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TITLE: Chlorhexidine Gluconate Wipes for Infection Prevention in Acute and Critical Care: A Review of Clinical Effectiveness and Cost-Effectiveness

DATE: 13 April 2016 CONTEXT AND POLICY ISSUES Health care-associated infections are among the most common types of adverse events reported in acute care settings, and the infection rates of difficult-to-treat pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) have steadily and significantly increased over time in Canadian hospitals.1,2 Health care-associated infections can lead to considerable morbidity and mortality; it has been reported that approximately 10% of patients hospitalized for acute care in the United States with health care-associated infections died during their stay.3 Furthermore, management of these infections incurs significant health care costs compounded by lengthier hospital stays; for example, Canadian hospital costs associated with MRSA have been reported at up to $59 million annually.1 Infections are particularly a concern in acute or critical care settings when commonly used medical devices such as catheters provide routes for bacteria to enter the bloodstream. Thus, cleaning skin surfaces prior to procedures that would breach the epithelial barrier or on an ongoing basis at venous access sites provides one strategy to reduce the risk of infection. Chlorhexidine gluconate (CHG) is an antiseptic that can be used on skin and environmental surfaces, and has displayed broad-spectrum activity against several organisms, including multi-drug resistant (MDR) bacteria.3,4 It is available in a variety of formulations and concentrations, such as bulk solution that can be diluted in water or alcohol, and prepackaged, 2% aqueous CHG-impregnated wipes.4 These disposable wipes may offer an advantage over other skin surface decontamination methods, such as bathing with non-antimicrobial soap and water, as a consistent concentration of CHG would be applied that would not need to be rinsed off the skin; it has also been suggested that a residue of antiseptic left on the skin surface could be beneficial.4 Wipes may also enable patients who have difficulty with traditional bathing procedures (e.g., due to physical disability) to optimize reduction of bacteria on skin surfaces before procedures. However, the value of the use of this technology in different hospital units that may have varying endemic bacteria and diverse patient populations with varying clinical statuses is currently unclear, and information regarding the benefit of CHG wipes for infection control would be useful to inform clinical practice and policy.

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 2

The purpose of this report is to review the evidence of clinical- and cost-effectiveness of 2% CHG wipes for infection prevention in acute and critical care settings. RESEARCH QUESTIONS 1. What is the clinical effectiveness of chlorhexidine gluconate wipes for infection prevention

in adults patients in acute care? 2. What is the clinical effectiveness of chlorhexidine gluconate wipes for infection prevention

in adults patients in critical care?

3. What is the cost-effectiveness of chlorhexidine gluconate wipes for infection prevention in adult patients in acute or critical care?

KEY FINDINGS Conflicting evidence on the clinical effectiveness of chlorhexidine gluconate (CHG) wipes for infection prevention in critical care settings was identified from five publications. Based on evidence from systematic reviews of mostly non-randomized trials, the use of 2% CHG-impregnated washcloths appeared to be associated with a reduction in health care-associated infections and bacterial transmission, while two randomized controlled trials suggested that CHG wipes do not provide an advantage over alternative bathing methods with respect to infection prevention. When reported, adverse events associated with CHG wipes were limited to mild skin reactions. Considering the methodological limitations of the evidence from non-randomized trials in particular, results should be interpreted with caution. No evidence regarding the clinical effectiveness of CHG wipes in acute care settings, or cost-effectiveness of CHG wipes in either acute or critical care units, was identified. METHODS Literature Search Methods A limited literature search was conducted on key resources including PubMed, EBSCOhost CINAHL, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2011 and March 15, 2016. Rapid Response reports are organized so that the evidence for each research question is presented separately. Selection Criteria and Methods One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 3

Table 1: Selection Criteria Population Q1: Adult patients in acute care

Q2: Adult patients in critical care (e.g., intensive care unit setting) Q3: Adult patients in acute or critical care

Intervention 2% chlorhexidine gluconate wipes (may also be referred to as impregnated preparation or washcloths)

Comparator • Daily bathing with non-antimicrobial soap and water or bath-in-a-bag wipes

• Routine care • Any active comparator

Outcomes Q1 and Q2: • Clinical effectiveness (e.g., rates of transmission and infection

with antibiotic-resistant organisms [e.g., MRSA, VRE, multidrug-resistant gram-positive bacteria], hospital-acquired infections, length of stay, bloodstream infections)

• Harms (e.g., skin irritation, chlorhexidine resistance) Q3: Cost-effectiveness outcomes

Study Designs Health technology assessments, systematic reviews and meta-analyses, randomized controlled trials, non-randomized studies, economic evaluations

MRSA = methicillin-resistant Staphylococcus aureus; VRE = vancomycin-resistant Enterococcus. Exclusion Criteria Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published prior to 2011. In addition, studies were excluded if the patient population consisted of surgical patients or pregnant women, or if the study comparators were alternative chlorhexidine preparations (e.g., sponge and solution). Critical Appraisal of Individual Studies The included systematic reviews were critically appraised using the AMSTAR instrument,5 while randomized and non-randomized studies were critically appraised using the Downs and Black checklist.6 Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described narratively. SUMMARY OF EVIDENCE Quantity of Research Available A total of 352 citations were identified in the literature search. Following screening of titles and abstracts, 307 citations were excluded and 45 potentially relevant reports from the electronic search were retrieved for full-text review. No potentially relevant publications were retrieved from the grey literature search. Of these potentially relevant articles, 40 publications were excluded for various reasons, while five publications met the inclusion criteria and were included in this report. Appendix 1 describes the PRISMA flowchart of the study selection.

