Risks and benefits of using chlorhexidine gluconate in handwashing: A systematic literature review

State of the Science Review

Risks and beneﬁts of using chlorhexidine gluconate in handwashing:

A systematic literature review

D1X XMarcia Maria Baraldi D2X XRN, MsC

*, D3X XJuliana Rizzo Gnatta D4X XRN, MsC, PhD

, D5X XMaria Clara Padoveze D6X XRN, MsC, PhD

School of Nursing, University of S

ao Paulo and Hospital Alem

ao Oswaldo Cruz S

ao Paulo, S

ao Paulo, Brazil

University Hospital of University of S

ao Paulo, S

ao Paulo, Brazil

Department of Collective Health Nursing, School of Nursing, University of S

ao Paulo, S

ao Paulo, Brazil

Background: Antimicrobial soaps containing chlorhexidine gluconate (CHG) are indicated for hand hygiene

(HH) in speciﬁc situations. This study aimed to identify whether the continuous use of CHG for HH affects the

reduction of healthcare-associated infections (HAI), the selection of microorganisms resistant to CHG, or

hands skin damage.

Methods: Systematic review was performed using the protocol of the Joanna Briggs Institute, including clini-

cal trials and observational comparative studies. Search was conducted via PubMed, Medline, CINAHL,

LILACS, Embase, Cochrane Library, Scopus, Web of Science, ProQuest, Google Scholar, and gray literature. To

evaluate outcomes, 3 independent reviews were conducted: HAI rates, presence of resistance genes or higher

minimum inhibitory or bactericidal concentration, and damage to skin integrity.

Results: Studies showed no signiﬁcant difference in HAI rates when using CHG for HH. Among 13 studies, 10

suggested an association with use of and tolerance to CHG. The use of CHG was associated with skin reaction

events.

Conclusions: Strong evidence regarding the risks and beneﬁts of CHG for HH is still lacking. Due to potential

risk of selecting mutants carrying genes for cross-resistance to CHG and antibiotics, it is advisable to reserve

the use of CHG for purposes other than HH.

rights reserved.

Key Words:

Hand hygiene

Health care personnel

Resistance

Anti-infective agents

Integrity of the skin

There is a lack of consensus regarding the indication of antimicro-

bial soap for hand hygiene (HH). According to the Centers for Disease

Control and Prevention

and the World Health Organization,

there is

a lack of evidence demonstrating the clinical beneﬁts—that is, reduc-

tion of infection rates—regarding the use of soap with or without an

antimicrobial. Chlorhexidine gluconate (CHG) is 1 of the main anti-

septic agents present in antimicrobial soaps. Its broad spectrum activ-

ity, acceptable tolerability, and good safety margin make CHG 1 of the

most widely used biocides.

When it comes to the use of germicides, there is concern regarding

the issue of microbial resistance. This is of particular relevance in the

face of global awareness concerning the cautious use of antimicro-

bials. So far, the molecular mechanism of bacterial resistance to anti-

septics is still poorly understood.

4,5

Decreased susceptibility to CHG

has been found to be mediated by certain genes, including qacA, qacB,

smr, norA, and ebr.

The term resistance itself should be used with

caution because cutoff points are not yet known and product concen-

trations used on the market are usually higher than those required

for the inhibition of microorganisms.

In addition, in the literature,

there are reports of skin reactions as the antiseptic concentration

increases.

CHG is widely used in health care settings for a variety of

purposes.

7-9

Therefore, a synthesis of evidence regarding the beneﬁts

and risks of CHG for HH will be helpful in driving the rational use of

soap containing this antimicrobial. The objective of this work was to

analyze the effects of continuous use of CHG for HH through a sys-

tematic literature review focused on 3 outcomes: reduction of infec-

tions related to health care−associated infections (HAIs), selection of

microorganisms resistant to CHG, and occurrence of skin damage.

METHODS

To answer the proposed question (Q), we performed 3 independent

systematic reviews by addressing the following: Q1—is the use of soap

containing CHG for HH associated with a reduction in HAI transmis-

sion? Q2—is the use of CHG associated with the selection of microor-

ganisms resistant to this antiseptic agent? Q3—is the use of soap with

CHG associated with the occurrence of damage to skin integrity?

* Address correspondence to Marcia Maria Baraldi, RN, MsC, Rua Treze de Maio

1815. Bela Vista. CEP 01327-001. Infection Prevention and Control Service, Hospital

Alem

ao Oswaldo Cruz, S

ao Paulo, Brazil.

E-mail address: [email protected] (M.M. Baraldi).

Conﬂicts of interest: None to report.

https://doi.org/10.1016/j.ajic.2018.11.013

American Journal of Infection Control 47 (2019) 704−714

Contents lists available at ScienceDirect

American Journal of Infection Control

journal homepage: www.ajicjournal.org

These reviews were ﬁnished in April 2017 and updated in Septem-

ber 2018. The method design followed the protocol recommended by

the Joanna Briggs Institute,

which was applied to the checklist pro-

posed by the Systematic Review and Meta-Analysis Protocols 2015.

Data sources

We performed a systematized search of indexed descriptors

and key words using PubMed, Medline, CINAHL, LILACS, Embase,

Cochrane Library, Scopus, Web of Science, ProQuest Dissertations and

Theses, Google Scholar, and gray literature, with no language restric-

tions. The search protocol included publications from 1985 based on

delivery of the ﬁrst recommendation guide for HH.

An overview of

the search strategy is described in Table 1; details are provided as a

supplementary ﬁle.

The ﬁrst phase of study selection occurred via an independent

reading by 2 reviewers (M.M.B. and J.R.G.) of titles and abstracts for

inclusion of preselected articles; after preselection was complete,

the articles were read in full. The consensual decision making

process for the inclusion of articles took place in a meeting

between reviewers. Disagreements were discussed with a third

reviewer (M.C.P.). Cross-references were obtained using selected

publications.

Study eligibility criteria

We included nonrandomized and randomized clinical trials and

observational studies that evaluated the following outcomes: Q1—

HAI rates; Q2—presence of resistance genes or higher minimum

inhibitory concentration (MIC) or minimum bactericidal concentra-

tion (MBC); Q3—evaluation of skin integrity of health professionals.

