Clinical application of skin antisepsis using aqueous olanexidine: a scoping review.

Surgical site infections (SSIs) and catheter-related bloodstream infections (CRBSIs) caused by bacteria from surfaces poorly disinfected with chlorhexidine gluconate (CHG) and povidone-iodine (PVP-I) are increasing. Olanexidine gluconate (OLG) was developed in 2015 in Japan to prevent SSI and CRBSI caused by bacteria resistant to CHG and PVP-I. This scoping review aimed to identify the knowledge gap between what is known and what is not known about the disinfection efficacy of OLG. We searched MEDLINE through PubMed, the Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the International Clinical Trials Registry Platform search database, ClinicalTrials.gov, and the Web-based database of Japanese medical articles for works published to July 18, 2021. Manual reference searches were also carried out. A total of 131 studies were screened. Forty-seven studies were included in this review and classified into two major categories: studies on pharmacological effects and spectrum (n = 29) and studies on clinical and adverse effects (n = 18). Olanexidine gluconate showed bactericidal activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, in addition to common Gram-positive and Gram-negative bacteria. In clinical settings, although there is limited evidence on SSI prevention, 1.5% OLG might be more effective than 10% PVP-I and 1% CHG in preventing SSI. However, the clinical usefulness of OLG is unclear due to the limited number of clinical studies. Also, clinical research is limited to studies targeting SSI prevention, and there are no clinical studies on CRBSI. Further clinical studies are needed on SSI and CRBSI prevention.

INTRODUCTION

Microorganisms on the skin surface can cause various infections in hospital settings. Among such infections, surgical site infection (SSI) and catheter‐related bloodstream infection (CRBSI) lead to higher mortality rates, longer hospital stays, and higher medical costs. , , ,

Various disinfectants have been developed to prevent SSIs and CRBSIs. Regarding the balance between disinfection efficacy and adverse events, the guidelines of the Centers for Disease Control and Prevention and the National Institute for Health and Clinical Excellence recommend the use of alcohol‐containing chlorhexidine gluconate (CHG). , Chlorhexidine gluconate use is associated with a lower incidence of CRBSI, when compared to the use of povidone‐iodine (PVP‐I) or alcohol. Thus, CHG is recommended for CRBSI prevention. , , ,

However, the occurrence of SSI and CRBSI caused by bacteria on surfaces that are poorly sterilized with CHG or PVP‐I has been increasing in recent years. , , , , Specifically, Staphylococcus aureus and Enterococcus species are the most common causative bacteria of SSIs and CRBSIs. , Clinical studies have shown that PVP‐I is ineffective in disinfecting surfaces with enterococci, which include vancomycin‐resistant enterococci (VRE). , Furthermore, the studies have reported the inefficacy of CHG in disinfecting surfaces with methicillin‐resistant S. aureus (MRSA) and VRE. ,

To prevent SSIs and CRBSIs caused by bacteria resistant to CHG and PVP‐I, olanexidine [1‐(3,4‐dichlorobenzyl)‐5‐octylbiguanide] gluconate (OLG) was developed in Japan in 2015. In vitro, OLG has a broad‐spectrum, disinfecting, and fast‐acting activity against drug‐resistant bacteria. , , , , ,

A randomized controlled trial (RCT) comparing the activity of OLG and PVP‐I showed that OLG is superior to PVI in the prevention of SSIs. Although some of the disinfection effects of OLG have been clarified, some aspects of the clinical use of OLG need clarification: whether OLG is more effective than CHG for skin disinfection, which is recommended for CRBSI and SSI prevention; whether CHG is effective in preventing non‐SSI infections; and whether OLG is more effective than other disinfectants against resistant bacteria in clinical settings.

Therefore, we undertook a scoping review to clarify what is currently known and what remains unclear about OLG’s disinfectant activity. Specifically, we focused on two points: OLG’s pharmacological effect, including its spectrum and associated adverse events; and its clinical effects, including prevention of SSI and CRBSI. The results were summarized separately for each of these points.

METHODS

The present scoping review included all studies on OLG, regardless of their design. The studies included in vitro studies of animals and humans, case reports, observational studies, and RCTs. Conference abstracts with unavailable full texts were excluded, due to insufficient information for this review. We followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses extension for Scoping Reviews (PRISMA‐ScR) Checklist. We searched MEDLINE through PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the International Clinical Trials Registry Platform (ICTRP) search database, ClinicalTrials.gov, and the Web‐based database of Japanese medical articles (Ichu‐shi) for articles published to July 18, 2021. Manual reference searches were also undertaken as appropriate. When searching MEDLINE/CENTRAL/CINAHL, we used the following search terms: “olanexidine”, “OPB‐2045” (OPB; the development code of olanexidine), “olanedine”, and “olanexidine gluconate”. When searching Ichu‐shi, the search terms used in the MEDLINE/CENTRAL/CINAHL search were translated into Japanese. There was no language restriction. The extracted studies were screened independently by two reviewers (ES and YS) to determine their eligibility for inclusion. Disagreements were discussed and resolved between the two reviewers. If the disagreement could not be resolved, the decision was left to a third reviewer (HY).

RESULTS

A total of 131 studies (25 from PubMed, 13 from CENTRAL, 80 from Ichu‐shi, six from CINAHL, two from the manual reference search, and five from ICTRP/ClinicalTrials.gov) were screened (Fig. 1, Table S1). Twenty‐nine studies were excluded during the first screening (duplicates, 11; unavailable full text, 18). In the second screening that entailed a review of full texts, 50 studies were excluded: four in which OLG was not mentioned and 46 conference abstracts (Table S2). Finally, 47 studies were included in the review.

Fig 1

Flowchart of study screening and inclusion in the present scoping review of studies regarding the clinical application of skin antisepsis using olanexidine. CINAHL, Cumulative Index to Nursing and Allied Health Literature; ICTRP, International Clinical Trials Registry Platform.

Forty‐seven studies were classified into two major categories based on their focus areas: studies on pharmacological effects and spectrum (n = 29) and studies on clinical and adverse effects (n = 18). The studies on pharmacological effects and spectrum were animal or in vitro studies. The studies on clinical and adverse effects were human studies (Table 1).

Table 1

Summary of included studies that reported the clinical use of olanexidine gluconate (OLG)