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 4

Additional references of potential interest that did not meet the selection criteria are provided in Appendix 5. Summary of Study Characteristics Five publications were identified for inclusion in this report: two systematic reviews with meta-analyses,7,8 two randomized controlled trials (RCTs),9,10 and one non-randomized study.11 A detailed summary of study characteristics is provided in Appendix 2. Study Design The systematic review by Shah et al.7 included six primary studies published between 2007 and 2013. Four of the six studies with unreported study designs provided data to be pooled in the meta-analysis; two studies had a quasi-experimental design and were excluded from the meta-analysis because the relative risks for the study populations could not be calculated. The literature search for the meta-analysis by O’Horo et al.8 captured studies published up until May 23, 2011. A total of 12 studies conducted between 2005 and 2010 were included in the review, including one RCT and 11 studies with a quasi-experimental design. The open-label RCT by Boonyasiri et al.9 used block randomization to assign patients in groups of four to either the intervention or control groups. The study by Noto et al.10 was a cluster-randomized, controlled crossover study. Each of the five adult intensive care units (ICUs) was randomized at the start of the study to either the intervention or control treatment for 10 weeks followed by a two-week washout period and a crossover to the other treatment; each ICU switched three times, for a total of four 10-week periods of alternating intervention and control treatments. The non-randomized study by Chung et al.11 had an interrupted time series design, in which the outcomes were measured monthly over the 13 month control period and then again over the 11 month intervention period. Country of Origin The two meta-analyses7,8 and one RCT10 were conducted by authors in the United States of America, one RCT9 was conducted in Thailand, and the non-randomized study11 was conducted in South Korea. Patient Population All five publications that met inclusion criteria for this review recruited adult patients admitted to critical care settings. The setting for one study11 was limited to medical ICUs, and the remaining four studies recruited patients from multiple units, including:

• Medical ICUs7-11 • Coronary or cardiac ICUs7-10 • Respiratory care units7,9 • Trauma ICUs7,8,10 • Surgical ICUs7,8,10

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 5

• Bone marrow transplantation units7,8 • Neurological ICUs10

One systematic review8 considered ICU and non-ICU settings; of the 12 included studies, 11 were conducted in various ICUs, and one study was conducted in long-term care acute hospitals. The study conducted in the long-term care acute hospitals evaluated a different preparation of CHG and was not included in the review’s subgroup analysis of 2% CHG-impregnated washcloths. Interventions and Comparators All studies evaluated bathing with 2% CHG-impregnated washcloths; three studies examined commercially prepared 2% aqueous CHG-impregnated cloths manufactured by Sage Products8,10 or GAMA Healthcare,11 one systematic review did not specify the source of the CHG wipes,7 and one study used 2% CHG-impregnated wipes prepared by the study hospital’s pharmacy department but not otherwise described.9 When reported, CHG bathing was performed daily.8-11 One meta-analysis8 included several CHG formulations, but reported a subgroup analysis of 2% CHG-impregnated washcloths (evaluated in seven of 12 studies included in the meta-analysis). Comparators included daily bathing with soap and water,7,8 disposable non-antimicrobial washcloths,7,8,10 non-medicated wet towels,11 or standard of care (not otherwise defined).8 One study compared daily CHG bathing with twice daily bathing with soap and water.9 Outcomes The identified studies evaluated the incidence and prevalence rates of several health care-associated infections, such as: bloodstream infections (BSIs),8 central-line associated bloodstream infections (CLABSIs),7,9,10 ventilator-associated pneumonia (VAP),9,10 catheter-associated urinary tract infections (CAUTIs).9,10 and Clostridium difficile (C. difficile) infections.10 Other outcomes of interest were related to transmission of MDR bacteria, including MDR bacteria-related favourable events (i.e., eradication of bacterial infection or persistently negative bacterial swabs throughout the ICU stay),9 and rates of carbapenem-resistant Acinetobacter baumannii (CRAB).11 Some studies also reported length of stay in the hospital and ICU9,10 and adverse skin reactions.8,9,11 Summary of Critical Appraisal Strengths of both systematic reviews7,8 were related to the comprehensive literature search and duplicate study selection with a reported consensus mechanism. Duplicate data extraction was also performed in one meta-analysis,8 but it was unclear whether this was done in the review by Shah et al.7 In addition, both meta-analyses used appropriate statistical methods to pool results, and reported on the statistical heterogeneity of included studies. However, the review by Shah et al.7 suffered from unclear reporting; patient characteristics of the four studies in the meta-analysis were insufficiently described, making it difficult to assess the clinical similarities or differences, and the appropriateness of pooling data from these studies. The reporting of the study characteristics of the two studies excluded from the meta-analysis and narratively summarized were also minimal. Furthermore, while the authors stated that six studies qualified for inclusion in the critical appraisal, the quality assessments of these included studies were not provided, limiting confidence in the review conclusions based on the study findings. In contrast,