Study appraisal and risk of bias

Each study was assessed according to the Joanna Briggs Levels of

Evidence. The risk of bias was assessed by using the Critical Appraisal

Tools from the Joanna Briggs Institute. Papers were evaluated according

the type of study (13 items for randomized controlled trials, 9 items for

quasi-experimental studies, 8 items for cross sectional studies).

The

authors adopted a minimum of 5 and 6 afﬁrmative answers in the

checklist respectively, for the cross-sectional or quasi-experimental

studies, and randomized controlled trials as the threshold for a paper

to be included in this review.

RESULTS

The search strategy resulted in 1,908 articles. After applying the

inclusion and exclusion criteria, followed by a quality evaluation of

the studies, the ﬁnal sample consisted of 4 studies for Q1, 13 studies

for Q2, and 7 studies for Q3. A summary of the research process is

depicted in Figure 1. It was not possible to conduct a meta-analysis

for each research question because of the large amount of heteroge-

neity among studies.

Q1: Is the use of soap containing CHG for HH associated with a reduction

in HAI transmission?

Among the 4 studies included, 3 were carried out in teaching hos-

pitals, and all of them involved the care team. The 4 articles were

published between 1991 and 2005. The ﬁndings that respond to Q1

are shown in Table 2.

P01

mentions the possibility of a change in the behavior of pro-

fessionals as they were being observed. However, results also showed

that nonantimicrobial soap was used more than soap containing

CHG. Despite the trend in reduction in HAI rates when using CHG,

there was no statistically signiﬁcant difference between soaps. The

isolated microorganisms were mainly coagulase-negative Staphylo-

coccus, Staphylococcus aureus, Enterobacteriaceae, Corynebacterium

spp, and Micrococcus spp (in order of frequency), microorganisms

considered normal for the microbiota of the skin.

P02

points out that, despite decreasing the number of infections,

there was no statistical signiﬁcance in favor of CHG.

P03

analyzed variables that could interfere with the outcome,

such as weight of the neonates, study site, and follow up time, and

concluded there were no signiﬁcant differences in infection risk dur-

ing the period of CHG use and the period of use of the alcohol-based

product for any type of infection.

P04

showed that, with the use of triclosan, the mean weekly rate

of new methicillin-resistant Staphylococcus aureus (MRSA) cases was

reduced from 3.4%-0.14% (P > .0001) in the experimental ward, with-

out signiﬁcant changes in rates in the control unit, which continued

using CHG. Therefore, there was no association between the use of

CHG and the reduction of HAI rates in the evaluated units.

Q2: Is the use of CHG associated with the selection of microorganisms

resistant to this antiseptic agent?

To answer this question, 13 articles that met the inclusion criteria

were analyzed. They employed a variety of study designs. The ﬁnd-

ings that correspond to the second question are described in Table 3.

In P01,

authors deﬁned CHG resistance based on MRSA isolates

possessing qacA/B genes. This study was performed as a community-

based cluster randomized controlled trial investigating skin and soft

tissue infection prevention. The study group (which received CHG 4%

for weekly 10-minute shower) was comprised by 10,030 soldiers

from an outpatient ambulatory. In this study, 720 MRSA isolates were

identiﬁed. Only 10 (1.6%) of 615 isolates were resistant to CHG,

including 3 from the CHG group and 7 from the non-CHG group (P >

.99). Therefore, an association between use of and resistance to CHG

was not shown. However, among its limitations, the study did not

assess adherence levels of the study group, which could create bias.

P02

showed no association between the use of CHG and the pres-

ence of the qacA/B genes in Staphylococcus epidermidis isolates or

increased MICs or MBCs for CHG. The highest exposure of scrub

nurses to CHG was not associated with higher MIC or MBC. This study

did not identify the presence of qac genes in a collection sample from

the 1960s. The authors offered the hypothesis that introduction of

qac genes might be associated with the more recent scaled use of

CHG or related compounds.

P03

deﬁned resistance as MIC ≥4 mg/mL. They identiﬁed this level

of resistance to CHG in 72 of 206 MRSA isolates from a national collec-

tion initiated in 1998 in Taiwan. However, all strains did not harbor

qacA/B genes. Most of the strains were ST239 and ST59, but the later

strains had no detected resistance to CHG.

Table 1

Overview of PICO search strategy for literature review (April 2017, updated in

September 2018)

Problem (“hand hygiene” [MeSH Major Topic])

Intervention (“chlorhexidine gluconate” [Other Term])

Comparison (Q1) (“1-propanol” [MeSH Major Topic] OR “ethanol” [MeSH Major

Topic]) OR (“soaps” [MeSH Major Topic])

Outcome (Q1) (“disease transmission, infectious” [MeSH Major Topic]) OR

(“disease transmission” [Other Term])

Outcome (Q2) (“microbial sensitivity tests” [MeSH Major Topic] OR “qace”

[Other Term]) OR (“qnrb” [Other Term]) OR (“multidrug-

resistant” [Other Term]) OR (“mdr genes” [Other Term])

Outcome (Q3) (“skin diseases” [MeSH Major Topic] OR “hand dermatoses”

[MeSH Major Topic]) OR (“dermatitis, irritant” [MeSH Major

Topic])

MeSH, Medical Subject Heading; qrnb, plasmid-mediated quinolone resistance gene;

PICO, problem, intervention, comparison, outcome; Q, question.

M.M. Baraldi et al. / American Journal of Infection Control 47 (2019) 704

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714 705

P04

studied MRSA strains collected in 4 different years. They

identiﬁed that qacA/B genes were absent in 1990, but were identiﬁed

in the following years and ranged from 26.7%-35%. Regarding the

MRSA strains without qacA/B genes, MIC ≥4 mg/mL was identiﬁed in

20.2% (37 of 183). This study demonstrated an increase in the propor-

tion of tested MRSA isolates with high CHG MICs in an environment

with long-term use of CHG. They observed an increasing presence of

ST239 harboring qacA/B genes, which could represent an advantage

in clonal spread.

P05

identiﬁed 11.8% (72) of 608 S aureus isolates with qacA/B

genes. Most of these strains were MRSA ST239 and ST5, which were

the most prevalent in units with high routine use of CHG as a decolo-

nization agent. However, this study did not evaluate the amount of

CHG used, making a comparison between the prevalence of resis-

tance genes and CHG impossible.

