REVIEW

Infectious Disease Management and Controlwith Povidone Iodine

Maren Eggers

Received: June 6, 2019 / Published online: August 14, 2019� The Author(s) 2019

ABSTRACT

With reports of vancomycin-resistant entero-cocci recently emerging in hospital settings,renewed focus is turning to the importance ofmultifaceted infection prevention efforts.Careful compliance with established hygienepractices by healthcare workers together witheffective antiseptic options is essential for theprotection of patients from infectious agents.For over 60 years, povidone iodine (PVP-I) for-mulations have been shown to limit the impactand spread of infectious diseases with potentantiviral, antibacterial and antifungal effects. Inaddition to a lack of reported resistance, thebenefits of PVP-I include an excellent safetyprofile and a broad spectrum of effect due to itsmultimodal action. Studies have shown thathand washing with PVP-I-based antiseptics iseffective for the decontamination of skin, whilePVP-I mouthwashes and gargles significantlyreduce viral load in the oral cavity and theoropharynx. The importance of PVP-I has beenemphasised by its inclusion in the World HealthOrganization’s list of essential medicines, and

high potency for virucidal activity has beenobserved against viruses of significant globalconcern, including hepatitis A and influenza, aswell as the Middle-East Respiratory Syndromeand Sudden Acute Respiratory Syndrome coro-naviruses. Together with its diverse applicationsin antimicrobial control, broad accessibilityacross the globe, and outstanding safety andtolerability profile, PVP-I offers an affordable,potent, and widely available antiseptic option.

Funding Mundipharma Singapore HoldingPte Limited.

Keywords: Infection control; Infectiousdisease; Povidone iodine; Sterility; Viraloutbreak

AbbreviationsHFMD Hand, foot, and mouth diseaseHIV Human immunovirusICU Intensive care unitMDCK Madin–Darby canine kidneyMERS Middle East Respiratory SyndromeMRSA Methicillin-resistant Staphylococcus

aureusPVP-I Povidone iodineSARS Severe Acute Respiratory SyndromeUV UltravioletWHO World Health Organization

Enhanced digital features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.9168032.

M. Eggers (&)Labor Prof Gisela Enders MVZ GbR, Stuttgart,Germanye-mail: eggers@labor-enders.de

Infect Dis Ther (2019) 8:581–593

https://doi.org/10.1007/s40121-019-00260-x

BACKGROUND

The importance of robust infection preventionpractices has been highlighted recently withreports of vancomycin-resistant enterococci(VRE) emerging in hospitals in Switzerland [1],Australia [2] and New Zealand [3]. Recently, anAustralian study has shown that Enterococcifaecium, the microorganism responsible forvarious nosocomial infections, was behind over30% of enterococcal bacteremia cases surveyedin the country [4]. It was found that 90% ofthese were ampicillin-resistant CC17 strains,while 50% were also vancomycin-resistant.Other evidence suggests that some E. faeciumstrains may be expressing limited resistance toalcohol-based sanitisers, although at concen-trations significantly lower than is recom-mended for use in hospital settings [5]. Thecontinuing spread of antibiotic resistance is anarea of significant concern and necessitates thecareful consideration of more rigorous man-agement practices, as well as the assessment ofalternative antiseptics for broad hygieneapplications.

Povidone iodine (PVP-I) is a widely-availablealternative antiseptic to alcohol that is com-monly used in clinical settings, including forskin disinfection before and after surgery. It isusually applied to the skin as a liquid or apowder and can be used to treat current infec-tions and prevent the spread of opportunisticpathogens. PVP-I has a broad antimicrobialspectrum and is active against a plethora ofviruses and antibiotic-resistant bacterial strains(Table 1). Susceptible Gram-negative bacteria

include Klebsiella pneumoniae, a commonpathogen in hospitals, and susceptible Gram-positive bacteria include methicillin-resistantStaphylococcus aureus and Escherichia coli. Inaddition, PVP-I has been shown to be superiorto chlorhexidine in hand washing studiescomparing efficacy against bacteria and viruses(Table 2).