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 6

the systematic review and meta-analysis by O’Horo et al.8 described the characteristics of the individual studies in sufficient detail, and the conclusions acknowledged the limitations of the findings due to their derivation from non-randomized studies. Additional strengths of this review were the statistical and graphical assessment of publication bias, and the provision of funding information and conflict of interest declarations for the individual studies and the review authors.8 Limitations common to both meta-analyses were the lack of an a priori published research objectives or a protocol, as well as the absence of an excluded studies list.7,8 The two RCTs9,10 and the non-randomized study11 were generally reported well, with clearly described study objectives, inclusion and exclusion criteria, interventions, comparators, and main outcomes. Two of the three studies were randomized,9,10 and one RCT9 concealed the random sequence by using sealed, opaque envelopes. The second RCT10 used random number generation to assign treatment groups by unit at the beginning of the study; however, it was not indicated whether this assignment strategy was concealed from the staff at the time of random number generation. The participants were not blinded to the intervention in any of the studies, but the outcome assessors were blinded in the two RCTs.9,10 It was unclear whether outcome assessors in the non-randomized study11 were unaware of the treatment groups; blinding those analyzing data is feasible and would reduce the chance of bias in the direction of the intervention. All three studies were conducted in settings and in conditions that would be representative of usual care for the majority of patients in an ICU, but two studies9,11 excluded patients who were admitted to the ICU for less than 48 hours. While this is reflective of the intent to focus on new, hospital-acquired infections, this may exclude some patients who would still require bathing and who may represent patients with significantly different characteristics than those admitted to an ICU for longer periods of time. Appropriate statistical tests were used in all studies, although there was limited description of patient characteristics in the study by Chung et al.,11 leaving it unclear whether major confounders were considered in the data analysis. The main findings were clearly reported in two studies;10,11 however, one RCT9 presented the infection rate without reporting simple outcome data (e.g., total number of catheter-days per group) or estimates of the variability in the data, which limits interpretation of the results. In addition, patients who died within 48 hours, were missing culture data, or those who transferred to another ward were excluded from the analysis in this study.9 These patients are unlikely to be representative of those remaining in the trial, and it is unclear whether their losses to follow-up were related to the study treatments. Finally, a power calculation was performed for the two RCTs9,10 to determine the number of study patients required to provide at least an 80% chance of detecting a statistically significant difference between groups. Additional details regarding study strengths and limitations are provided in Appendix 3. Summary of Findings Five publications7-11 regarding the clinical effectiveness of CHG wipes for infection prevention in adult patients in a critical care setting met the inclusion criteria for this review. No relevant studies were identified regarding the clinical effectiveness of CHG wipes for infection prevention in adult patients in acute care, or regarding the cost-effectiveness of the use of CHG wipes in acute or critical care settings; therefore, no summary can be provided for these questions. What is the clinical effectiveness of chlorhexidine gluconate wipes for infection prevention in adults patients in critical care?

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 7

The studies included in this review reported results pertaining to rates of health care-associated infections,7-10 MDR bacterial transmission,9,11 length of stay in the hospital and ICU,9,10 and adverse events.8-11 Additional details regarding study findings are provided in Appendix 4. Health care-associated infections Four of the identified studies reported on the acquisition of health care-associated infections, including any BSI8 and CLABSIs in particular,7,9 VAP,9 and CAUTI.9 To account for the potentially rare nature of individual health care-associated infections, one study reported a composite primary outcome including CLABSI, CAUTI, VAP, or C. difficile infection.10 In this study, the expected number of ICU admissions over the study period (approximately 10, 000 patients) would provide at least 95% power to detect a difference in the primary outcome of 0.1 infections per 1,000 patient-days. The results from two meta-analyses showed that the relative risk of CLABSIs or BSIs (including but not limited to CLABSIs) in patients bathed with 2% CHG-impregnated washcloths was 0.417 and 0.468 times that of the control group, respectively; the control groups in these studies represented a mixed selection of comparators including soap and water, non-antimicrobial washcloths, and standard of care (not otherwise described). One of the reviews excluded two studies from the meta-analysis but summarized the results narratively; these study findings supported the meta-analysis results, suggesting that CHG bathing was associated with a decrease in CLABSIs in ICU patients.7 However, a recent RCT that compared daily bathing of ICU patients with 2% CHG-impregnated washcloths with twice daily bathing with soap and water found no significant difference in the incidence of CLABSIs between the two treatment groups.9 Likewise, this study found that there was no difference between groups in the incidence of VAP and CAUTIs.9 The RCT that reported a composite primary outcome across all ICUs (including the surgical unit) also found no significant difference in the composite infection rate between CHG and disposable non-antimicrobial washcloths.10 This result was consistent when individual infection rates were compared between CHG and control groups for the combined ICU population. Furthermore, a subgroup analysis of the primary outcome by ICU confirmed that there was no significant difference in infection rates between treatment groups in any individual unit. MDR bacterial transmission In one RCT,9 the proportion of patients with MDR bacteria-related favourable events appeared to decrease from day 3 to day 14 in both groups (44% to 35% in the control group, 36% to 29% in the CHG group), but there was no significant difference in the number of favourable events between treatment groups at any time point. This study also showed that the overall prevalence of carbapenem-resistant enterobacteriaceae was not significantly different between the CHG (4.8%) and control (4.0%) groups at any time point up to day 14, or at any swab site. The interrupted time series study11 evaluated the rates of CRAB before and after the implementation of daily bathing with 2% CHG-impregnated washcloths in a medical ICU, and found a significant decrease in the CRAB prevalence and incidence density in the CHG bathing period compared with the control period. However, after the initial decreases from the end of the