No.	First author, year	Country	Design	Object	Intervention	Comparison	Outcomes	Main findings
Pharmacological effects
1	Seyama et al. 2019 21	Japan	In vitro	Microorganisms, containing clinical isolates	1.5% OLG	None	Viable bacterial count (CFU/mL) after 1.5% OLG administration using time‐kill assay	1.5% OLG showed fast‐acting fungicidal activity against all Gram‐positive and Gram‐negative bacteria tested, including multidrug‐resistant strains, Candida albicans, Microsporum canis, and Malassezia furfur
2	Medical package insert 28	Japan	In vitro animal study	Microorganisms, containing clinical isolates	1.5% OLG	None	MBC or log10 reduction	Spectrum of 1.5% OLG against bacteria, viruses, and fungi is described based on the results of clinical trials undertaken by pharmaceutical companies
3	Imai et al. 2020 33	Japan	In vitro	Norovirus (all 11 genotypes of GI, GII, and GIV)	OLG‐HR (1.5%), 1.5% OLG, 0.5% OLG	EtOH, 0.1% benzalkonium chloride, 0.5% CHG	Log10 reduction	Two types of disinfectants using OLG (hand sanitizer and surgical bandage), two types of ethanol solutions with different pH (approximately 3 and 7), and the base ingredient of OLG hand sanitizer were evaluated for their ability to kill 11 types of human noroviruses
4	Hagi et al. 2015 23	Japan	In vitro	Microorganisms, containing clinical isolates	1.5% OLG	CHG (concentration unknown) PVP‐I (concentration unknown)	MBC (μg/mL)	MBC of OLG was low for both Gram‐positive cocci and Gram‐positive rods, including multidrug‐resistant bacteria. The bactericidal spectrum of OLG was comparable to that of CHG and PVP‐I OLG probably binds to the cell membrane, disrupts membrane integrity, and its bacteriostatic and bactericidal effects are caused by irreversible leakage of intracellular components
5	Inoue et al. 2015 25	Japan	In vitro	Microorganisms, containing clinical isolates	1.5% OLG	None	MBC (μg/mL)	Bactericidal efficacy of OLG against MRSA and VRE was compared with CHG and PVP‐I using MBC as an indicator, and the bactericidal efficacy was equal or better
6	Nishioka et al. 2018 22	Japan	In vitro animal study	Applied to the skin of the Yucatan micropig (culture collections)	1.5% OLG	0.5% CHG 10% PVP‐I 1% CHG‐AL	Log10 reduction at 30 s and 3 min	OLG showed a fast‐acting bactericidal activity that was similar to or stronger than that of CHG formulations up to a concentration of 1% and PVP‐I with a short exposure time of 30 s, and substantivity until 12 h after rinsing, whereas the other antiseptics hardly showed any substantivity
7	Nakaminami et al. 2019 20	Japan	In vitro	qacA/B‐positive or negative MRSA	1.5% OLG	None	MBC50 (50% strain bactericidal) and MBC90 (90% strain bactericidal) (μg/mL)	Fast‐acting bactericidal activity of OLG against qacA/B‐positive MRSA is higher than that of CHG
8	Nii et al. 2019 31	Japan	In vitro	Human oral keratinocytes with the addition of LPS from Porphyromonas gingivalis	0.1% OLG	None	Degree of decrease in pro‐inflammatory cytokines produced by human oral keratinocytes after application of 0.1% OLG	Inflammatory cytokines, which cause chronic inflammatory reactions such as periodontitis, decreased after application of 0.1% OLG, suggesting that OLG could have anti‐inflammatory effects
9	Imai et al. 2021 34	Japan	In vitro	Influenza A (H1N1), human coronavirus OC43, feline infectious peritonitis virus, human herpesvirus, respiratory syncytial virus	OLG‐HR (1.5%), 1.5% OLG, 0.5% OLG	EtOH, 0.1% benzalkonium chloride, 0.5% CHG)	Mean log10 reduction	OLG‐containing disinfectants are as effective as EtOH in disinfecting some viruses
10	Nakata et al. 2017 36	Japan	In vitro animal study	Microorganisms from Male cynomolgus monkey's skin Applied to normal skin without any treatment to simulate a standard pre‐surgical application, and dirty skin with blood	1% OLG, 1.5% OLG, 2% OLG	0.5% CHG, 10% PVP‐I and normal saline (as a negative control)	Bacterial count after 10 min and 6 h, and the log10 reduction after application of the antiseptic The bactericidal effect of the antiseptic on blood‐contaminated skin	Bactericidal effects of OLG were comparable to those of commercial antiseptics such as CHG and PVP‐I in non‐blood‐contaminated conditions Effect of OLG was hardly affected by blood, unlike commercial antiseptics
11	Sakagami et al. 2000 29	Japan	In vitro	MRSA	OLG (concentration unknown)	None	MIC and MBC of OLG	OLG showed strong bactericidal activity against MRSA Marked decrease in MRSA cell numbers was recognized as the OLG concentration was increased
Pharmacological effects
12	Umehara et al. 2000 40	Japan	In vitro	Dog liver microsomes	OLG (concentration unknown)	None	Measurement of metabolites of OLG	Olanexidine is likely to be mediated by the CYP2D subfamily in dog liver microsomes
13	Umehara et al. 2000 41	Japan	In vitro	Rat and dog liver microsomes	OLG (concentration unknown)	None	Measurement of metabolites of OLG	Degraded products of OPB‐2045 are produced by C‐C bond cleavage after monohydroxylation, dihydroxy‐ lation, and ketol formation at the site of the octyl side chain with possible involvement of cytochrome P450 systems
14	Sakagami et al. 2000 30	Japan	In vitro	Pseudomonas aeruginosa	OLG (concentration unknown)	None	MIC and MBC of OLG	OLG was bactericidal by acting on the cell membrane and cell wall of Pseudomonas aeruginosa at MIC Bactericidal effect of OLG was different at low and high concentrations
15	Nakazawa et al. 2018 24	Japan	In vitro	Staphylococcus aureus	1.5% OLG	20% CHG	MIC	OLG has bactericidal effect against MRSA with qacA/B gene
16	Fujio et al. 2000 42	Japan	Animal study	Rats	OLG (concentration unknown) subcutaneous administration	None	Reproductive and developmental adverse events	No effect of the drug application on the estrus cycle of female rats, fertilization rate, nursery condition of mothers after birth, and all cycles up to fetal development
17	Kudo et al.1998 38	Japan	Animal study	Rats	OLG (concentration unknown) subcutaneous administration	None	Measurement of metabolites absorbed subcutaneously	OLG remained in the skin and was poorly absorbed
18	Kudo et al.1998 43	Japan	Animal study	Rats	OLG (concentration unknown) subcutaneous administration	None	Measurement of metabolites absorbed subcutaneously	OLG remained in the skin and was poorly absorbed
19	Kudo et al. 1998 44	Japan	Animal study	Rats	OLG (concentration unknown) subcutaneous administration	None	Measurement of metabolites absorbed subcutaneously	OLG remained in the skin and was poorly absorbed
20	Kudo et al. 1998 39	Japan	Animal study	Rats	OLG (concentration unknown) subcutaneous administration	None	Measurement of metabolites absorbed subcutaneously	OLG remained in the skin and was poorly absorbed
21	Kudo et al. 1998 45	Japan	Animal study	Beagle dogs	OLG (concentration unknown) subcutaneous administration	None	Measurement of metabolites absorbed subcutaneously	OLG remained in the skin and was poorly absorbed
Pharmacological effects
22	Kudo et al. 1998 46	Japan	Animal study	Rats	OLG (concentration unknown) subcutaneous administration	None	Reproductive and developmental adverse events	No effect of the drug application on the estrus cycle of female rats, fertilization rate, nursery condition of mothers after birth, and all cycles up to fetal development
23	Takenaka et al. 1998 47	Japan	Animal study	Rats	OLG (concentration unknown) subcutaneous administration	None	Reproductive and developmental adverse events	No effect of the drug application on the estrus cycle of female rats, fertilization rate, nursery condition of mothers after birth, and all cycles up to fetal development
24	Takenaka et al. 1998 48	Japan	Animal study	Rabbits	OLG (concentration unknown) subcutaneous administration	None	Reproductive and developmental adverse events	No effect of the drug application on the estrus cycle of female rats, fertilization rate, nursery condition of mothers after birth, and all cycles up to fetal development
25	Takenaka et al. 1998 49	Japan	Animal study	Rats	OLG (concentration unknown) subcutaneous administration	None	Reproductive and developmental adverse events	No effect of the drug application on the estrus cycle of female rats, fertilization rate, nursery condition of mothers after birth, and all cycles up to fetal development
26	Takenaka et al. 1998 50	Japan	Animal study	Rats	OLG (concentration unknown) subcutaneous administration	None	Reproductive and developmental adverse events	No effect of the drug application on the estrus cycle of female rats, fertilization rate, nursery condition of mothers after birth, and all cycles up to fetal development
27	Hosoya et al. 2016 32	Japan	Gray paper	None	None	None	None	Brief description of the bactericidal action of OLG and the results of clinical trials
28	Oie 2019 69	Japan	Gray paper	None	None	None	None	OLG has the advantages of less dripping and nonflammability. However, OLG is expensive
29	Taketomi 2015 70	Japan	Gray paper	None	None	None	None	OLG product features were described
Clinical effects
30	Harihara et al. 2015 52	Japan	RCT	Adults	1.5% OLG	Placebo 0.5% CHG	Bacteria count after 10 min of application	Rate of adverse events in 1.5% OLG, 0.5% CHG, and placebo Rate of adverse events in 1.5% OLG and 10% PVP‐I
31	Obatake et al. 2020 51	Japan	Not mentioned	Children	OLG (concentration unknown)	None	Disinfection effect after 10 min of application	Evaluation after 10 min of application of OLG to normal skin revealed good disinfection effect
32	Nagai et al. 2000 53	Japan	RCT	Adults	OLG (0.02%, 0.05%, 0.1%, 0.2%)	CHG (0.05%, 0.5%)	Exponential reduction value of total viable bacteria before and after application	OLG was found to be more effective than CHG in reducing skin bacteria after 30 s and 3 min of application to normal skin
33	Kobayashi et al. 2000 54	Japan	Not mentioned	Adults	0.05% OLG	None	Wound infection prevention and disinfection effects	Application of 0.05% OLG to wounded skin was found to be effective in preventing wound infection and disinfection
34	Matsumoto et al. 2018 58	Japan	Retrospective study	Adults	OLG (concentration unknown)	None	SSI incidence rate at 30 days postoperatively	OLG was effective in preventing surgical site infection
35	Harihara et al. 2020 57	Japan	Retrospective study	Adults	1.5% OLG (applicator)	10% PVP‐I 1% CHG	All SSI incidence rates Adverse events	Incidence rate of SSI in gastrointestinal surgery was found to be lower in 1.5% OLG Incidence rate of rash was found to be higher with OLG compared to PVP‐I
36	Obara et al. 2020 26	Japan	RCT	Adults	1.5% OLG	10% PVP‐I	30‐day postoperative SSI rate	30‐day postoperative SSI rate in semiclean gastrointestinal surgery was found to be lower in 1.5% OLG than 10% PVP‐I
37	Shiyanagi et al. 2019 56	Japan	Retrospective study	Children	1.5% OLG (applicator)	10% PVP‐I	All SSI incidence rates	Incidence rate of SSI in clean surgery was found to be low for 1.5% OLG and 10% PVP‐I
38	Yamamoto et al. 2020 55	Japan	RCT	Adults	Single application OLG applicator (concentration unknown)	Double applications OLG applicator (concentration unknown)	30‐day postoperative incisional SSI rate	No difference in the incidence of SSI at 30 days postoperatively between single and double applications of OLG
39	Sugai, 1999 65	Japan	Not mentioned	Adults	OLG (0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%)	Placebo	Adverse events	Adverse events resulting from the application of OLG to healthy adults
Pharmacological effects
40	Sugai, 1999 66	Japan	Not mentioned	Adults	OLG (0.1%, 0.5%)	None	Adverse events	Adverse events resulting from the application of OLG to healthy adults
41	Sugai, 1999 67	Japan	Not mentioned	Adults	0.1% OLG 0.5% OLG	None	Adverse events	Adverse events resulting from the application of OLG to healthy adults
42	Sugai, 1999 68	Japan	Not mentioned	Adults	OLG (0.005%, 0.01%, 0.03%, 0.05%, 0.1%)	Placebo	Adverse events	Adverse events resulting from the application of OLG to healthy adults
43	Obara et al. 2020 26	Japan	RCT	Adults	1.5% OLG	Placebo 0.5% CHG	Adverse events	Rate of adverse events in 1.5% OLG and 10% PVP‐I
44	Shiyanagi et al. 2019 56	Japan	Retrospective study	Adults	1.5% OLG	10% PVP‐I	Adverse events	Rate of adverse events in 1.5% OLG and 10% PVP‐I
45	Matsuoka et al. 2019 60	Japan	Retrospective study	Adults	1.5% OLG	PVP‐I (concentration unknown)	Adverse events	Incidence rate of chemical burn was found to be lower with 1.5% OLG compared to 10% PVP‐I
46	Iijima et al. 2020 59	Japan	Case report	34 y.o. woman	OLG (concentration unknown)	None	Adverse events	Erythma and pruritus appeared on day 10 after OLG application
47	Nagai et al. 2018 61	Japan	Case report	65 y.o. man 64 y.o. woman	OLG (concentration unknown)	None	Adverse events	Erythma appeared after day 6 of OLG application