P06

evaluated the impact of the intervention of a daily bath with

CHG to prevent colonization and infection in patients in a bone mar-

row transplantation unit. The primary outcome of interest in the

study was infection or colonization owing to vancomycin-resistant

enterococcus, but there was also interest in other gram-negative bac-

teria. There was a signiﬁcant decrease in the incidence of colonization

and infection caused by vancomycin-resistant enterococcus during

the intervention period; in contrast, the infection rates of multidrug-

resistant gram-negative organisms increased. Of note, years after the

intervention, there was an outbreak caused by Pseudomonas aerugi-

nosa. The authors suggested that the molecular mechanisms of resis-

tance to CHG were probably closely linked to the presence of an

efﬂux pump. They also observed a shift in P aeruginosa from poly-

clonal before to clonal after the intervention, suggesting this was

owing to extensive use of CHG in the unit.

P07

was based on the rationale that if exposure to CHG exerts

an effect on the sele ction of CHG resistance, this effect would be

different according to the extent of CHG use. For this, they created

a usage index of liters consumed per beds per year. In this stud y,

no organism had an MIC exceeding 128 mg/L. Interestingly, this

study did not observe an association between CHG index of expo-

sure and MIC or zone diameters for individual species. However,

when all studied organisms were analysed together, they observed

Publications identified in databases:

Q1:764

Q2: 533

Q3: 611

Publications identified in other

data sources:

Q1: 08

Q2: 18

Q3: 3

Publications after deleting duplicates

Q1: 348

Q2: 429

Q3: 522

Publications excluded

after reading the

abstract:

Q1: 308

Q2: 402

Q3: 495

Publications selected for full

reading:

Q1: 40

Q2: 27

Q3: 27

Publications included in the

qualitative synthesis

Q1: 04

Q2: 13

Q3: 07

Publications deleted after

full reading:

Q1: 36

Q2: 14

Q3: 20

Identification

Selection

Eligibility

Inclusion

Q1: queson 1

Q2: queson 2

Q3: queson 3

Fig 1. Summary of study selection used to compose article samples inserted in review of questions 1, 2, and 3 (Q1, Q2, and Q3).

706 M.M. Baraldi et al. / American Journal of Infection Control 47 (2019) 704

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714

Table 2

Synthesis of review study characteristics that answer Q1: Is the use of soap containing CHG for HH associated with the reduction of HAI transmission? (Brazil, 2017-2018)

Publication/level of

evidence* (Critical

Appraisal

)

Study design Scenario and aim Duration Product

evaluated

Comparison Sample Results

P01

Marena et al,

2002

2.c

(6/9)

Nonrandomized,

prospective,

crossover

Scenario: 2 surgical wards (1 vascular

and 1 neurologic) of an Italian teaching

hospital with 1,200 beds

Aim: “to improve the motivation and

awareness of the importance of HH

practices, to assess the effectiveness of

a new chemical system in checking HH

compliance, and to evaluate the efﬁ-

cacy and tolerability of 2 soap solu-

tions used during regular working

hours”

4 mo CHG 4% Nonantimicrobial

soap

74 professionals

(46% medical staff,

43% nurses, 8%

nursing techni-

cians)/patients

hospitalized dur-

ing study

There was a trend in

reduction of infec-

tion rates but no

signiﬁcant statis-

tical difference

P02

Doebbeling et al,

1992

2.c

(5/9)

Nonrandomized,

prospective,

crossover

Scenario: ICU of a US university hospital

with 46 beds (23 surgical, 12 medical-

surgical, 11 cardiovascular)

Aim: “to compare the effects of 2

agents on nosocomial infection rates in

the ICU”

8 mo CHG 4% Nonantimicrobial

soap, followed by

isopropyl alcohol

60%

1,352 patients in the

CHG group £ 542

soap + isopropyl

under the care of

577 professionals

Although the num-

ber of infections

decreased, there

was no statistical

relevance in favor

of CHG

P03

Larson et al,

2005

2.c

(8/13)

Prospective clinical

trial, crossover

Scenario: 2 neonatal ICUs from a North

American hospital (43- and 50-bed

units)

Aim: “to compare the effect of 2 hand

hygiene regimens on infection rates

and skin condition and microbial

counts of nurses’ hands in neonatal

intensive care units”

2 y Antiseptic

detergent

containing

CHG 2%

Alcohol product

with 61% ethanol

and emollients

2,932 patients

(1,692 used CHG

and 1,240 used

ethanol) under

the care of 119

nurses

There were no sig-

niﬁcant differen-

ces in infection

rates between the

2 ICUs

P04

Webster, 1991

2.d

(6/9)

Prospective and

retrospective

Scenario: all neonates in the neonatal

ICU and wards of largest Australian

metropolitan hospital

Aim: “to evaluate the effects of triclo-

san on the methicillin-resistant

Staphylococcus aureus (MRSA) rates in

a neonatal intensive care nursery and

to measure the amount of skin damage

caused by handwashing

with triclosan”

10 mo

CHG 4%

(Hibiclens

)

Triclosan 1%

(Novaderm

)

46 prospectively

admitted

newborns

The mean weekly

MRSA rate of new

cases was reduced

from 3.4%-0.14%

(P > .0001) in the

experimental area

(triclosan)

CHG, chlorhexidine gluconate; HAI, health care−associated infection; HH, hand hygiene; ICU, intensive care unit; MRSA, methicillin-resistant Staphylococcus aureus; Q, question.

*Levels of evidence classi ﬁed according to the Joanna Briggs Institute Levels of Evidence, indicated by number and letter (ie 2 c).

The Critical Appraisal Tool from Joanna Briggs Institute tool was applied speciﬁcally for each type of study design. The numerator indicates the number of afﬁrmative answers and the denominator the total number of checklist questions

ex: 6/9.

(Retrospective) + 7 wk (prospective).