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 8

control period to the beginning of the CHG period, there was no further reduction in the CRAB prevalence or incidence density levels or trends over the CHG period (11 months). Length of stay Two RCTs reported that daily bathing with 2% CHG-impregnated washcloths had no significant impact on length of stay in either the ICU or the hospital, when compared with a control bathing method.9,10 Adverse events Three studies reported on adverse skin reaction events.8,9,11 One systematic review and meta-analysis8 with an unclear total number of included patients reported that adverse event data was available in six studies. Among the seven studies included in the subgroup analysis of 2% CHG-impregnated washcloths, a total of six patients from three studies had rashes, one of which was possibly related to CHG.8 Adverse event data were not available for the control groups in these studies. One RCT indicated that 2.5% of patients in the CHG group experienced mild skin reactions, while skin reactions were not reported for the control group.9 No adverse skin reactions were reported during the CHG bathing period of the interrupted time series study.11 Among all secondary outcomes analyzed by ICU in the RCT by Noto et al.,10 the unadjusted in-hospital mortality rate in the trauma ICU was the only outcome that was significantly reduced in the CHG group compared with the control group. However, this difference between treatment groups was eliminated after adjustment for the expected mortality rate. Limitations The primary limitation of this review is the lack of identified evidence regarding the clinical effectiveness of CHG wipes in a non-ICU acute care setting, and regarding the cost-effectiveness of CHG wipes in acute or critical care. Furthermore, few primary studies were identified that were conducted in non-surgical settings to be included in this report; both systematic reviews included some studies from surgical ICUs, which may be notable if these patients are anticipated to respond differently to the use of CHG wipes than other ICU patients. One of the three primary studies11 and the majority of studies included in the two systematic reviews7,8 identified for this report were non-randomized before-and-after studies, in which there may be differences beyond the intervention, such as variation in staff practices or patient populations, that could have contributed to the observed differences between the CHG and control groups in these studies. Data from the two RCTs9,10 that randomized patients to CHG or control bathing within the same period of time may be more reliable, and these studies did not observe differences infection rates or MDR bacteria-related events between treatment groups. However, results from these RCTs may also be subject to influence by the structured nature of clinical trials that may differ from real-world clinical practice, or potentially altered staff or patient behaviour in light of study observation. The study by Noto et al.10 was described as a pragmatic effectiveness trial rather than an efficacy trial, meaning that the study treatments were performed as part of routine patient care rather than by research personnel according to a strict study protocol, thereby reducing the risk that results may have been unrealistic due to study design. However, as a result of this pragmatic approach, compliance with the intervention was not assessed and the authors acknowledged that the potential impact of this factor was unknown. In addition, the RCT by Boonyasiri et al.9 compared once daily CHG bathing with twice daily bathing with soap and water; it is unclear whether the lack of observed difference

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 9

between groups was due to the similar clinical effectiveness of the two methods, the potential benefit of increased bathing frequency, both, or another unknown reason. Therefore, results from all studies should be interpreted with caution. The most recent systematic review by Shah et al.7 excluded the RCT by Noto et al.10 from the meta-analysis because it was judged not to meet inclusion criteria regarding study methodology; specifically, the rates of health care-associated infection were low to begin with in that hospital and may not be generalizable to other ICUs. However, Noto et al.10 evaluated a composite primary outcome to account for rare individual infection events and performed a power calculation to increase the likelihood of observing a true difference between groups, suggesting an attempt to address this limitation by study design. It is therefore unclear whether the exclusion of this RCT from the meta-analysis by Shah et al.7 was justified, which is particularly important given the conflicting results reported by these two studies. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING Conflicting evidence on the clinical effectiveness of CHG wipes for infection prevention in critical care settings was identified from five publications. When reported, adverse events associated with CHG wipes were limited to mild skin reactions. No evidence regarding the clinical effectiveness of CHG wipes in acute care settings, or cost-effectiveness of CHG wipes in either acute or critical care units, was identified. The results from two systematic reviews (based primarily on before and after studies)7,8 and one interrupted time series trial11 suggested that 2% CHG-impregnated washcloths are associated with reduced BSIs and bacterial transmission compared with alternative bathing methods; however, these studies were limited by their quasi-experimental design in which the results may have been influenced by confounding variables. The results from two recent RCTs9,10 suggested that there is no difference in the clinical effectiveness of CHG or control bathing methods for patients in several types of ICUs. Considering the methodological advantages of RCTs, one of which had a sample size of over 10,000 patients and was relatively well done, these results may be more trustworthy than those from the three non-RCT publications included in this review. However, it is unclear whether changes in staff or patient behaviour as a result of known observation in the context of a prospective controlled trial, or differences in bathing frequency between intervention and control groups may have influenced the RCT findings. Therefore, firm conclusions about the clinical effectiveness of 2% CHG washcloths based on the studies identified for this review are limited. The patient populations in the identified studies were broad and included any adult patient over 18 years admitted to a variety of ICUs. While a subgroup analysis in the RCT by Noto et al.10 did not identify significant differences between treatment groups in any individual ICU, it is possible that there are differences in patient characteristics, endemic MDR bacteria, or clinical practice considerations specific to particular care units that may influence infection control decisions. Additional evidence from well conducted RCTs in acute care and non-surgical ICU settings is required to support conclusions regarding the clinical effectiveness of CHG wipes for infection prevention. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 10

REFERENCES 1. Patient safety in Ontario acute care hospitals: a snapshot of hospital-acquired infection

control practices [Internet]. Ottawa: Canadian Institute for Health Information; 2008 Oct 30. [cited 2016 Apr 5]. Available from: https://secure.cihi.ca/free_products/PSAF_AIB_2008_10_23_e.pdf

2. Surveillance for methicillin-resistant Staphylococcus aureus in Canadian hospitals - a report update from the Canadian Nosocomial Infection Surveillance Program. Can Commun Dis Rep [Internet]. 2005 Feb 1 [cited 2016 Apr 5];31(3). Available from: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/05vol31/dr3103a-eng.php

3. Raines K, Rosen K. The effect of chlorhexidine bathing on rates of nosocomial infections among the critically ill population: an analysis of current clinical research and recommendations for practice. Dimens Crit Care Nurs. 2016 Mar;35(2):84-91.

4. Vergnano S. Decolonization and decontamination: what's their role in infection control? Curr Opin Infect Dis. 2015 Jun;28(3):207-14.

5. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet]. 2007 [cited 2016 Apr 12];7:10. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdf

6. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health [Internet]. 1998 Jun [cited 2016 Apr 12];52(6):377-84. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdf

7. Shah HN, Schwartz JL, Luna G, Cullen DL. Bathing with 2% chlorhexidine gluconate: evidence and costs associated with central line-associated bloodstream infections. Crit Care Nurs Q. 2016 Jan;39(1):42-50.