Abbreviations: CFU, colony forming unit; CHG, chlorhexidine gluconate; CHG‐AL, clorhexidine gluconate alcohol; EtOH, ethanol; LPS, lipopolysaccharide; MBC, minimum bactericidal concentration; MIC, minimum inhibitory concentration; MRSA, methicillin‐resistant Staphylococcus aureus; OLG‐HR, OLG/ethanol hand rub; PVP‐I, povidone‐iodine; RCT, randomized controlled trial; SSI, surgical site; VRE, vancomycin‐resistant enterococci.

In many studies, CHG and PVP‐I used were formulated without alcohol. In studies in which CHG and PVP‐I with alcohol were used, supplementary explanations were provided.

Pharmacology

Structural formula

Olanexidine gluconate is a biguanide antiseptic solution that was developed by Otsuka Pharmaceutical Factory, Inc. in 2015. To reduce skin irritation without decreasing its antimicrobial effect, the medicinal ingredient olanexidine (1‐(3,4‐dichlorobenzyl)‐5‐octylbiguanide [OPB‐2045]) is converted to gluconate, and the solubilizer polyoxyethylene (20) polyoxypropylene (20) glycol (POEPOPG) is added to complete OPB. The chemical formula is 1‐(3,4‐dichlorobenzyl)‐5‐octylbiguanide mono‐d‐gluconate (Fig. 2).

Fig 2

Chemical structure of olanexidine.

Mechanism of action

There were four studies on bactericidal action , , , and one on the inhibitory action of inflammatory chemokines.

Bactericidal action (in vitro/animal studies)

The mechanism underlying the bactericidal action of OLG differs between low and high concentrations, although the detailed mechanism has not been elucidated. At low concentrations (median effective dose [ED50], 8.4–25 μg/mL as the lower limit; no upper limit concentration), OLG has a higher affinity for bacterial surface proteins such as the lipoteichoic acid of Gram‐positive bacteria and lipopolysaccharide (LPS) of Gram‐negative bacteria, compared to CHG with an ED50 of 27–610 μg/mL. Similarly, for phospholipids such as lysyl‐phosphatidylglycerol (L‐PG) and phosphatidylethanolamine (PE), at a concentration higher than the minimal inhibitory concentration (0.63 μg/mL against Gram‐positive bacteria and 4.0 μg/mL against Gram‐negative bacteria), OLG had a stronger disruptive effect than CHG on membranes containing L‐PG and PE. These actions cause irreversible leakage of intracellular components, which leads to a bactericidal effect. However, at high concentrations (>160 μg/mL), OLG showed a bactericidal effect by aggregating bacteria through a protein denaturation effect , (with olanexidine at a concentration of 15 000 μg/mL), which means that it has both low and high concentration effects.

Inhibitory action of inflammatory chemokines (in vitro)

In addition to the bactericidal effects of OLG, it is reported that OLG has an inhibitory action on inflammatory chemokines. Nii et al. administered the LPS of Porphyromonas gingivalis to immortalized human oral keratinocytes, which are regarded as oral epithelial cells, and tested whether the inflammatory cytokines produced by human oral keratinocytes decreased after 0.1% OLG application. The levels of inflammatory cytokines such as interleukin‐8, chemokine (C‐C motif) ligand 20, and growth‐regulated oncogene protein‐α, which cause chronic inflammatory reactions such as periodontitis, decreased after 0.1% OLG application. This suggests that OLG could inhibit the inflammatory response.