PVP-I formulations first became available in1955, and the active ingredient is listed on theWorld Health Organization’s (WHO) List ofEssential Medicines, a list of the most importantmedicines necessary for any functional health-care system. PVP-I is available over the counterand is often used as a broad-spectrum topicalantiseptic treatment for minor cuts, burns, andabrasions, as well as in surgical operating the-atres. Widespread use in diverse clinical andnon-clinical settings over recent decades hasmade the numerous advantages of PVP-I for-mulations more apparent. In addition to abroad-spectrum effect and excellent safety pro-file, active iodine has various properties that canaid in wound healing, with a strong evidence-based rationale existing for the application ofPVP-I in treating infected wounds. The Euro-pean Wound Management Association haspublished a position paper that acknowledgesthe broad spectrum of PVP-I activity againstbacteria, viruses, fungi and endospores [6]. Incontrast to other antiseptics, significant resis-tance or cross-resistance has not been observedfor iodine, likely due to the various mechanismsthrough which iodine elicits its effects. It hasthus found diverse applications in healthcare asa sterilising agent for pre- and post-operative

Table 1 Comparison of antimicrobial activities of common antiseptic classes [12, 13]

Antiseptic type Inactivates

Bacteria Bacterial spores Enveloped viruses Non-enveloped viruses

Quaternary ammonium ? ? – –

Chlorine ? Variable ? ?

Ethanol ? – ? Variable

Iodine ? ? ? ?

Phenolic ? – ? Variable

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skin cleaning, for the prevention and treatmentof infections in ulcers, and in many otherapplications. The formulations are typicallymanufactured with concentrations of 7.5–10%PVP-I in solution, with oral formulationsincluding 1% oral gargle, in addition to surgicalscrubs, ointments, and swabs.

Preclinical and clinical safety and efficacydata show that PVP-I exhibits characteristicsthat are well-suited to wound-healing scenarios,including efficacy against biofilms, good toler-ability and some degree of anti-inflammatoryeffect [7, 8]. Of clinical relevance, healing inclean wounds is not suppressed by PVP-I, whileit is supported in wounds that are colonised bymicroorganisms. It is particularly useful for thetreatment of sensitive wounds and those wherean extended duration of therapy is needed.Medicated gauzes are now widely available,making the formulations easier to apply [9].

PVP-I also elicits potent antiviral activity,with commercially available formulationsshown to be more effective in terms of viralreduction than alcoholic and non-alcoholicsanitisers, as well as antimicrobial soaps [10].Alcohol is a widely used antiseptic likely due toits affordability and relative ease of manufac-ture, but has been shown to be less effectivethan PVP-I at killing microorganisms [11].

Compliance with Ethics Guidelines This articleis based on previously conducted studies anddoes not contain any studies with human par-ticipants or animals performed by any of theauthors.

MECHANISMS OF ACTION OF PVP-I

PVP-1 refers to an iodine preparation com-monly used in both household and healthcaresettings. It consists of a complex of povidone,hydrogen iodide, and elemental iodine whichtargets structures critical to the survival andreplication of microorganisms. Common for-mulations typically consist of a 10% PVP-Isolution containing 1% available iodine.

Following application, elemental iodine cantake on several forms in aqueous solution, withthe molecular I2 and hypoiodous acid (HOI)being the most effective in terms of antimicro-bial activity [16]. The iodine molecules are freeto oxidise vital pathogen structures such asamino acids, nucleic acids and membranecomponents. An equilibrium is achieved insuch circumstances, with more PVP-boundiodine released into solution to replace theiodine that is consumed by germicidal activity.The maintenance of this equilibrium ensureslong-lasting efficacy during bouts of microor-ganism proliferation, as well as better tolerabil-ity for patients due to lower levels of irritation.Electron microscopy and biochemical observa-tions support the hypothesis that PVP-I disruptsmicrobial cell walls by inducing pore formation,leading to cytosol leakage [17]. The lack ofreported resistance to PVP-I to date is thoughtto be due to the sheer diversity of susceptibletargets within each pathogen, an importantaspect to be considered in the face of risingconcerns for antibiotic resistance.

Table 2 Data from direct comparisons of antimicrobial activities of common antiseptics in hand washing studies [14, 15]

Antiseptic type Bacterial CFUs Escherichia coli Murine norovirus

Chlorhexidine ?? ??? ?