8. O'Horo JC, Silva GL, Munoz-Price LS, Safdar N. The efficacy of daily bathing with chlorhexidine for reducing healthcare-associated bloodstream infections: a meta-analysis. Infect Control Hosp Epidemiol. 2012 Mar;33(3):257-67.

9. Boonyasiri A, Thaisiam P, Permpikul C, Judaeng T, Suiwongsa B, Apiradeewajeset N, et al. Effectiveness of chlorhexidine wipes for the prevention of multidrug-resistant bacterial colonization and hospital-acquired infections in intensive care unit patients: a randomized trial in Thailand. Infect Control Hosp Epidemiol. 2016 Mar;37(3):245-53.

10. Noto MJ, Domenico HJ, Byrne DW, Talbot T, Rice TW, Bernard GR, et al. Chlorhexidine bathing and health care-associated infections: a randomized clinical trial. JAMA [Internet]. 2015 Jan 27 [cited 2016 Mar 17];313(4):369-78. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383133

11. Chung YK, Kim JS, Lee SS, Lee JA, Kim HS, Shin KS, et al. Effect of daily chlorhexidine bathing on acquisition of carbapenem-resistant Acinetobacter baumannii (CRAB) in the medical intensive care unit with CRAB endemicity. Am J Infect Control. 2015 Nov 1;43(11):1171-7.

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 11

APPENDIX 1: Selection of Included Studies

307 citations excluded

0 potentially relevant reports retrieved from other sources (grey

literature, hand search)

45 potentially relevant reports

40 reports excluded: ‒ irrelevant study design (1) ‒ irrelevant population (16) ‒ irrelevant intervention (10) ‒ irrelevant comparator (2) ‒ irrelevant outcomes (1) ‒ already included in at least one of the selected

systematic reviews (6) ‒ other (review articles, duplicate publication,

editorials)(4)

5 reports included in review

352 citations identified from electronic literature search and

screened

45 potentially relevant articles retrieved for scrutiny (full text, if

available)

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 12

APPENDIX 2: Characteristics of Included Publications

Table A1: Characteristics of Included Systematic Reviews and Meta-Analyses First Author,

Publication Year, Country

Types and numbers of primary studies

included

Population Characteristics

Intervention Comparator(s) Clinical Outcomes, Length of Follow-

Up Shah, 20167 USA

N = 6 (included in review; 2 with quasi-experimental design); N = 4 (included in meta-analysis; study types NR) Eligible study designs: RCTs, non-randomized controlled trials, pre– and post–quasi-experimental cohort, case-control

Adult patients (number NR) with central lines in adult ICUs (including: medical, coronary, respiratory, surgical, bone marrow transplantation, and trauma ICUs)a

Patient characteristics NR for 2 studies excluded from meta-analysis

2% CHG-impregnated washcloths

Daily bath with soap and water or non–anti-microbial washcloths

CLABSI rate Length of follow-up NR

O’Horo, 20128 USA

N = 12 (1 RCT, 11 quasi-experimental design)

Adult patients in ICUs (11 studies; including: medical, coronary, surgical, bone marrow transplantation, and trauma ICUs), long-term acute care hospitals (1 study)

Daily bathing (11 studies) or twice daily (1 study) bathing with CHG: 2% CHG-impregnated washcloths (7 studies);b CHG liquid solutions (4% or prepared from bulk 4% solution; 5 studies) n = 67,775

Daily bath (11 studies) or twice daily bath(1 study) with soap and water, disposable non-antimicrobial washcloths, or standard of care n = 69,617

Health care-associated BSI rate, including CLABSIs; adverse skin reactions 137,392 patient days reported

BSI = bloodstream infection; CHG = chlorhexidine gluconate; CLABSI = central line-associated bloodstream infection; ICU = intensive care unit; NR = not reported; RCT = randomized controlled trial; USA = United States of America. a Two studies included medical ICUs only; one study included medical ICUs and a respiratory unit; one study enrolled patients from nine different adult ICUs (including medical and surgical ICUs). b Four of seven studies of CHG-impregnated washcloths conducted in medical, trauma, and cardiology ICUs; two of seven conducted in surgical ICUs; one study included mixed (medical and surgical) ICUs.

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 13

Table A2: Characteristics of Included Clinical Studies First Author,

Publication Year, Country, Study

Name

Study Design Patient Characteristics

Intervention(s) Comparator(s) Clinical Outcomes

Boonyasiri, 20169 Thailand

Open-label RCT 1:1 block randomization was used to assign patients in groups of 4 to either the intervention or control groups for each ICU

Adult patients in medical ICU, respiratory care unit, or cardiac care unit for ≥ 48 hours Randomized: n = 481 Analyzed: n = 388

Once daily bathing with 2% CHG-impregnated washcloths n = 189

Twice daily bathing with non-antimicrobial soap and water n = 199

MDRa bacteria-related favourable events (defined as persistently negative swabs throughout ICU admission, or negative swab at a site previously found to be MDR-positive); MDR bacterial colonization; hospital-acquired infections (VAP, CLABSI, CAUTI); length of ICU and hospital stay; adverse skin reactions

Chung, 201511 South Korea

NRS: Interrupted time series design

Adult patients admitted to a medical ICU for ≥ 48 hours

Once daily bathing with 2% CHG-impregnated washcloths Intervention period admissions: n = 1,540

Daily bathing with non-medicated, wet towels Control period admissions: n = 1,514

Prevalence and incidence of CRAB; adverse skin reactions

Noto, 201510 USA

RCT: Cluster-randomized, crossover study Units were randomized to begin with either the

Adult patients admitted to adult ICUs (neurological, surgical, trauma, cardiovascular, medical ICUs)

Once daily bathing with 2% CHG-impregnated washcloths n = 4,488

Daily bathing with disposable non-antimicrobial cloths n = 4,852

Composite primary outcome: CLABSI, CAUTI, possible or probable VAP, or Clostridium difficile infection based on CDC NHSN

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 14

Table A2: Characteristics of Included Clinical Studies First Author,

Publication Year, Country, Study

Name

Study Design Patient Characteristics

Intervention(s) Comparator(s) Clinical Outcomes

intervention or control for 10 weeks followed by a 2 week washout period (bathing with control cloths) before crossing over to the other treatment for 10 weeks. Each unit crossed over 3 times.