Spectrum (in vitro)

Nine studies validated the spectrum: seven for bacteria and fungi , , , , , , and four for viruses. , , , Several studies , , , used the minimum bactericidal concentration (MBC) at which bacterial growth did not occur as an indicator of the bactericidal effect of skin disinfectants.

Bacteria

Seyama et al. undertook a study to examine the bactericidal effect of 1.5% OLG on Gram‐positive cocci, including MRSA and VRE, Gram‐negative bacteria (Burkholderia cepacia and Pseudomonas aeruginosa), and fungi. The number of most Gram‐positive cocci, including MRSA and VRE, reduced within 15 s after 1.5% OLG application (Table 2).

Table 2

Antimicrobial spectrum of olanexidine gluconate (OLG)

First author, year	Microorganism	Method	Time and indicator	Result
Effective
Bacteria
Seyama et al. 2019 21	Gram‐positive bacterium
	Enterococcus faecalis	Evaluation of bactericidal effect by time kill assay (<10, detection limit)	Viable bacterial count (CFU/mL) at 0 s, 15 s, 30 s, and 1 min after 1.5% OLG administration	15 s: <10 30 s: <10 1 min: <10
	Vancomycin‐resistant enterococci
	Staphylococcus aureus			1 min: <10
	Methicillin‐resistant Staphylococcus aureus
	Staphylococcus epidermidis			15 s: <10 30 s: <10 1 min: <10
	Methicillin‐resistant Staphylococcus epidermidis
	Gram‐negative bacterium
	Acinetobacter baumannii	Evaluation of bactericidal effect by time kill assay (<10, detection limit)	Viable bacterial count (CFU/mL) at 0 s, 15 s, 30 s, 1 min after 1.5% OLG administration	15 s: <10 30 s: <10 1 min: <10
	Enterobacter cloacae
	Extended spectrum β‐lactamase producing Klebsiella pneumoniae
	Escherichia coli
	Pseudomonas aeruginosa
	Multidrug‐resistant Pseudomonas aeruginosa
	Serratia marcescens
	Bacteroides fragilis
Fungi
Seyama et al.2019 21	Candida albicans	Evaluation of bactericidal effect by time kill assay (<10, detection limit)	Viable bacterial count (CFU/mL) at 0 s, 15 s, 30 s, and 1 min after 1.5% OLG administration	30 s: <10 10 min: <10
	Malassezia furfur
	Trichophyton rubrum			10 min: <10
	Microsporum canis			3 min: <10 10 min: <10
Virus
Medical package insert 28	Influenza A	No detailed description	No detailed description	Inactivation in 1 min or more
Imai et al.2021 34	Influenza A (H1N1)	Suspension test (comparison agents: OLG‐HR [1.5%], 1.5% OLG, 0.5% OLG, EtOH, 0.1% benzalkonium chloride, 0.5% CHG)	Mean log10 reduction ± 95% CI at 15 s, 30 s, 1 min	1.5% OLG, OLG‐HR, and EtOH completely inactivated at all time
Imai et al.2020 33	Norovirus (all 11 genotypes of GI, GII, and GIV)	Assay log10 RNA copies by RT‐qPCR (comparison agents: OLG‐HR, EtOH [pH 7], EtOH‐A [pH 3], OLG, base with OLG removed from OLG‐HR)	Log10 reduction at 30 s, 1 min	30 s: log10 reduction of OLG‐HR is the highest 1 min: log10 reduction of OLG‐HR is the highest
Imai et al.2021 34	Human coronavirus OC43	Suspension test (comparison agents: OLG‐HR [1.5%], 1.5% OLG, 0.5% OLG, EtOH, 0.1% benzalkonium chloride, 0.5% CHG)	Mean log10 reduction ± 95% CI at 15 s, 30 s, and 1 min	Viral titers after exposure to 0.5% OLG, 1.5% OLG, OLG‐HR, and EtOH for 15 s were under the quantification limits
	Feline infectious peritonitis virus
	Human herpesvirus			1.5% OLG, OLG‐HR, and EtOH completely inactivated at all time
	Respiratory syncytial virus			Viral titers were under the quantification limits at all time
Not effective
Bacterium
Seyama et al.2019 21	Burkholderia cepacia	Evaluation of bactericidal effect by time kill assay (<10, detection limit)	Viable bacterial count (CFU/mL) at 0 s, 15 s, 30 s, and 1 min after 1.5% OLG administration	At all time points: not killed
Seyama et al. 2019 21	Mycobacterium	Evaluation of bactericidal effect by time kill assay (<10, detection limit)	Viable bacterial count (CFU/mL) at 0 s, 15 s, 30 s, 1 min, 60 min after 1.5% OLG administration	At all time points: not killed
	Mycobacterium kansasii
	Mycobacterium intracellulare
	Mycobacterium fortuitum
	Mycobacterium chelonae
	Mycobacterium abscessus
	Mycobacterium avium
Fungi
Seyama et al.2019 21	Aspergillus brasiliensis	Evaluation of bactericidal effect by time kill assay (<10, detection limit)	Viable bacterial count (CFU/mL) at 0 s, 15 s, 30 s, and 10 min after 1.5% OLG administration	At all time points: not killed
Medical package insert 28		No detailed description	MBC (%) at 30 min	30 min: not killed
Medicalpackageinsert 28	Microsporum canis	No detailed description	MBC (%) at 30 min	30 min: not killed
Virus
Medicalpackage insert 28	Feline calicivirus	No detailed description	Log10 reduction (only mentioned at 10 min)	10 min: not killed

Note: All studies are in vitro and animal studies.

Abbreviations: CFU, colony forming unit; CHG, chlorhexidine gluconate; CI, confidence interval; EtOH, ethanol; MBC, minimum bactericidal concentration; OLG‐HR, olanexidine gluconate/ethanol hand rub; RT‐qPCR, reverse transcription–quantitative polymerase chain reaction.

For MRSA, two studies showed that 1.5% OLG was more effective for disinfection than 0.5% CHG and 10% PVP‐I (Table 3). , In addition, two studies , compared whether the MBC of OLG, CHG, and PVP‐I changed in the presence or absence of qacA/B, which encodes a disinfectant efflux pump thought to be responsible for methicillin resistance. The researchers reported that only the MBC of OLG remained unchanged in the presence or absence of qacA/B (Table 3).