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714 707

Table 3

Synthesis of review study characteristics that answer Q2: Is the use of CHG associated with the selection of microorganisms resistant to this antiseptic agent? (Brazil, 2017-2018)

Publication/level of

evidence*

(MAStARI

)

Study design Scenario and aim Product evaluated Microorganism Technique used Results

P01

Schlett et al,

2014

1.c

(9/12)

Randomized

clinical trial

Scenario: community-based cluster

randomized controlled trial for skin

and soft tissue infection prevention

in outpatient unit for medical clinic

infantry trainees using 3 study

groups—(1) standard group: educa-

tional brieﬁng; (2) enhanced stan-

dard group: educational

brieﬁng + supplemental educa-

tion + weekly additional 10-minute

shower; (3) CHG group: weekly 10-

minute shower with CHG 4%

Clinical cultures and swabs from

anterior nares collected

Aim: “to determine the prevalence of

CHG resistance in clinical and colo-

nizing MRSA isolates”

CHG 4% (Hibiclens) MRSA ATCC 700699 used as a control

strain

Breakpoints adopted

Susceptible: ≤ 4 mg/mL; low-

level resistance: 8-64 m g/mL;

high-level resistance: 512 mg/

Detection of presence of gene

(qacA/B) by PCR

No difference in the prevalence

of presence of genes between

study groups

P02

Skovgaard et al,

2013

3.d

(7/9)

Cross-sectional Scenario: isolates from 8 surgical

nurses exposed to CHG (high-level

exposure) and 10 patients before

and after orthopedic surgery; iso-

lates of blood sample collections

dated 1965-1966

Aim: “evaluate if exposure to chlor-

hexidine selects CHG-tolerant S epi-

dermidis and the consequences of

long-term exposure to CHG”

CHG 85%

ethanol, 0.5% CHG/

0.5% glycerol (Idu-

scrub)

CHG 4% (Hibiscrub)

CHG 20%

CHG 20% + 96%

ethanol

S epidermidis MIC and MBC using broth micro-

dilutions

Gene qac detection by PCR

ATCC 12228 as control

MIC and MBC were similar

among patients and scrub

nurses.

Highest measured MBC was 15

mg/L; isolate harbored qac

genes

5/26 isolates from patients

before hospitalization har-

bored qac genes

MIC and MBC values had no

signiﬁcant differences among

qac-positive or negative

strains.

qac genes were not present in

isolates from 1965-1966

P03

Sheng et al, 2009

4.c

(8/9)

Cross-sectional Scenario: 206 MRSA isolates randomly

selected from a collection of clinical

samples from inpatients and outpa-

tients from different health care set-

tings

Aim: “ to determine the susceptibility

of MRSA isolates to CHG and the

prevalence of MRSA isolated with

qacA/B and smr genes; to determine

clonal spread of MRSA strains resis-

tant to CHG”

CHG 4% (Hibiscrub) MRSA MIC by agar dilution

Detection of qacA/B and smr

genes by multiplex PCR

Deﬁnition of resistance to

CHG: MIC ≥ 4 mg/mL

Typing of strains by MLST and

SCCmec

72/206 (35%) of MRSA isolates

showed MIC ≥ 4 mg/mL;

among them, 67 (93.1%)

carried qacA/B genes

No isolate harbored the smr

gene

MRSA majority were ST59

SCCmec IV or V and ST239

SCCmec III (48.0% resistant to

CHG)

P04

Wang et al,

2008

4.c

(7/9)

Descriptive

longitudinal

Scenario: university hospital with high

prevalence of MRSA and long-term

CHG use; MRSA isolates (240) caus-

ing bloodstream infections and other

clinical specimens collected in 1990,

1995, 2000, and 2005

Aim: “understand changes in sus-

ceptibility to CHG as well as the pro-

portion of MRSA isolates carrying

qacA/B gene”

CHG 4% MRSA MIC by agar dilution method

Detection of qacA/B genes by

PCR

Deﬁnition of resistance to

CHG: MIC ≥ 4 mg/mL

Typing of strains by MLST

83/240 (34.6%) showed MIC ≥ 4

mg/mL

Proportion of isolates with

MIC ≥ 4 mg/mL increased from

1.7% in 1990 to 50% in 1995

and remained 46.7% in 2005

46/57 (80.7%) of MRSA with

qacA/B genes expressed MIC ≥

4 mg/mL

(continued on next page)

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714

Table 3 (Continued)

Publication/level of

evidence*

(MAStARI

)

Study design Scenario and aim Product evaluated Microorganism Technique used Results

P05

Li et al, 2013

4.c

(7/9)

Cross-sectional Scenario: 608 S aureus samples of clini-

cal specimens collected at a teaching

hospital, 414 MRSA and 194 MSSA;

CHG was used as a decolonization

agent in the ICU and surgical ward

Aim: “to determine the prevalence,

molecular characteristics, and geno-

type-phenotype correlation of hospi-

tal-acquired S aureus infections”

- S aureus Detection of qacA/B genes by

PCR

Typing of strains by MLST and

SCCmec

Genes qacA/B were found in

11.8% (72/608) of isolates

Majority of strains harboring

qacA/B genes were ST239 and

ST5; among them, MRSA

ST239 SCCmec III was

predominant

P06

Mendes et al,

2016

1.d

(8/9)

Quasi-

experimental

Scenario: 1,393 patients and 127 iso-

lates from a stem cell and hemato-

poietic stem cell transplantation

unit. Intervention: daily bath with

CHG 2%

Aim: “to evaluate the impact of CHG

bathing on colonization and infec-

tion by MDR bacteria; to assess the

CHG MIC and presence of efﬂux

pump genes before and after the

implementation of daily bathing

with CHG”

CHG 2% P aeruginosa,

K pneumoniae,

A baumannii,

E faecium

MIC by agar dilution with CHG

ATCC13883 and ATCC25922

used as controls

Assessment of MIC of CHG in

the presence of efﬂux pump

inhibitors CCCP: MIC reduc-

tion at least 4-fold in the pres-

ence of CCCP

Detection of genes of resis-

tance by PCR

Evaluation of clonality by PFGE

CCCP response was higher in the

intervention period for all

tested microorganisms Gene

cepA found in P aeruginosa

(44.5%, preintervention),

K pneumoniae (62,9%),

A baumannii (42.4%)

Changes in clonal pattern of

P aeruginosa after intervention

P07

Block et al, 2002

4.d

(7/9)

Cross-sectional Scenario: clinical isolates (blood, urine,

respiratory tract, wounds, and

others) from an acute and tertiary

care hospital with adult and pediat-

ric patients; hospital use of CHG in

aqueous (0.5%), alcohol 70% (0.5%),

and surgical scrub (4%) formulation

Aim: “to evaluate the relationship

between the use of CHG and the sus-

ceptibility of isolated microorgan-

isms in patients of a general

hospital”

