamination regimens. Crit Care Med. 2005;33(2):30714.

24. Bleasdale SC, Trick WE, Gonzalez IM, Lyles RD, Hayden MK, Weinstein RA. Eectiveness of chlorhexidine bathing to reduce catheterassociated bloodstream infections in medical intensive care unit patients. Arch Intern Med. 2007;167(19):20739.

25. Camus C, Sebille V, Legras A, Garo B, Renault A, Le Corre P, et al. Mupirocin/chlorexidine to prevent methicillinresistant Staphylococcus aureus infections: post hoc analysis of a placebocontrolled, randomized trial using mupirocin/chlorhexidine and polymyxin/tobramycin forthe prevention of acquired infections in intubated patients. Infection. 2014;42(3):493502. doi:http://dx.doi.org/10.1007/s15010-013-0581-1

Web End =10.1007/s1501001305811 .

26. Derde LP, Dautzenberg MJ, Bonten MJ. Chlorhexidine body washing to control antimicrobialresistant bacteria in intensive care units: a systematic review. Intensiv Care Med. 2012;38(6):9319. doi:http://dx.doi.org/10.1007/s00134-012-2542-z

Web End =10.1007/ http://dx.doi.org/10.1007/s00134-012-2542-z

Web End =s001340122542z .

27. Pittet D, Angus DC. Daily chlorhexidine bathing for critically ill patients: a note of caution. JAMA. 2015;313(4):3656. doi:http://dx.doi.org/10.1001/jama.2014.18482

Web End =10.1001/jama.2014.18482 .