Table 3

Comparison of the bactericidal effects of olanexidine gluconate (OLG), chlorhexidine gluconate (CHG), and povidone‐iodine (PVP‐I)

First author, year	Microorganism	Object	Time and indicator	Concentration of OLG	Comparison (concentration)	Result
Gram‐positive bacterium
Hagi et al. 2015 23	Methicillin‐susceptible Staphylococcus aureus	Clinical isolates (30 strains)	MBC (μg/mL) at 30 s, 1 min, 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of PVP‐I was the lowest (OLG, >3,480; PVP‐I, 1,560) 1 min: MBC of PVP‐I was the lowest (OLG, >1,740; PVP‐I, 781) 3 min: MBC of CHG was the lowest (OLG, 869; CHG, 156)
Inoue et al. 2015 25	Methicillin‐resistant Staphylococcus aureus	Culture collections (1 strain)	MBC (μg/mL) at 30 s, 1 min, 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of OLG was equal to that of PVP‐I and lower than that of CHG 1 min: MBC of OLG was equal to that of PVP‐I and lower than that of CHG 3 min: MBC of OLG was equal to that of PVP‐I and lower than that of CHG
		Clinical isolates (30 strains)				30 s: MBC of PVP‐I was the lowest (OLG, >3,475; PVP‐I, 1,563) 1 min: MBC of OLG was the lowest 3 min: MBC of OLG was the lowest
		Applied to the skin of mice (culture collections)	Log of the number of survived bacteria at 30 s, 3 min, and 10 min	1.5%	0.5% CHG 10% PVP‐I	30 s: Log of the number of survived bacteria of 1.5% OLG was the lowest 3 min: Log of the number of survived bacteria of 1.5% OLG was equal to that of 10% PVP‐I and lower than that of 0.5% CHG 10 min: Log of the number of survived bacteria of 1.5% OLG was equal to that of 10% PVP‐I and lower than that of 0.5% CHG
Nishioka et al. 2018 22		Applied to the skin of the Yucatan micropig (culture collections)	Log10 reduction at 30 s and 3 min	1.5%	0.5% CHG 10% PVP‐I 1% CHG‐AL	30 s: log10 reduction of 1.5% OLG was equal to that of 1% CHG‐AL and higher than those of 0.5% CHG and 10% PVP‐I 3 min: log10 reduction of 1.5% OLG was equal to that of 1% CHG‐AL and higher than those of 0.5% CHG and 10% PVP‐I
Nakaminami et al. 2019 20		Clinical isolates (19 qacA/B‐positive strains and 10 qacA/B‐negative strains)	MBC50 (50% strain bactericidal) and MBC90 (90% strain bactericidal) (μg/mL) at 2 min, 5 min and 30 min	Unknown	CHG (unknown) PVP‐I (unknown)	2 min: MBC of OLG was equal to that of PVP‐I and lower than that of CHG 5 min: MBC of OLG was equal to that of PVP‐I and lower than that of CHG 30 min: MBC of OLG was equal to that of PVP‐I and lower than that of CHG MBC of OLG was the same with or without qacA/B
Hagi et al. 2015 23	Coagulase‐negative Staphylococcus	Clinical isolates (20 strains)	MBC (μg/mL) at 30 s, 1 min, and 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of OLG was the lowest 1 min: MBC of OLG was the lowest 3 min: MBC of OLG was the lowest
Nishioka et al. 2018 22	Staphylococcus epidermidis	Applied to the skin of the Yucatan micropig (culture collections)	Log10 reduction at 30 s and 3 min	1.5%	0.5% CHG 10% PVP‐I 1% CHG‐AL	30 s: log10 reduction of 1.5% OLG was equal to those of 1% CHG‐AL and 10% PVP‐I. Log10 reduction of 1.5% OLG was higher than that of 0.5% CHG 3 min: log10 reduction of 1.5% OLG was equal to those of 1% CHG‐AL and 10% PVP‐I. Log10 reduction of 1.5% OLG was higher than that of 0.5% CHG
Hagi et al. 2015 23	Enterococcus spp.	Culture collections (34 strains)	MBC (μg/mL) at 30 s, 1 min, and 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of OLG was the lowest 1 min: MBC of OLG was the lowest 3 min: MBC of OLG was the lowest
Hagi et al. 2015 23	Enterococcus faecalis	Clinical isolates (30 strains)	MBC (μg/mL) at 30 s, 1 min, and 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of OLG was the lowest 1 min: MBC of OLG was the lowest 3 min: MBC of OLG was the lowest
Inoue et al. 2015 25		Clinical isolates (30 strains)	MBC (μg/mL) at 30 s, 1 min, 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of OLG was the lowest 1 min: MBC of OL G was the lowest 3 min: MBC of OLG was the lowest
Inoue et al. 2015 25	Vancomycin‐resistant Enterococcus faecalis	Culture collections (1 strain)	MBC (μg/mL) at 30 s, 1 min, and 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of OLG was the lowest 1 min: MBC of OLG was the lowest 3 min: MBC of OLG was the lowest
		Applied to the skin of mice (culture collections)	Log of the number of survived bacteria at 30 s, 3 min, and 10 min	1.5%	0.5% CHG 10% PVP‐I	30 s: Log of the number of survived bacteria of 1.5% OLG was the lowest 3 min: Log of the number of survived bacteria of 1.5% OLG was the lowest 10 min: Log of the number of survived bacteria of 1.5% OLG was the lowest
Nishioka et al. 2018 22		Applied to the skin of the Yucatan micropig (culture collections)	Log10 reduction at 30 s and 3 min	1.5%	0.5% CHG 10% PVP‐I 1% CHG‐AL	30 s: log10 reduction of 1.5% OLG was equal to that of 1% CHG‐AL. Log10 reduction of 1.5% OLG was higher than those of 0.5% CHG and 10% PVP‐I 3 min: log10 reduction of 1.5% OLG was equal to those of 1% CHG‐AL and 0.5% CHG. Log10 reduction of 1.5% OLG was higher than that of 10%PVP‐I
Hagi et al. 2015 23	Gram‐positive bacilli	Culture collections (9 strains)	MBC (μg/mL) at 30 s, 1 min, and 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of PVP‐I was the lowest (OLG, 1,740; PVP‐I, 781) 1 min: MBC of PVP‐I was the lowest (OLG, 1,740; PVP‐I, 781) 3 min: MBC of OLG was the lowest
Gram‐negative bacterium
Hagi et al. 2015 23	Gram‐negative strains except Burkholderia cepatcia	Culture collections (34 strains)	MBC (μg/mL) at 30 s, 1 min, 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of OLG was the lowest 1 min: MBC of OLG was the lowest 3 min: MBC of OLG was the lowest
	Burkholderia cepacia	Culture collections (2 strains)	MBC (μg/mL) at 30 s, 1 min, 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of PVP‐I was the lowest (OLG, >6,950; PVP‐I, 391) 1 min: MBC of PVP‐I was the lowest (OLG, >6,950; PVP‐I, 391) 3 min: MBC of PVP‐I was the lowest (OLG, 434; PVP‐I, 195)
	Escherichia coli	Clinical isolates (20 strains)	MBC (μg/mL) at 30 s, 1 min, 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of OLG was the lowest 1 min: MBC of OLG was the lowest 3 min: MBC of OLG was the lowest
	Klebsiella pneumoniae	Clinical isolates (20 strains)	MBC (μg/mL) at 30 s, 1 min, 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of OLG was the lowest 1 min: MBC of OLG was the lowest 3 min: MBC of OLG was the lowest
	Pseudomonas aeruginosa	Clinical isolates (20 strains)	MBC (μg/mL) at 30 s, 1 min, 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of PVP‐I was the lowest (OLG, 869; PVP‐I, 781) 1 min: MBC of OLG was the lowest 3 min: MBC of OLG was the lowest MBC
	Serratia marcescens	Clinical isolates (20 strains)	MBC (μg/mL) at 30 s, 1 min, 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of PVP‐I was the lowest (OLG, 3,480; PVP‐I, 391) 1 min: MBC of PVP‐I was the lowest (OLG, 434; PVP‐I, 391) 3 min: MBC of OLG was the lowest
Hagi et al. 2015 23	Acinetobacter baumannii	Clinical isolates (20 strains)	MBC (μg/mL) at 30 s, 1 min, and 3 min	Unknown	CHG (unknown) PVP‐I (unknown)	30 s: MBC of OLG was the lowest 1 min: MBC of OLG was the lowest 3 min: MBC of OLG was the lowest
Nishioka et al. 2018 22		Applied to the skin of the Yucatan micropig (culture collections)	Log10 reduction at 30 s and 3 min	1.5%	0.5% CHG 10% PVP‐I 1% CHG‐AL	30 s: log10 reductions of all skin antiseptics were equivalent 3 min: log10 reductions of all skin antiseptics were equivalent

Note: All studies are in vitro and animal studies.