CHG 20% solution from

the hospital pharmacy

MRSA, S aureus,

S coagulase

negative,

K pneumoniae,

P aeruginosa,

A baumannii,

Candida

albicans

MIC in agar dilution of CHG

diluted from 0.5-256 mg/L

MIC in disk diffusion contain-

ing 50 mg of CHG

Index of intensity of CHG

usage (L/bed/year) categorized

as low, intermediate, and high

No signiﬁcant association

between exposure indices of

CHG and MICs or zone diame-

ters for individual species

All organisms together with

signiﬁcant correlation

between both MIC and zone of

inhibition

P08

Vali et al, 2017

2.c

(8/9)

Cross-sectional Scenario: isolates of MRSA (121) and

MSSA (56) from clinical specimens

Aim: “identify the lineages of MRSA

and MSSA with reduced susceptibil-

ity to CHG”

CHG MRSA

MSSA

MIC-CHG 100 mg/mL in water

with broth microdilution

MBC by subculturing 10 ml

from each well with no grow

Use of ECOFF = MIC ≥ 4 mg/L,

MBC ≥ 30 mg/L

No attempt to compare use

and resistance to CHG

Genes qacA-C identiﬁed in 12.3%

of MRSA and qacA in 5.4% of

MSSA

Reduced susceptibility

observed to CHG (MBC ≥ 30

mg/L) in MSSA isolates in non-

qac strains

P09

McNeil et al,

2015

2.c

(7/9)

Longitudinal Scenario: 247 patients and isolates

selected from S aureus surveillance

study, children’s hospital, and noso-

comial infections from 2007-2013.

CHG highly used since 2002 for

different purposes

Aim: “to examine all S aureus isolates

from nosocomial infections for the

presence of qacA/B and smr and to

correlate with clinical ﬁndings”

CHG S aureus MIC and MBC using broth mac-

rodilution ATCC 29213 used as

control

Detection of smr and qacA/B

genes by PCR

PFGE and MLST typing

111/247 (44.9%) isolates with 1

or both genes, more frequent

smr (33.1%)

Among 98 MRSA strains, 44

were smr and 26 qacA/B

MIC

>256 was observed in

strains smr and quaA/B-posi-

tive

Signiﬁcant differences in

MBC

among isolates with

both genes

Cross-sectional CHG MRSA, MSSA

(continued on next page)

M.M. Baraldi et al. / American Journal of Infection Control 47 (2019) 704

−

714 709

Table 3 (Continued)

Publication/level of

evidence*

(MAStARI

)

Study design Scenario and aim Product evaluated Microorganism Technique used Results

P10

Hughes et al,

2017

2.c

(6/9)

Scenario: 188 isolates from several

clinical sample collections from an

800-bed tertiary hospital. Use of

CHG for HH, surgical scrubs, and skin

antisepsis

Aim: “to detect the prevalence of

phenotypic tolerance to triclosan

and CHG in clinical S aureus isolates;

to compare the prevalence of MIC to

CHG or triclosan and whether raised

MIC was related to clonal spread of

MRSA”

MIC by agar dilution method

ATCC 25923 used as control

Deﬁnition of MIC for CHG: ≥ 4

mg/L; triclosan: ≥ 1 mg/L

MLST, SCCmec, and spa type by

PCR

Isolates with qacA exhibited

raised MIC to CHG

ST22 and ST239 exhibited MIC

for CHG: ≥ 4 mg/L

ST22 exhibited MIC for triclo-

san: > 1 mg/L

MIC for MSSA 0.5-4 mg/L

MIC for MRSA 1-8 mg/L

P11

Bhardwaj et al,

2017

2.c

(7/9)

Laboratory-

based,

experimental

Scenario: selected strains or plasmids

from laboratory collection, serial

passage experiments

Aim: “to test the hypothesis that

serial exposure to sub-MIC CHG

selects for VRE faecium mutants with

reduced susceptibility to CHG and

other membrane and cell wall− tar-

geting antimicrobials, with particu-

lar focus on daptomycin”

CHG 4% (Hibiclens) E faecium MIC for CHG by broth microdilu-

tion

MIC for daptomycin by Etest

Genome sequencing analysis

RT-qPCR

Phosphate assay, lipidomic

analysis

Gene deletion and agar CHG

susceptibility assay

After serial passages, reduced

CHG emerged (4-fold shift in

CHG MIC)

Subpopulations with reduced

daptomycin susceptibility

detected

Adaptive changes in genes

identiﬁed

P12

Wu et al, 2016

2.c

(7/9)

Laboratory-

based,

experimental

Scenario: 14 clinical isolates; serial

passages of sub-MIC concentration

of antibiotics, germicides, and anti-

microbial Chinese herbs (ACHs)

Aim: “to examine whether concen-

trations of antibiotics, biocides, and

ACHs below the minimum inhibitory

concentration could lead to mutual

cross-resistance or decreased sus-

ceptibility in bacteria”

CHG S aureus Exposure of strains to antibiotics,

CHG, and Rhizoma coptidis

extract at sub-MICs

MIC using geometric microdi-

lution

ATCC 25923 as control

Most strains showed change in

susceptibility to CHG <4-fold

MIC increase, except for 6 iso-

lates

CHG exposure: cross-resis-

tance to at least 1 antibiotic; 7

strains became less suscepti-

ble to Rhizoma coptidis extract

(≥ 4-fold MIC increase)

P13

Hijazi et al, 2016

1.d

(8/12)

Longitudinal Scenario: followup study of previous

report showing efﬁcacy of MRSA

infection control measures in inten-

sive care unit; CHG baths used rou-

tinely over 6 years; 81 isolates,

including MRSA strains, from clinical

specimens (blood and screening

samples)

Aim: “qacA/B genes were screened in

Staphylococcus isolates collected

over another 6- year period in the

same intensive care unit”

CHG MRSA, MSSA, S

epidermidis

MIC by agar dilution

Ethidium bromide used as

positive control for qacA pump

activity

Detection of qacA/B by PCR

Whole genome sequencing

MLST typing

Antibiotic susceptibility by

disk diffusion

Presence of qacA/B in S aureus

Presence of qacA/B in S epider-

midis associated with reduced

susceptibility to CHG; 65% of S

epidermidis belonged to MDR

clone ST2

ATCC, American Type Culture Collection; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; CHG, chlorhexidine gluconate; ECOFF, epidemiological cut-off value (upper limit of normal MIC distribution for a given antimicrobial agent and

species); HH, hand hygiene; MDR, multidrug-resistant; MIC, minimum inhibitory concentration; MLST, multilocus sequence typing; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus;

PCR, polymerase chain reaction; PFGE, pulsed-ﬁeld gel electrophoresis; Q, question; RT-qPCR, real-time quantitative polymerase chain reaction; S aureus, Staphylococcus aureus; SCCmec, staphylococcal cassette chromosome; S epidermidis,

Staphylococcus epidermidis.