Admitted to ICUs during study period: n = 10,783 Analyzed: n = 9,340 (1,443 patients admitted during washout period excluded)

definitions Secondary outcomes: rates of individual infections included for composite primary outcome; in-hospital mortality; length of ICU and hospital stay; health care-associated BSI; primary outcome rate by ICU

BSI = bloodstream infection; CAUTI = catheter-associated urinary tract infection; CDC = Centers for Disease Control and Prevention; CHG = chlorhexidine gluconate; CLABSI = central line-associated bloodstream infection; CRAB = carbapenem-resistant Acinetobacter baumannii; ICU = intensive care unit; MDR = multidrug-resistant; NHSN = National Healthcare Safety Network; NRS = non-randomized study; RCT = randomized controlled trial; USA = United States of America; UTI = urinary tract infection; VAP = ventilator-associated pneumonia. a MDR bacteria included: extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli, ESBL-producing Klebsiella pneumoniae, MDR Pseudomonas aeruginosa, MDR Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci (VRE).

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 15

APPENDIX 3: Critical Appraisal of Included Publications

Table A3: Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR5 Strengths Limitations

Shah, 20167 • Articles were selected for inclusion in duplicate, and a method for

resolving disagreements was described • A comprehensive literature search of multiple databases was

performed, including a review of reference lists in identified articles • Appropriate statistical methods were used to pool results, and an

assessment of heterogeneity was provided

• No a priori published research objectives or protocol described • Unclear whether data were extracted in duplicate • Only published studies were included in the literature search

strategy • Excluded studies list not provided • Study characteristics not sufficiently described for two studies

excluded from meta-analysis • Patient characteristics not described in detail for the four studies

included in the meta-analysis • Quality assessments of individual studies not provided or used

appropriately to form conclusions • Risk of publication bias not assessed • Conflict of interest declarations provided for review authors but not

for individual included studies O’Horo, 20128 • Study selection and data extraction performed in triplicate, and a

method for resolving disagreements was described • A comprehensive literature search of multiple databases was

performed, including a review of reference lists in identified articles • A grey literature search for conference proceedings and data in

clinical trials registers was performed • Characteristics of included studies described in sufficient detail • Quality assessments of individual studies was provided and used

to form conclusions • A random-effects model was appropriately used to pool results,

and an assessment of statistical and clinical heterogeneity was provided

• Likelihood of publication bias was assessed by Egger’s test and displayed with a funnel plot

• Potential conflicts of interest addressed for the review authors and sources of funding reported for individual included studies

• No a priori published research objectives or protocol described • Excluded studies list not provided

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 16

Table A4: Strengths and Limitations of Randomized Controlled Trials and Non-Randomized Studies using the Downs and Black Checklist6

Strengths Limitations Boonyasiri, 20169 – Randomized controlled trial • The study objective was clearly described • Patient inclusion and exclusion criteria are provided • Interventions, comparators, and main outcomes are clearly

described in the methods section • List of principle confounders provided • Adverse events associated with intervention were considered • Actual probability values reported • The staff, places, and facilities where the patients were treated

were representative of the treatment the majority of patients receive

• Outcome assessors were blinded to the patient groupings • Different lengths of follow-up adjusted for using survival analyses • Appropriate statistical tests were used to assess the main

outcomes • Compliance with the intervention was reliable • Main outcome measures were accurate • Patients in both treatment groups were recruited from the same

hospital, over the same period of time • Patients were randomized and treatment allocation was concealed • Power calculation performed

• Total number of catheter-days not reported; main findings represented as a rate per 1,000 catheter-days

• Statistical estimates of variability in the data for the main findings (e.g., confidence intervals) not provided

• Study patients not entirely representative of ICU population (patients admitted for < 48 hours excluded from the study)

• Patients were not blinded to the intervention they received • Not all randomized patients were included in the analysis

Chung, 201511 – Non-randomized study • The study objective was clearly described • Patient inclusion and exclusion criteria are provided • Interventions, comparators, and main outcomes are clearly

described in the methods section • Main findings clearly described • Statistical estimates of variability in the data provided for the main

findings • Adverse events associated with intervention were reported • Actual probability values reported • The staff, places, and facilities where the patients were treated

were representative of the treatment the majority of patients

• Patients in the intervention and control groups were not recruited over the same period of time or randomized (interrupted time series study design)

• Principle confounders not described, and it is unclear whether they were adjusted for in the analysis

• Study patients not entirely representative of ICU population (patients admitted for < 48 hours excluded from the study)

• No attempt was made to blind study patients to the intervention they received or to blind outcome assessors

• Treatment allocation was not concealed • Unclear compliance with the intervention • Power calculation was not performed

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 17

Table A4: Strengths and Limitations of Randomized Controlled Trials and Non-Randomized Studies using the Downs and Black Checklist6

Strengths Limitations receive

• Different lengths of follow-up adjusted for by expressing the outcome as rate per unit time