Abbreviations: CFU, colony forming unit; MBC, minimum bactericidal concentration.

However, 1.5% OLG was more effective in disinfection against VRE than 0.5% CHG and 10% PVP‐I. , Inoue et al. also compared the MBC of OLG, CHG, and PVP‐I against MRSA and VRE: the MBC of OLG against MRSA and VRE was equal to or lower than that of CHG or PVP‐I (Table 3).

Regarding the bactericidal effect on resistant bacteria other than MRSA and VRE, such as methicillin‐resistant Staphylococcus epidermidis, extended‐spectrum β‐lactamase‐producing Klebsiella pneumoniae, and multidrug‐resistant P. aeruginosa, 1.5% OLG killed these bacteria within 15 s after 1.5% OLG application (Table 3). However, B. cepacia was not eliminated more than 30 min after 1.5% OLG application, , and the bactericidal effect of 1.5% OLG on B. cepacia was comparable to those of CHG and PVP‐I (concentrations unknown) reported in a previous study. Furthermore, 1.5% OLG had a poor bactericidal effect on Mycobacterium, consistent with the previously reported bactericidal effect of CHG (concentration unknown). ,

Fungi

Surfaces contaminated with Candida albicans and Malassezia furfur were disinfected within 30 s after 1.5% OLG application, whereas those contaminated with Microsporum canis and Trichophyton rubrum were disinfected within 3 and 10 min, respectively, after 1.5% OLG application. However, Aspergillus brasiliensis was not eliminated even after 10 min of 1.5% OLG application (Table 2).

Viruses

Influenza A virus, which has an envelope, was inactivated by 1.5% OPB for more than 1 min after application. However, feline calicivirus, which does not have an envelope, was not inactivated even 10 min after application.

In addition, Imai et al. reported on the efficacy of OLG hand rub against 11 genotypes of noroviruses, in which ethanol was added to OLG (concentration unknown) for hand disinfection. The OLG hand rub had the highest antiviral effect, when compared to other agents (ethanol [pH 7], ethanol‐A [pH 3], and OLG), suggesting its potential for use as a hand sanitizer (Table 2). Imai et al. also reported on the potential usage of OLG formulations as environmental disinfectants for the control of infections by enveloped viruses (influenza A [H1N1], human coronavirus, feline infectious peritonitis virus, human herpesvirus, and respiratory syncytial virus).

Immediate and sustained bactericidal action (in vitro/animal studies)

Four studies were identified: three on the time‐to‐onset of bactericidal action , , and two on the duration of bactericidal action. ,

Immediate efficacy (in vitro/animal studies)

As mentioned in the section on spectrum, 1.5% OLG showed a disinfectant effect on a wide range of bacteria within 30 s (Tables 2 and 3). Furthermore, Nishioka et al. compared the bacterial counts of MRSA, S. epidermidis, VRE, Acinetobacter baumannii, Corynebacterium minutissimum, and Cutibacterium acnes, which were problematic in SSI, while comparing 1.5% OLG with 0.5% CHG and 10% PVP‐I. Compared to 10% PVP‐I and 0.5% CHG, 1.5% OPB showed an equivalent or greater reduction in bacterial counts 30 s after application.

Substantivity (animal studies)

Nishioka et al. discussed the amount of disinfectant left in the stratum corneum after 4, 8, and 12 h of rinsing immediately after application. The concentration of 1.5% OLG left was 2.8–4.2 times higher in the stratum corneum than that of 1.5% CHG at all incubation times. This indicated that the rate of washout for 1.5% OLG was lower than that for 1.5% CHG. The proportion of bacteria after 12 h of 1.5% OLG application was lower than that after 4 and 8 h, indicating that the bactericidal action time was approximately 12 h. Regarding the long action time of OLG, the reduced effectiveness of disinfectants was generally attributed to sweating and contamination with blood. Nakata et al. evaluated the effectiveness of reducing bacteria after 10 min and 6 h of application of 0.5% CHG, 10% PVP‐I, and 1.5% OLG on blood‐contaminated monkey skin. The decrease in bacterial count after 1.5% OLG application was higher than that after the application of 0.5% CHG or 10% PVP‐I, indicating that the decrease in bactericidal action with blood contamination was smallest after 1.5% OLG application, compared to 0.5% CHG and 10% PVP‐I.

Pharmacokinetics (animal studies)

Thirteen studies on pharmacokinetics were identified: three on dermal absorption, , , eight on metabolism and excretion, , , , , , , , and five on biogenesis. , , , ,

Concerning dermal absorption, Kudo et al. reported two studies: one in which the radioactivity at the injection site was measured at 1, 8, and 24 h after dermal administration of biguanide 14C‐labeled OLG (concentration unknown) in rats and another in which the dermal absorption of 0.1% OLG after the application was measured in intact and damaged rat skin. Olanexidine gluconate remained in the skin and was poorly absorbed in both studies. Regarding reproduction and development, Fujio et al. and Takenaka et al. , , , , carried out animal experiments on rats and rabbits. Parental animals treated subcutaneously with 0.04%–0.0004% OLG showed no effect of the drug application on the estrus cycle of female rats, fertilization rate, nursery condition of mothers after birth, and all cycles up to fetal development.

Clinical setting

Considering that the balance between the benefits and disadvantages is important for clinical adaptation, we provide a description of the efficacy and safety.

Efficacy

Normal skin

Three studies were undertaken on normal skin. , , Two of the studies were RCTs. Two studies included adults, and one study included children. One study compared 1.5% OLG, 0.5% CHG, and placebo. One study compared OLG with CHG; the concentration of OLG ranged from 0.02% to 0.2%, and that of CHG ranged from 0.05% to 0.5%. One study determined the efficacy of OLG (concentration unknown) without a comparator (Table 4).

Table 4

Effect of olanexidine gluconate (OLG) on normal skin and wounded skin

First author, year	Design	Object	Intervention	Comparison	Efficacy
Effect of OLG on normal skin
Harihara et al.2015 52	RCT	Adults; region: abdomen, groin	1.5% OLG 237 cases	Placebo 119 cases	Item: bacteria count after 10 min of application
				0.5% CHG 236 cases	Result: (OLG vs. placebo) 1.5% OLG < placebo
					(OLG vs. CHG) 1.5% OLG is noninferior to 0.5% CHG
Obatake et al. 2020 51	Not mentioned	Children; region: umbilicus, groin	OLG (concentration unknown), 20 cases	None	Item: disinfection effect after 10 min of application
					Result: good bactericidal effect
Nagai et al. 2000 53	RCT	Adults; region: back	OLG (concentration: 0.02%, 0.05%, 0.1%, and 0.2%) Total 30 cases	CHG (concentration: 0.05% and 0.5%) Total 30 cases	Item: exponential reduction value of total viable bacteria before and after application
					Result: 30 s after application
					CHG (0.05%, 0.5%) < OLG (0.05%, 0.1%, 0.2%)
					3 min after application
					CHG (0.05%) < OLG (0.1%, 0.2%)
Effect of OLG on wounded skin
Kobayashi et al. 2000 54	Not mentioned	Adults; sutured skin wound after surgical operation	0.05% OLG 50 cases	None	Item: wound infection prevention and disinfection effects
			Application period: immediately after suture and postoperative days 3, 7, and 14		Result: 59.6%

Note: All studies are in vivo and human studies.

Abbreviation: RCT, randomized controlled trial.