*Levels of evidence classi ﬁed according to the Joanna Briggs Institute Levels of Evidence.

The MAStARI tool was applied speciﬁcally for each type of study design. The numerator indicates the number of afﬁrmative answers and the denominator the total number of checklist questions.

710 M.M. Baraldi et al. / American Journal of Infection Control 47 (2019) 704

−

714

a signiﬁcant correlation between the exposure index and suscepti-

bility (MIC or zone of inhibition). The highest MICs tended to con-

centrate in patients in surgical intensive care and hematology-

oncology units.

P08

characterized a collection of MRSA and methicillin-suscepti-

ble Staphylococcus aureus (MSSA) strains. The qac gene was more fre-

quently identiﬁed in MRSA (12.3%) than MSSA (5.4%) strains.

However, the authors observed a reduced susceptibility to CHG in

MSSA isolates that did not harbor qac genes and pointed out that

other mechanisms may be involved in tolerance to CHG.

P09

was performed in a children’s hospital with a high use of

CHG since 2002. A high proportion of S aureus strains having at least

1 gene related to CHG tolerance (smr or qacA/B) was identiﬁed. Of

note, the proportion of these genes varied with time, although the

reasons for these temporal changes were unclear. The study showed

smr-positive strains were more likely to be associated with resistance

to methicillin, ciproﬂoxacin, and clindamycin. There was no differ-

ence in mortality rates in patients with and without antiseptic toler-

ance genes. Because MIC

strains harbored both genes, the authors

suggested they may have had a synergistic effect on antiseptic efﬂux.

P10

demonstrated the characteristics of MRSA and MSSA regard-

ing CHG and triclosan in a collection of clinical sample isolates. Higher

MICs were observed for CHG, with lower levels observed for triclosan.

However, at least 1 strain exhibited higher MICs for both antiseptics.

ST22 SCCmec IV MRSA was associated with higher MICs for CHG.

In P11,

the authors observed an in vitro evolution of Enterococ-

cus faecium resistance to vancomycin. After serial passaging using

CHG 4% for 21 days, they detected a reduced MIC for CHG. This reduc-

tion showed a 4-fold increase compared with strains undergoing

serial passaging in media without CHG. They also observed adaptive

changes in genes, such as global nutritional response, nucleotide

metabolism, phosphate acquisition, and glycolipid biosynthesis.

Reduced daptomycin susceptibility emerged in a subpopulation of

strains undergoing serial CHG passaging.

P12

also tested serial passage of bacterial cells at concentrations

below the MIC for selected antibiotics, CHG, and antimicrobial

Chinese herbs, predominantly Rhizoma coptidis. This study demon-

strated that among strains exposed to subconcentrations of CHG,

many of them exhibited less susceptibility to at least 1 antibiotic and

to Rhizoma coptidis extract.

In P13,

the authors searched for qacA/B genes in samples of

Staphylococcus from an intensive care unit in which CHG baths were

a routine part of infection measures. Among S epidermidis strains,

there was a minimal increase in MIC values (1 doubling dilution) of

qacA/B positive strains compared with qacA/B negative strains.

However, CHG MIC never exceeded 4 mg/mL. Regarding S aureus, qac

carriage was not associated with an increase in CHG MIC.

In summary, of the 13 studies analyzed, 3 did not associate the use

of CHG (P01, P02, and P07) with the selection of resistant microorgan-

isms. Of note, only 1 study addressed the use of CHG speciﬁcally for

HH (P02). Other studies suggested a potential association between

the use of CHG and selection of strains exhibiting tolerance or harbor-

ing genes of tolerance to CHG. The 2 in vitro studies (P11 and P12)

demonstrated an association between exposure to CHG and selection

of tolerant strains, including cross-resistance with antibiotics.

Q3: Is the use of soap with CHG associated with the occurrence of

damage to skin integrity?

The included articles were published between 1995 and 2005;

there has been no publication on this topic since then. Of the 7

included studies—all involving care professionals—6 were carried

out in intensive care units and wards and 1 was performed in a labo-

ratory. The ﬁndings that answer the third question are shown in

Table 4.

P01,

P02,

P03,

and P07

adopted the same validated instru-

ments to assess skin conditions: the Visual Scoring of Skin Condition

and the Hand Skin Assessment form, which is a self-rating scale. All

of them compared the use of GCH 2.0% with the use of ethanol con-

taining emollients or nonantimicrobial soap. Although the duration

of the interventions varied (P01: 4 weeks; P02: 2 years; P03: 4

weeks), P01, P02, and P03 demonstrated improvement in skin condi-

tion in the group that used the nonantimicrobial soap and alcohol-

based product when compared to CHG. P07 was the only study that

identiﬁed similar rates of skin reactions in both groups.

P04

was the only study that compared the use of CHG 4.0% with

a nonantimicrobial soap using a personal questionnaire to assess the

perception of soaps. The results indicated that skin irritation and

hand dryness resulted from the use of CHG.

P05

was the only study that compared the use of CHG 4.0% with

another antimicrobial soap (triclosan 1.0%). The results showed that

skin health was worse in the group that used CHG.

P06

was a descriptive study that used a self-administered ques-

tionnaire to identify subjects with dermatitis. It revealed that people

with skin lesions on their hands had had contact with disinfectants,

especially CHG and glutaraldehyde.

The analysis of the 7 studies suggests that the use of CHG is associ-

ated with a higher number of skin reaction events when compared

with other products, such as alcohol-based products, triclosan, and

quaternary ammonium.

DISCUSSION

Regarding Q1, despite a full review of 36 articles, only 4 met the

criteria for answering the research question. However, these were

not recent studies, having been conducted between 1991 and 2005,

and it was not possible to establish a deﬁnite beneﬁt of CHG use in

relation to decreasing HAI rates. This can be explained by the difﬁ-

culty of isolating the effects of HH from other interventions address-

ing HAI prevention. The only study that compared the use of 4.0%

CHG with nonantimicrobial soap was P01, and no differences were

found in the rates of HAI.

The authors of the P02 study concluded

that the improvement could be explained, at least in part, by better

compliance with HH instructions for soap and water when CHG was

used.