Povidone-iodine ??? ??? ???

n-Propanol ??? Not compared Not compared

CFUs Colony-forming units

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PVP-I AGAINST ANTIMICROBIAL-RESISTANT BACTERIAL STRAINS

The emergence of antibiotic resistant strains ofbacteria, including VRE and methicillin-resis-tant Staphylococcus aureus (MRSA), has become asignificant issue for healthcare facilitiesthroughout the world. Indeed, studies haveshown that approximately 42% of S. aureusisolates in Europe and Japan harbour genes thatenable resistance to quaternary ammoniumcompounds and chlorhexidine, with chlorhex-idine overuse thought to be a factor in emergingresistance in some strains of Gram-negativebacteria [18, 19]. The prevalence of methicillinresistance harboured by strains of S. aureuscapable of causing bloodstream infectionbetween 1990 and the early 2000s in the UKrose significantly from 2 to[ 40%, with meanoverall rates of bacteraemia involving MRSAranging from 0.10 to 0.19 per 1000 occupiedbeds [7]. The overuse of antibiotics is thought tobe a contributing factor towards rising antibi-otic resistance, and is now being discouraged infavour of the wider usage of antiseptics, towhich it is more difficult for bacteria to developresistance [7].

While evidence of cross-resistance toantiseptics and antibiotics has been docu-mented for many agents, in over a century ofuse, no significant acquired resistance or cross-resistance has been reported for iodine whenused for specific indications [20]. This strikinglack of resistance is thought to be due to thediverse mechanisms through which iodinesimultaneously exerts its effects. Although someaspects remain to be fully understood, iodine’smicrobicidal activity is known to involve theoxidation of bacterial cell components, includ-ing amino/fatty acids, nucleotides, lipids in thecell membrane, and enzymes in the cytosol,ultimately promoting their denaturation anddeactivation [16]. More specifically, the multi-modal action of iodine is known to arise fromthe potent oxidation of NH–, OH–, and SH–groups on amino acids, nucleotides and unsat-urated fatty acids, and the emergence of resis-tance is likely to be prevented by the sheerdiversity of targets affected. Such effects

eventually result in the simultaneous inactiva-tion of bacterial enzymes, a loss of genomeintegrity, and cell wall damage, overwhelmingthe microorganism’s repair mechanisms.

In a hallmark study, the development ofbacterial resistance to iodine was investigatedby serial passage of two strains of Pseudomonasaeruginosa, two strains of Escherichia coli, twostrains of Klebsiella aerogenes, and one strain ofSerratia marcescens in the presence of sub-opti-mal concentrations of iodine that were insuffi-cient to cause cell death [21]. The investigatorsfound that, after 20 passages, nodetectable change was observed in the minimalinhibitory concentration of iodine needed, northe time taken until cell death occurredbetween the parent strain and the passagedsubcultures when exposed to efficacious con-centrations of iodine. The PVP-I formulationcontaining up to 1% available iodine was ableto kill all strains tested in under 5 min, withmost cells being destroyed within 30 s. Whiledilute concentrations were noted to take inexcess of 10 min to achieve an effect, even theseiodine dilutions were successful in killing allstrains upon prolonged exposure. In real-worldscenarios, over-the-counter PVP-I formulationsare accommodating of such prolonged exposureto healthy skin, with some commercial formu-lations known to be active for 12–14 h, com-pared to the 1–4 h of activity documented forchlorhexidine against fungi and endospores. Ofparticular note, clinical isolates of chlorhexi-dine-resistant Klebsiella pneumoniae that are alsocross-resistant to colistin have recently beenidentified [22]. While chlorhexidine is com-monly used in disinfectants, these new findingssuggest that exposure to chlorhexidine is asso-ciated with stable resistance to colistin, anantibiotic of last resort for multidrug-resistantinfections.

PVP-I IN ANTIVIRAL APPLICATIONS

Various experimental models have been devel-oped to examine the antiviral properties ofparticular agents, with testing recommended tobe taken in a stepwise approach. The EuropeanCommittee of Standardization (CEN)

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recommends that the first phase involve anin vitro suspension test with enveloped viruses(representing the bulk of emerging infectiousdisease threats). Phase 2 involves similar con-ditions, but with non-enveloped viruses, whilethe third and final phase involves human handsin a simulation study. In addition to a virucidalhand test, variations on the latter step caninclude a quantitative non-porous surface testwithout mechanical action, a quantitative car-rier test, and a so-called 4-field test involvingsurface disinfection with mechanical action(Fig. 1).