In an RCT that assessed the efficacy of 1.5% OLG on normal skin, OLG showed a significant reduction in bacterial counts after 10 min of application on both the abdomen and groin, compared to placebo. Furthermore, 1.5% OLG was not inferior to 0.5% CHG. Obatake et al. collected samples from the skin (groin and umbilicus) both before and after disinfection with OLG (concentration unknown) and compared the presence or absence of bacteria. It was reported that OLG had a good bactericidal effect on both the groin and umbilical areas; however, specific data were unavailable. In a comparison of the number of viable bacteria before and after disinfection with various concentrations of OLG and CHG, both after 30 s and 3 min of disinfectant application, the exponential reduction in total viable bacterial counts was higher in the OLG groups than in the CHG groups at all concentrations.

Wounded skin

One study evaluated wounded skin. The study population consisted of 50 adult inpatients who underwent clean or semiclean surgical procedures (Table 4). The researchers applied 0.05% OLG to surgically sutured wounds on postoperative days 3, 7, and 14. No antiseptics were used for comparison. The efficacy rate determined by infection prevention and disinfection efficacy was 59.6% (95% confidence interval, 44.4–73.6). The efficacy was adjudged comprehensively based on progress after application and was not described in detail.

Prevention of SSI

Five studies evaluated the effect on SSI prevention. , , , , Two studies were RCTs, and three were retrospective observational studies. One study included children, and the remaining four studies included adults. One study compared OLG, PVP‐I, and CHG, two studies compared OLG to PVP‐I, , and one study had no comparator. One study compared a single application of OLG to two applications of OLG (Table 5).

Table 5

Effect of olanexidine gluconate (OLG) in the prevention of surgical site infection

First author, year	Design	Object	Intervention	Comparsion	Efficacy
Matsumoto et al. 2018 58	Retrospective study	Adults; surgical type: gastrointestinal surgery breast malignancy inguinal hernia repair	OLG (concentration unknown), 100 cases	None	Item: SSI incidence rate at 30 days postoperatively
					Result: 1% (1 case/100 cases)
OLG vs. PVP‐I, OLG vs. CHG
Harihara et al. 2020 57	Retrospective study	Adults; surgical type: gastrointestinal surgery	1.5% OLG (applicator), 2,077 cases	10% PVP‐I, 1,556 cases	Item: All SSI incidence rate
				1% CHG, 1,514 cases	Result: 1.5% OLG < 1% CHG < 10% PVP‐I
Obara et al. 2020 26	RCT	Adults; surgical type: semiclean gastrointestinal surgery	1.5% OLG, 299 cases	10% PVP‐I, 298 cases	Item: 30‐day postoperative SSI rate
					Result: 1.5% OLG < 10% PVP‐I
Shiyanagi et al. 2019 56	Retrospective study	Children; surgical type: clean surgery (inguinal hernia, umbilical hernia, undescended testis, scrotal ema)	1.5% OLG (applicator), 164 cases	10% PVP‐I, 130 cases	Item: all SSI incidence rate
					Result: no occurrence of either OLG or PVP‐I
Single application vs. double applications
Yamamoto et al. 2020 55	RCT	Adults; surgical type: gastrointestinal surgery	Single application OLG applicator (concentration unknown), 198 cases	Double applications OLG applicator (concentration unknown), 202 cases	Item: 30‐day postoperative incisional SSI rate
					Result: no significant difference

Note: All studies are in vivo and human studies.

Abbreviations: CHG, chlorhexidine gluconate; PVP‐I, povidone‐iodine; RCT, randomized controlled trial; SSI, surgical site infection.

A retrospective study examined the effect of OLG (concentration unknown) on the prevention of SSI in 100 patients undergoing gastrointestinal surgery, breast malignancy surgery, and inguinal hernia repair. This study reported only one case (1%) of SSI within 30 days postoperatively in the OLG group. However, 84% of all patients in the study had a low‐risk National Nosocomial Infections Surveillance SSI risk index.

Obara et al. undertook an RCT with a large sample size comparing 1.5% OLG with 10% PVP‐I for disinfection during adult gastrointestinal surgery. A total of 587 patients were included; 294 and 293 patients in the 1.5% OLG and 10% PVI groups, respectively. The 30‐day postoperative SSI rate was significantly lower in the 1.5% OLG group (7% in the 1.5% OLG group vs. 13% in the 10% PVP‐I group; adjusted risk ratio, 0.48; 90% confidence interval, 0.03–0.74; p = 0.002). Similarly, in another retrospective study of adult gastrointestinal surgery patients, the overall SSI incidence rate was significantly lower in the 1.5% OLG group (7.2% in the 1.5% OLG group vs. 10.0% in the 10% PVP‐I group). This study did not describe the detailed statistical methods and results. A retrospective study of clean pediatric surgeries found no difference between the 1.5% OLG group and the 10% PVP‐I group because no postoperative SSI occurred in either group.

Regarding the comparison between 1.5% OLG and 1% CHG, a retrospective study of adult gastrointestinal surgery patients revealed that the overall SSI incidence rate was significantly lower in the 1.5% OLG group (7.2% in the 1.5% OLG group vs. 9.8% in the 1% CHG group). However, this study did not describe detailed statistical methods or results.

One RCT compared single and double application of OLG (concentration unknown) for disinfection during laparoscopic or robotic standby gastrointestinal surgery in adults. The incident rate of all SSIs within 30 days after surgery was not significantly different between the two groups, and single application was noninferior to double application (3.1% in the single application group vs. 2.0% in the double application group, p = 0.537).

Prevention of CRBSA

No relevant studies were identified.

Safety

The overall incidence of adverse events in OLG was very low, ranging from 2% to 5.8%. , , , , , , Erythema, dermatitis, and pruritus each accounted for approximately 1.0%–1.9% of adverse events. , , , The time of appearance of skin rash was approximately 3–17 days (median, 7 days) after application (Table 6). The severity of the disease ranged from mild to moderate, with some cases of spontaneous resolution and resolution after oral antihistamine or topical corticosteroid use. , , , , , ,

Table 6

Safety of olanexidine gluconate (OLG)