Assessing the impact on infection rates through a single inter-

vention is complex owing to multiple contributory factors, such as

patient risk, unit characteristics, and team behavior. Other practices,

such as frequency and quality of HH, are important measures for

reducing the risk of cross-transmission.

To date, the results of the

studies presented in this review suggest that the use of CHG-based

products, when compared with nonantimicrobial soap, triclosan, and

alcohol-based products, does not bring a higher reduction in HAI

rates. However, we found few studies performing such comparisons,

and those that did were heterogeneous in terms of methodologic

design. For this reason, it was not possible to carry out a meta-analy-

sis to evaluate this outcome.

When measuring the impact of an antimicrobial product on HH,

several factors need to be carefully considered. CHG has good antimi-

crobial activity and residual effect, which could be compensated for

by an improvement in the adhesion rate of HH using a nonantimicro-

bial soap.

Overall, we observed a number of studies that assessed

(in logarithms) reduction in the contamination of the hands of care

professionals, but they did not make associations regarding the

impact of this reduction on incidence rates of HAI. We identiﬁed a

scarcity of well-designed and controlled research addressing this sub-

ject. The careful choice of strategies, interventions, tools, and design is

essential for achieving better quality studies that do not include mul-

tiple interferences.

Regarding question 2, the results of the present review showed

that 10 out of 13 studies suggested that the prolonged use of CHG

M.M. Baraldi et al. / American Journal of Infection Control 47 (2019) 704

−

714 711

Table 4

Synthesis of review study characteristics that answer Q3: Is the use of soap with CHG associated with the occurrence of damage to the integrity of the hands skin? (Brazil, 2017-2018)

Publication/level of

evidence*

(MAStARI

)

Study design Scenario and aim Product/exposure time Comparison Assessment of skin conditions Results

P01

Larson et al,

2001

1.d

(8/13)

Prospective ran-

domized clinical

trial

Scenario: 50 professionals from 2 adult critical care

units in the United States

Aim: “to compare skin condition and skin microbiol-

ogy among intensive care unit personnel using one of

two HH regimens (2% CHG and a waterless handrub

containing 61% ethanol with emollients)”

CHG 2%/4 wk Nonantimicrobial

soap and alcohol

61% with

emollients

Two validated instruments: the

VSS form, which uses stereo-

microscopy, and the HSA form,

which is a self-rating scale

Participants in the alcohol group

had improvements in hand

skin evaluation score

P02

Larson et al,

2005

1.d

(8/13)

Experimental,

crossover

Scenario: nursing staff from 2 neonatal ICUs from a

North American hospital (43- and 50-bed units)

Aim: “to compare the effect of 2 hand hygiene regi-

mens on infection rates and skin condition and

microbial counts of nurses’ hands in neonatal inten-

sive care units”

CHG 2%/2 y Nonantimicrobial

soap with isopro-

pyl alcohol 60%

and emollients

Measured by 2 tools monthly:

HSA form and VSS form

Nurses’ skin condition improved

using alcohol-based product

compared to CHG

P03

Larson et al,

2000

1.d

(7/9)

Quasi-experimental,

prospective,

randomized

Scenario: 16 nurses with no dermatologic conditions

from a 47-bed neonatal ICU in New York

Aim: “to compare 2 hand care regimens in a neonatal

intensive care unit”

CHG 4% and 2%/4 wk Nonantimicrobial

soap wash with

subsequent alco-

hol-based rinse

for degerming as

necessary

Two validated instruments: VSS

form and HAS form

Signiﬁcant improvement in skin

condition (P = .005) in group

that used nonantimicrobial

soap and alcohol-based prod-

uct compared to CHG

P04

Marena et al,

2002

1.d

(6/9)

Prospective, ran-

domized,

crossover

Scenario: 74 professionals from 2 surgical (vascular and

neurologic) wards of a 1,200-bed Italian hospital

Aim: “to improve the motivation and awareness of

the importance of HH practices, to assess the effec-

tiveness of a new chemical system in checking HH

compliance, and to evaluate the efﬁcacy and tolera-

bility of 2 soap solutions used during regular working

hours”

CHG 4%/4 mo Nonantimicrobial

soap

Questionnaire to assess personal

perception of hand soaps used

and to report untoward effects

CHG caused skin irritation and

dryness in the hands of 5

health workers during the

study; 2 presented clear signs

of acute dermatitis after use

for 2 and 4 d, respectively

P05

Webster, 1992

1.d

(6/9)

Experimental,

nonrandomized

Scenario: 109 professionals from 2 neonatal ICUs

Aim: to evaluate the effectiveness of triclosan 1%

against MRSA and its effect on skin were compared

with chlorhexidine gluconate 4% (Hibiclens)

CHG 4%/7 wk Triclosan 1% Daily responses to structured

questionnaire

Sixty-ﬁve (60.7%) professionals

reported 1 or more skin prob-

lems, such as dryness, redness,

peeling, cracking, and bleed-

ing, while using triclosan

when CHG reached 95.3%

P06

Stingeni et al,

1995

4.c

(7/8)

Descriptive Scenario: 1,301 professionals of an Italian hospital

Aim: to investigate the epidemiology of contact der-

matitis in health care personnel

CHG 4%, 1.5%, and 0.5%

Sectional study

Alcohol:

benzethonium

(quaternary)

glutaraldehyde

hydrogen perox-

ide

PVPI

Self-administered questionnaire

to identify subjects with der-

matitis; all persons who

reported skin diseases were

examined

Hand dermatitis was the most

frequent and occurred in

21.2% of examined subjects

(P < .001); 94% of lesions were

related to contact with disin-

fectants, especially CHG and

glutaraldehyde

P07

Cimiotti et al,

2003

2.c

(7/9)

Quasi-experimental,

prospectively

controlled study

Scenario: 50-bed neonatal intensive care unit in the

United States

Aim: to describe skin reactions and compare typical

reactions associated with HH with an antimicrobial

soap and use of alcohol-based hand-hygiene products

2.0% CHG/1 y 61% ethanol con-

taining emollients

and nonantimi-

crobial soap

Two methods used: an instru-

ment to collect data on skin

condition and hand hygiene

habits and a postcard-size

diary card plus patch testing

for nurses with dermatologic

reactions

Seven of 58 nurses (1.1%) had

skin reactions associated with

the alcohol-based product

compared with 4 of 58 nurses

(1.0%) that had reactions asso-

ciated with antiseptic soap

containing CHG; patch test

was positive in 3 of 4 nurses

CHG, chlorhexidine gluconate; HAS, Hand Skin Assessment; HH, hand hygiene; ICU, intensive care unit; MRSA, methicillin-resistant Staphylococcus aureus; PVPI, povidone-iodine; VSS, Visual Scoring of Skin.