• Appropriate statistical tests were used to assess the main outcomes

• Main outcome measures were accurate Noto, 201510 – Randomized controlled trial • The study objective was clearly described • Patient inclusion and exclusion criteria are provided • Interventions, comparators, and primary and secondary outcomes

are outlined in the methods section • List of principle confounders provided • Simple outcome data reported for main findings • Statistical estimates of variability in the data provided for the main

findings • Actual probability values reported • All patients admitted to the ICUs during the study period were

included in the study • The staff, places, and facilities where the patients were treated

were representative of the treatment the majority of patients receive

• Outcome assessors were blinded to the treatment assignments • Post-hoc analyses were clearly described • Different lengths of follow-up adjusted for by expressing the

outcome as rate per unit time • Appropriate statistical tests were used to assess the main

outcomes • Main outcome measures were accurate • Patients in both treatment groups were recruited from the same

hospital, over the same period of time • Intention-to-treat analysis used • Power calculation performed

• Minor adverse events potentially associated with chlorhexidine (e.g., skin reactions) not addressed

• Patients were not blinded to the intervention they received • Units were randomized to initial treatment assignment, but this

alternated every 10 weeks, so treatment group allocation was not concealed

• Compliance with the intervention was not specifically measured

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 18

APPENDIX 4: Main Study Findings and Author’s Conclusions

Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions

Systematic Reviews and Meta-analyses Shah, 20167 – Systematic review Meta-analysis results (4 of 6 studies provided data for pooling): • CHG: 124 CLABSIs/17,229 central catheter-

days • Control: 223 CLABSIs/16,565 central

catheter-days • RR for CLABSI with CHG = 0.46 (95% CI,

0.34 to 0.63) • Z score = 4.84, P < 0.0001; heterogeneity: X2

= 1.87, P = 0.6 Narrative results (2 of 6 studies with a quasi-experimental study design): • 2% CHG bathing was associated with a

decrease in CLABSIs in ICU patients.

• Bathing with 2% CHG-impregnated washcloths reduces CLABSIs.

O’Horo, 20128 – Meta-analysis Subgroup analysis for CHG-impregnated washcloths (7 studies): • CHG: 69 BSIs/34,416 patient-days • Control: 171 BSIs/37,399 patient-days • RR for BSI with CHG-impregnated

washcloths = 0.41 (95% CI, 0.25 to 0.65) • Z score = 3.78, P = 0.0002 • Heterogeneity: X2 = 12.80, I2 = 53%

(statistical heterogeneity was moderate, clinical heterogeneity was high)

Adverse events (reported in 3 studies that used CHG-impregnated washcloths): • 6 patients with rashes; 1 possibly related to

CHG

• “In conclusion, existing data—largely obtained, however, from nonrandomized controlled trials—support the practice of daily bathing with CHG for decreasing healthcare-associated BSIs and CLABSIs. This is most convincingly demonstrated in the [medical ICU] population, where most of the studies were undertaken. Further research is needed to determine whether this strategy has a role in other intensive care environments or non-intensive care environments….Future studies should provide data on the characteristics of the patient populations to assess the comparability of treatment and control groups.” Page 266

Primary Clinical Studies Boonyasiri, 20169 – Randomized controlled trial MDR bacteria-related events: • Day 3:

o Favourable events: CHG = 72/165 (43.6%); control = 60/166 (36.1%); P = 0.20

o Bacterial colonization at any site: CHG (n = 189): 32.8%; control (n = 199): 29.1%

• Day 5: o Favourable events: CHG = 46/121

(38.0%); control = 46/119 (38.7%); P > 0.99

o Bacterial colonization at any site: CHG (n = 134): 24.6%; control (n = 149):

• There was no observed benefit of 2% CHG-impregnated washcloths compared with routine twice daily bathing with non-antimicrobial soap regarding any outcome; however; the study was likely underpowered to detect a difference in the rates of hospital-acquired infections.

• The time spent bathing with 2% CHG-impregnated washcloths was less than that of soap and water, costs were low, and health care providers and patients were satisfied with the washcloths. Therefore, 2% CHG-impregnated washcloths may be a suitable alternative method for bathing in the ICU.

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 19

Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions

24.8% • Day 7:

o Favourable events: CHG = 35/86 (40.7%); control = 33/95 (34.7%); P = 0.50

o Bacterial colonization at any site: CHG (n = 101): 21.7%; control (n = 117): 26.5%

• Day 14: o Favourable events: CHG = 10/35

(28.6%); control = 16/46 (34.8%); P = 0.72

o Bacterial colonization at any site: CHG (n = 40): 22.5%; control (n = 61): 26.2%

Incidence of hospital-acquired infections (number per 1,000 catheter-days): • VAP: CHG = 6.1; control = 6.5 (P = 0.74) • CLABSI: CHG = 9.9; control = 7.8 (P = 0.17) • CAUTI: CHG = 6.0; control = 5.7 (P = 0.42) Mean length of stay, days (median; range): • In ICU: CHG = 14.6 (9; 3 – 212); control =

16.5 (10; 3 – 136) • In hospital: CHG = 31.8 (21; 4 – 335); control

= 35.9 (23; 4 – 307) Adverse events: • Rate of skin reactions: CHG = 2.5%; control

NR • All skin reactions mild (grade 1 [faint

erythematous macule or dry skin] and grade 2 [erythematous papule])

Chung, 201511 – Non-randomized study Rates of CRAB: • Prevalence: CHG period = 18.2%; control

period: 25.8% (P = 0.002) • Incidence density (cases per 1,000 patient-

days): CHG period = 21.2; control period: 44.0 (P < 0.001)

• Within the CHG period: o Decrease in the incidence density level

(–0.604; 95% CI, –0.904 to –0.305; P < 0.001)

o No significant change in the incidence density trend over time (0.003; 95% CI, –0.038 to 0.043; P = 0.885).

o No significant difference in the prevalence rate level (–0.213; 95% CI, –0.547 to 0.121; P = 0.212) or prevalence rate trend over time (–0.027; 95% CI, –

• “In conclusion, daily bathing with chlorhexidine-impregnated washcloths significantly reduced acquisition and environmental contamination of CRAB in the medical ICU with CRAB endemicity. Further multicenter, cluster-randomized trials will be needed to evaluate the effect of daily chlorhexidine bathing as a component of an infection prevention bundle in a CRAB endemic setting.” Page 1176

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 20

Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions

0.073 to 0.019; P = 0.249). • Within the control period:

o No significant change in the level or trend over time for prevalence or incidence density.