Similarly, the US Center for Disease Controlrecommends a standardised method simulatinghand washing with the antiseptic formula to betested to determine efficacy in reducing handmicroflora [23]. New test models have enabledthe assessment of PVP-I formulations againsthighly infective and dangerous pathogens thatmay not be possible to test in vivo due to clin-ical risks and ethical considerations. Variouscommercially available formulations haveachieved the standards of the latest Europeanguidelines (EN 14476 and EN 1499), with effi-cacy demonstrated in both the Enveloped VirusTest Model (MVA) and Non-Enveloped Virus

Test Model (MNV). The use of such modelviruses can provide valuable data for informeddecision-making during public health crises.

EN 14476 is a standardised inactivation assaythat involves a virus suspension, an interferingsubstance (such as bovine serum albumin), andthe substance to be tested [24]. A virus controlmixture is used to compare the effects of theantiviral product following a specified contacttime (e.g. 15, 30 or 60 s), with virucidal activitycalculated by determining the difference inlogarithmic titre between the virus control andthe test virus cultures.

The assessment of microbicidal efficacy canbe challenging, due to the difficulties in directobservation and the sheer numbers of cells orparticles involved. Consensus within the medi-cal community has settled upon a minimummeasure required to evaluate microbicidal effi-cacy, referred to as the log10 reduction factor.This is a mathematical term measured by titra-tion at the endpoint and indicates the reductionin the number of living or viable microbes aftertreatments such as sanitisation, disinfection, orcleaning. European Standards (EN) stipulate aminimum level of C 4 log10 reduction in titrefor viruses and fungi, and a C 5 log10 reduction

Fig. 1 Stepwise approach according to the EuropeanCommittee of Standardization (CEN). Hand disinfectiontests highlighted in green. Stepwise approach as proposed at

the 2nd International Meeting on Respiratory Pathogens(IMRP) held in Singapore on March 9, 2018 (see: https://www.isirv.org)

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for bacteria, representing reductions in theabsolute number of microbes by 99.99% and99.999%, respectively (Table 3).

The introduction and use of model viruseshas significantly aided in the investigation ofnew anti-virucidal agents, particularly duringtimes of pressing need. For example, inDecember 2013, the Ebola virus was first dis-covered in Guinea, and rapidly became one ofthe most complex epidemics in recent history.Due to its high biosecurity level, research intovaccines and containment measures for thevirus was highly limited. Although yet to beconfirmed as a surrogate for Ebola virus, themodified vaccinia virus (MVA) was introducedin 2014 with a reference claim against ‘‘en-veloped viruses for hygienic hand rub and handwash’’ [10]. Such models allow for reasonableprogress to be made in comparing antiviralagents in certain settings. Similarly, Middle EastRespiratory Syndrome (MERS) was first discov-ered in 2012, with the virus now having infec-ted more than 1300 victims in 26 countries,resulting in more than 480 deaths. Transmis-sion is known to frequently occur in healthcaresettings, highlighting the need for suit-able models to test containment measures. Themodified vaccinia virus, Ankara, has been usedas a test model for MERS, with similar structuralfeatures and cultivation measures [24].

The influenza virus has been responsible forsome of the most significant epidemics in themodern world, with annual outbreaks resultingin approximately 3–5 million cases of severeillness and between 250,000 and 500,000 deathsper year [25]. An influenza study using plaqueinhibition assays showed that a 1.56-mg/mlPVP-I treatment can inhibit infections in MDCK

cells by human (eight strains) and avian (fivestrains) influenza A viruses, including H1N1,H3N2, H5N3 and H9N2, from 23 to 98%.Receptor binding analysis revealed thathaemagglutinin inhibition was the likely causeof the PVP-I virucidal activity, rather than theinhibition of host-specific sialic acid receptors.The finding also demonstrates two specificmechanisms of reduction of viral growth,namely, PVP-I blockade of viral attachment tothe host cell receptors and the inhibition ofviral release from infected cells [26].

PVP-I formulations are also known to havebroad antiviral properties. These effects aremechanistically similar in principle to iodine’santibacterial activity. For example, the virucidalmechanisms of action of PVP-I have beendetermined to involve the inhibition of essen-tial viral enzymes such as neuraminidase. Theinactivation of this enzyme blocks viral releasefrom the host cell, preventing further spread ofthe virus to uninfected cells. In addition, PVP-Ialso inhibits viral haemagglutinin, resulting inthe blockade of attachment to host cell recep-tors. By simultaneously targeting both criticalaspects of the viral machinery needed forreplication, PVP-I reduces the likelihood ofresistance emerging through sudden mutation.