*Levels of evidence classi ﬁed according to the Joanna Briggs Institute Levels of Evidence.

The MAStARI tool is applied speciﬁcally for each type of study design. The numerator indicates the number of afﬁrmative answers and the denominator the total number of checklist questions.

712 M.M. Baraldi et al. / American Journal of Infection Control 47 (2019) 704

−

714

might select tolerant strains. These studies involved different types of

species and strains, including MRSA, P aeruginosa, Klebsiella pneumo-

niae, and Acinetobacter baumannii. Some of these studies associate

the use of CHG with the presence of resistance genes (qacA, qacB)

showing an increased MIC or MBC. These genes encode efﬂux pumps,

which seem to be important resistance mechanisms.

It is relevant to

highlight that, so far, there is no standardized method available for

deﬁning CHG resistance, and even the concept of tolerance or

reduced susceptibility is not consensual.

9,20

Lack of a clearly deﬁned

susceptibility breakpoint means that an increase in MIC may not be

easily understood as resistance.

However, the simple presence of

gene encoding tolerance to biocides such as qac may not be a good

marker for resistance since there have been studies showing reduced

susceptibility to CHG in strains not harboring these genes.

7,9

Strains

containing these genes may have an ecologic advantage in environ-

ments with frequent use of germicides or other ﬁtness advantages,

regardless of the use of CHG.

Even so, these ﬁndings should be inter-

preted with caution, taking into consideration that the use of CHG

occurs mainly in areas with critical patients, where the use of antibi-

otics and invasive procedures is most frequent. Thus, antibiotic use,

cross-infection, and immunosuppression are confounding variables.

In an intensive care unit, a greater exposure to CHG occurs if the

antimicrobial soaps for HH contains CHG in their formulas. Although

the theory of cross-resistance to antibiotics remains controversial,

hypothetically, massive exposure to CHG may increase the risk of

resistance to some antibiotics.

The major concern involves the pos-

sibility of cross-resistance between germicides and antibiotics related

to qac genes. These genes are often present in integrons carried by

plasmids, which, in turn, are widely disseminated in gram-negative

bacteria. These integrons have been associated with the occurrence

of efﬂux pumps—efﬁcient mechanisms of resistance to antibiotics—

in gram-negative bacteria.

31,32

The tolerance of microorganisms to biocides has been reported by

different mechanisms, the acquisition of plasmids being 1 of the most

frequent.

The mechanism of action of germicides is different from

that of antibiotics, particularly because the latter have very speciﬁc

target sites, whereas germicides have more generic mechanisms that

reach cellular structures more broadly.

33,34

However, the transfer of

resistance genes between species is a possible phenomenon. For this

reason, some authors express concern about the widespread use of

germicides

31,33

and instead propose a “stewardship of biocides” ini-

tiative. Nevertheless, other authors believe this risk is still low—if

germicides are used in appropriate concentrations.

The ﬁndings from the reviewed studies demonstrated that detec-

tion of tolerance genes is frequent.

The clinical impact of this is not

yet evident. So far, the majority of articles presenting strains with

higher MIC or MBC to CHG have reﬂected concentrations below those

commercially available. The clinical relevance of such ﬁndings is still

unlikely.

Despite this, the identiﬁcation in some studies of simulta-

neous carriage of these strains of antibiotic resistance is a matter of

concern.

The concomitant carriage of resistance to antiseptics other

than CHG is also possible.

The concern about the large scale use of CHG should be regarded

globally because of the rapid evolution in the dynamics of develop-

ment and selection of resistance genes. In addition to the use of CHG

for routine HH, the continuous use of CHG for many other procedures

may lead to positive pressure in the selection of resistant microorgan-

isms. From this point of view, the indiscriminate use of this antiseptic

should also be reconsidered for other practices, such as skin prepara-

tion (eg, surgical skin antisepsis and preoperative baths). The rational

use of germicides for skin preparation is addressed by the World

Health Organization in its surgical site infection prevention guide-

lines, in which there is a recommendation to maintain preoperative

baths with CHG only in patients undergoing cardiac or orthopedic

surgery.

The studies using serial passage experiments were able to

demonstrate the potential of exposure to CHG to select mutants with

not only reduced MIC to CHG but also reduced susceptibility to other

antimicrobials and pointed out that antibiotics and biocides may

share mechanisms of actions that can be overcome by resistant

mutants.

21,22

Finally, with regard to the association of CHG use with the occur-

rence of damage to skin integrity (Q3), reactions were associated

with extensive use, appearing after days or weeks of continuous

use.

The main skin reactions reported were dryness, redness, crack-

ing, and sometimes bleeding.

It is unclear if skin irritation was

owing to the use of CHG itself or to the lack of emollients, such as

those included in alcohol handrub products. It is important to point

out, however, that the choice of CHG may have a potential detrimen-

tal impact on the skin health of professionals’ hands, and that lesions

may act as a gateway for microorganisms.

Our study, although comprehensive, has limitations, mainly owing

to the low number of high-quality articles offering evidence regard-

ing the risks and beneﬁts of CHG use in routine HH. Using a search

time frame beginning in 1985 could be a limitation since CHG

appeared in the literature years before. However, we took into con-

sideration that its scaled use potentially occurred after the ﬁrst HH

guideline, and that in many countries CHG was only available on the

market in the 1980s.

CONCLUSIONS

This study did not identify evidence in the literature regarding the

beneﬁts of routine use of CHG in HH for reducing HAI rates. The direct

relationship of CHG use and the emergence of resistance is still incon-

clusive, although studies have pointed out the potential selection of

CHG-resistant microorganisms. The continuous use of antimicrobial

soap with CHG for HH may lead to skin damage. Because of the poten-

tial risk of selecting mutants that carry genes for cross-resistance to

CHG and antibiotics, it is advisable to reserve the use of CHG for pur-

poses other than HH.

Acknowledgments

We would like to thank Librarian Juliana Takahashi, for her valu-

able aid in all the steps to build the literature searching strategy.

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