Adverse events: • No adverse skin reactions reported during

the CHG bathing period. Noto, 201510 – Randomized controlled trial Composite primary outcome (all ICUs; n = 9,340; 39,922 patient-days):a

• Number of infections: CHG period = 55; control period = 60

• Infection rate per 1,000 patient-days: CHG period = 2.86; control period = 2.90

• Rate difference between CHG and control periods = –0.04 (95% CI, –1.10 to 1.01; P = 0.95)

• No significant difference between groups after adjusting for age, sex, race, unit of admission, time, comorbid conditions, outcome; adjusted RR in CHG group = 0.94 (95% CI, 0.65 to 1.37; P = 0.83)

Subgroup analysis of rate difference in primary outcome between groups by ICU:b

• Cardiovascular ICU (n = 1892; 6347.1 patient-days): –1.38 (95% CI, –3.17 to 0.41; P = 0.16)

• Medical ICU (n = 2327; 9120.3 patient-days): –0.64 (95% CI, –2.61 to 1.33; P = 0.52)

• Neurological ICU (n = 1723; 8746.4 patient-days): –0.09 (95% CI, –2.46 to 2.28; P = 0.94)

• Trauma ICU (n = 2126; 7886.1 patient-days): 2.67 (95% CI, –0.36 to 5.70; P = 0.093)

Difference in secondary outcomes by treatment group (all ICUs; rates per 1,000 patient-days):a

• Rate difference of health care-associated BSI: –0.45; 95% CI, –1.87 to 0.97; P = 0.53

• Difference in length of ICU stay: 0.169 (95% CI, –0.01 to 0.321; P = 0.12)

• Difference in length of hospital stay: 0 (95% CI, 0 to 0; P = 0.38)

• In-hospital mortality; n (%): CHG = 367 (8.18%); control = 449 (9.25%): difference = –1.07 (95% CI, –2.2 to 0.07; P = 0.066)

• “In this pragmatic trial, daily bathing with chlorhexidine did not reduce the incidence of healthcare-associated infections including central line-associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, or C. difficile. These findings do not support daily bathing of critically ill patients with chlorhexidine.” Page 9

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 21

Table A5: Summary of Findings of Included Studies Main Study Findings Author’s Conclusions

• No significant difference in rates of individual infections (CLABSI, CAUTI, VAP, C. difficile) between CHG and control groups

Secondary outcomes by ICU: • Trauma ICU had a significant reduction in in-

hospital mortality: CHG = 6.17%; control = 8.58% (difference = –2.41%; 95% CI, –4.64 to –0.19; P = 0.033)

• Trauma ICU in-hospital mortality rate adjusted for University HealthSystem Consortium expected mortality rate: OR = 0.85 (95% CI, 0.51–1.39, P = 0.51)

• No other significant differences by ICU. BSI = bloodstream infection; CHG = chlorhexidine gluconate; CI = confidence interval; CAUTI = catheter-associated urinary tract infection; CLABSI = central line-associated bloodstream infection; CRAB = carbapenem-resistant Acinetobacter baumannii; ICU = intensive care unit; OR = odds ratio; RR = relative risk; UTI = urinary tract infection; VAP = ventilator-associated pneumonia; a Combined results from cardiovascular, medical, neurological, trauma, and surgical ICUs. b Results from surgical ICU not reported.

Chlorhexidine Wipes for Infection Prevention in Acute and Critical Care 22

APPENDIX 5: Additional References of Potential Interest

Previous CADTH Reports Chlorhexidine for the cleansing of contaminated traumatic wounds in the emergency department: clinical effectiveness and guidelines [Internet]. Ottawa: CADTH; 2014 Sep 10 [cited 2016 Apr 12]. Available from: https://www.cadth.ca/sites/default/files/pdf/htis/dec-2014/RB0733%20Traumatic%20Wound%20Cleaning%20Final.pdf Use of chlorhexidine gluconate with alcohol for the prevention of peripheral intravenous device infections: a review of clinical and cost effectiveness, and guidelines [Internet]. Ottawa: CADTH; 2014 Apr 3 [cited 2016 Apr 12]. Available from: https://www.cadth.ca/sites/default/files/pdf/htis/nov-2014/RC0540%20CHXG%20with%20alcohol%20Final.pdf

Chlorhexidine for the prevention of surgical site infections: clinical effectiveness and guidelines [Internet]. Ottawa: CADTH; 2013 Feb 11 [cited 2016 Apr 12]. Available from: https://www.cadth.ca/sites/default/files/pdf/htis/feb-2013/RB0564%20Surgical%20Site%20Infections%20Final.pdf Chlorhexidine impregnated wipes for pre-operative skin preparation: clinical evidence and guidelines [Internet]. Ottawa: CADTH; 2012 Dec 13 [cited 2016 Apr 12]. Available from: https://www.cadth.ca/sites/default/files/pdf/htis/dec-2012/RB0551%20PreOp%20Skin%20Wipes%20Final.pdf Systematic Reviews and Meta-analyses – Mixed Population Afonso E, Llaurado M, Gallart E. The value of chlorhexidine gluconate wipes and prepacked washcloths to prevent the spread of pathogens--a systematic review. Aust Crit Care. 2013 Nov;26(4):158-66.