First author, year	Design	Object	Intervention	Comparsion	Adverse event
Sugai, 1999 65	Not mentioned	Adults; region: forearm, back	OLG concentration: 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% Total 24 cases	Placebo 24 cases	Urticaria/light urticaria/phototoxic reaction: safety
Sugai, 1999 66	Not mentioned	Adults; region: back	0.1% OLG 9 cases	None	Association unknown: transient elevation of white blood cells 1 case
			0.5% OLG 9 cases
					Serum/urine OLG unchanged Concentration: below the lower limit of detection
Sugai, 1999 67	Not mentioned	Adults; region: forearm	0.1% OLG 6 cases	None	Local and systemic subjective/objective symptoms: none
			0.5% OLG 6 cases
			Application times: twice a day for 5 days		Serum/urine OLG unchanged concentration: below the lower limit of detection
Sugai, 1999 68	Not mentioned	Adults; region: skin with artificially inflicted incisions	OLG concentration: 0.005%, 0.01%, 0.03%, 0.05%, and 0.1% Total 25 cases	Placebo 25 cases	Light Urticaria/phototoxic/contact sensitization/contact phototoxic/contact urticaria reaction: safety
Harihara et al. 2015 52	RCT	Adults; region: abdomen, groin	1.5% OLG 237 cases	Placebo 119 cases	OLG erythema: 3 cases (1.3%)
				0.5% CHG 236 cases	Placebo erythema: 1 case (0.8%)
					CHG erythema: 2 cases (0.8%)
Harihara et al. 2015 52	RCT	Adults; surgical type: gastrointestinal surgery	1.5% OLG 52 cases	10% PVP‐I 54 cases	OLG All: 3 cases (5.8%) erythema:1 case (1.9%) dermatitis:1 case (1.9%) pruritus:1 case (1.9%)
					PVP‐I All: 4 cases (7.4%) erythema: 4 cases (7.4%)
Obara et al. 2020 26	RCT	Adults; surgical type: semiclean gastrointestinal surgery	1.5% OLG 299 cases	10% PVP‐I 298 cases	OLG
					All: 5 cases (2%) erythema:4 cases (1%) dermatitis:4 cases (1%) pruritus:2 cases (1%)
					PVP‐I
					All: 5 cases (2%) erythema: 1 case (<1%) dermatitis:2 cases (1%) pruritus:2 cases (17%)
Shiyanagi et al. 2019 56	Retrospective study	Children	1.5% OLG	10% PVP‐I	Chemical burn incidence rate:
		Surgical type: Clean surgery (inguinal hernia, umbilical hernia, undescended testis, scrotal edema)	(applicator) 164 cases	130 cases	OLG 0% vs. PVP‐I 5% (p < 0.05)
Matsuoka et al. 2019 60	Retrospective study	Surgical type: not mentioned	OLG (concentration unknown) 626 cases	PVP‐I (concentration unknown) 567 cases	Rash incidence rate:
					OLG 3.7% vs. PVP‐I 0.7% (p < 0.0001)
					Onset: days 3–17 (median, day 7)
Harihara, 2020 57	Retrospective study	Adults	1.5% OLG (applicator) 2,077 cases	10% PVP‐I 1,556 cases	OLG
		Surgical type: Gastrointestinal surgery			delayed onset dermatitis: a few cases/2,077 cases
				1% CHG 1,514 cases	PVP‐I and CHG: not mentioned
Iijima et al. 2020 59	Case report	34 y.o. woman	OLG (concentration unknown)	None	Type: erythma, pruritus Onset: Day 10
		Surgical type: cesarean section
Nagai et al. 2018 61	Case report	65 y.o. man	OLG (concentration unknown)	None	Type: erythma, pruritus
		Surgical type: thoracoscopic lobectomy			Onset: day 10
		64 y.o. woman; surgical type: thoracoscopic lobectomy			Type: erythma Onset: day 6

Note: All studies are in vivo and human studies.

Abbreviations: CHG, chlorhexidine gluconate; PVP‐I, povidone‐iodine; RCT, randomized controlled trial.

In an RCT comparing 1.5% OLG and 10% PVP‐I in adult gastrointestinal surgery, there was no significant difference in the rate of all adverse events between the two groups (2% in the 1.5% OLG group vs. 2% in the 10% PVP‐I group, p = 1.00). Although the results of the detailed statistical analysis were not described, another RCT also showed similar results (overall adverse event rate: 5.8% [3/52 cases] in the 1.5% OLG group vs. 7.4% [4/54 cases] in the 10% PVP‐I group). In contrast, a retrospective study comparing the incidence of postoperative dermatitis between OLG (concentration unknown) and PVP‐I (concentration unknown) revealed that OLG yielded a significantly higher incidence (3.7% in the OLG group vs. 0.7% in the PVP‐I group, p < 0.0001).

Only one study, a phase III trial, compared OLG with CHG in terms of adverse event rates. The subjects were adults with healthy skin (abdomen and groin), and there was no difference in the rates of skin eruption between 1.5% OLG and 0.5% CHG (1.3% [3/237 cases] in the 1.5% OLG group vs. 0.8% [2/236 cases] in the 0.5% CHG group). However, the results of detailed statistical analysis were not described in this study.

Ongoing clinical studies

Five ongoing clinical studies were identified. All are being undertaken in Japan, and three are related to SSI prevention. One study was related to disinfection at the time of blood culture collection, and one study was related to CRBSI (Table S3).

DISCUSSION

In the present scoping review, we searched and summarized the evidence from existing studies on OLG. The retrieved published works were classified into 29 in vitro studies or animal studies and 18 clinical studies. In addition to common Gram‐positive and Gram‐negative bacteria, OLG showed bactericidal activity against MRSA and VRE. In clinical settings, although there is limited evidence on SSI prevention, 1.5% OLG might be more effective than 10% PVP‐I and 1% CHG. However, its usefulness under other conditions is unclear.

In vitro studies have shown that the antimicrobial spectrum of OLG is broad and seems to be effective against resistant bacteria. However, its clinical usefulness remains unclear. Olanexidine gluconate showed a broad‐spectrum bactericidal effect on both Gram‐positive and Gram‐negative bacteria (Table 1), and the bactericidal effects on resistant bacteria such as MRSA and VRE were characteristic (Table 2). In emergency and intensive care, infections such as CRBSI and SSI caused by resistant bacteria (such as MRSA and VRE) are becoming a problem. , , , In addition, existing antiseptics such as PVP‐I and CHG are considered ineffective against these resistant bacteria. , , , Therefore, OLG could be a useful disinfectant in emergency and intensive care settings. However, clinical studies on OLG are limited, and its clinical usefulness remains unclear.

In clinical settings, the usefulness of OLG is limited to its potential effect on SSI prevention. Moreover, the superiority of OLG over standard skin antiseptics such as chlorhexidine alcohol (CHG‐AL) is unclear. All studies on the usefulness of OLG in clinical settings are related to SSI. An RCT comparing 1.5% OLG with 10% PVP‐I revealed that the overall SSI incidence rate was significantly lower in the OLG group. However, the comparator antiseptic used in this study was an aqueous formulation of PVP‐I, which is a nonalcohol‐based antiseptic and is already not recommended for use as a skin antiseptic in many countries. A study comparing 1.5% OLG with 1% CHG also revealed that the overall SSI incidence rate was significantly lower in the OLG group. However, the interpretation of the results is limited by the fact that this was a retrospective study, and the results of detailed statistical analyses were not described. Therefore, the clinical usefulness of OLG against CHG‐AL is still unclear. In the future, more studies comparing OLG with standard skin disinfectants and more studies on OLG for infection prevention are needed.

We reviewed studies on the in vitro pharmacological effects, antimicrobial spectrum, pharmacokinetics, and in vivo efficacy and safety on normal skin, wounded skin, and infection prevention. In the clinical setting, there were only studies related to the prevention of SSI with OLG, , , , and we did not identify any other studies on the prevention of infection, including CRBSI. Catheter‐related bloodstream infection is associated with high morbidity and mortality in critically ill patients , , , ; therefore, high‐quality clinical studies focusing on CRBSI prevention are needed in the future. A large randomized controlled study comparing 1.5% OLG and 1% CHG‐alcohol for the prevention of CRBSI during central venous catheter insertion is currently ongoing in Japan.

This review does have some limitations. The studies reviewed were all undertaken in Japan and, due to the novelty of the drug, the number of studies was limited.

CONCLUSION

Olanexidine gluconate is a novel disinfectant with a broad spectrum and bactericidal effect against organisms, including MRSA and VRE, that are resistant to existing disinfectants such as PVP‐I and CHG. Olanexidine gluconate might be more effective than PVI and CHG for SSI prevention. However, the clinical usefulness of OLG is unclear due to the limited number of clinical studies. In addition, clinical research is limited to studies targeting SSI prevention, and there is no clinical study on CRBSI. Therefore, further clinical studies are needed not only on the prevention of SSI but also on the prevention of CRBSI.

DISCLOSURE

Approval of the research protocol: N/A.

Informed consent: N/A.

Registry and registration no. of the study/trial: N/A.

Animal studies: N/A.

Conflict of interest: None.

ACKNOWLEDGMENT

The authors would like to thank Editage for English language editing.

Table S1. Search strategy on the applications of olanexidine.

Table S2. List of excluded studies.

Table S3. Ongoing studies on olanexidine.

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