Under such guidelines, PVP-I formulationshave been shown to elicit viral inactivationof[ 99.99% in test systems using a modifiedvaccinia virus [24]. Virucidal efficacy has insome cases been determined to occur within15 s of contact. Following a hand simulationstudy with the murine norovirus, it was foundthat hand washing with PVP-I was more effec-tive than chlorhexidine and soft soap, a goldstandard recommended by the WHO. PVP-I was

Table 3 Log10 reduction factor: the minimum measure of microbicidal efficacy [EN 14885]

Virus Bacteria Fungi/yeast

Log10 reduction to achieve (reduction in

microbial titre)

C 4 C 5 C 4

Microbial reduction (%) 99.99% 99.999% 99.99%

Standard EU Standards (EN) German

Guidelines

EU Standards

(EN)

EU Standards

(EN)

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also shown to be more virucidal against bothenterovirus and coxsackievirus when comparedto other disinfectants.

The need to develop potent antiviral for-mulations suitable for widespread use has beenbrought to prominence by the emergence ofrapid viral outbreaks over the past decade, manyof which have been coronaviruses. The MiddleEast Respiratory Syndrome coronavirus (MERS-CoV) is a single-stranded RNA virus first iden-tified during an outbreak in 2012 that eventu-ally spread to 21 countries worldwide, triggeringmass media coverage [24]. To date, the virusremains categorised as a high biosafety risk,with containment remaining the primary mea-sure to combat outbreaks, as no vaccines orspecific antiviral treatments have yet beendeveloped. However, randomised controlledclinical trials have shown that PVP-I and alco-hol-based hand rubs are more effective thansoap-based hand washes for hand hygiene inthe presence of such transmissible viruses [16].

In a study evaluating mouthwash, surgicalscrubs, and skin cleanser formulations of PVP-Ifor antiviral activity against the MERS coron-avirus, it was shown that the viral titre could bereduced by a factor of C4 log10, correspondingto a c.99.99% inactivation level [24]. Thisremarkable level of potency was achievedwithin 15 s of application of each PVP-I for-mulation, which included a 7.5% PVP-I surgicalscrub, a 1% PVP-I gargle/mouthwash and a 4%PVP-I skin cleanser formulation under thebrand name Betadine (Mundipharma, Limburg,Germany). The findings indicate that PVP-I-based hand hygiene products can be used todecontaminate virally-infected skin, while PVP-I mouthwash can reduce viral load in the oralcavity and the oropharynx, potentially aidingin the support of hygiene measures needed toreduce the severity of future MERS outbreaks.

An earlier cooperative study presentingresults in comparison with other antiseptics hasshown how PVP-I impacts the infectivity ofsome of the most significant human pathogenicviruses, including polio-, HIV-1, adeno-, rota-,mumps, rhino-, coxsackie-, rubella, herpes-,measles, and influenza viruses. Mumps andadeno-viruses have been decimated in test set-tings by a more than 3-log reduction within 60 s

of exposure to PVP-I concentrations higher than0.5% [27]. Influenza virus was inactivated by amore than 5-log reduction following 15 s at thesame dose levels, while HIV was reduced by amore than 4.5-log reduction after a 30-s expo-sure to doses higher than 0.05%. However,coxsackievirus and poliovirus type 1 wereobserved to be not as sensitive to PVP-I inacti-vation, with both viruses requiring doses higherthan 0.125% for inactivation, as was the case forrhinovirus. The authors concluded that PVP-Ipreparations were effective against measles,mumps, herpes, HIV, influenza, and rota-viru-ses, while rubella, polio-, adeno-, and rhino-viruses were only sensitive to higher doses. Thefact that both virus types could be either sensi-tive or resistant regardless of whether they wereenveloped or non-enveloped suggests thatmechanisms specific to certain viral types arelikely to some extent to influence iodine sensi-tivity. Overall, the findings are of particularrelevance given that an overwhelming propor-tion of sore throat cases are thought to be ofviral origin, and there appears to remain anoverprescribing of antibiotics in such cases.

PVP-I FOR HOSPITAL INFECTIONCONTROL

Hospital settings are particularly challenging forantisepsis, as antibiotic-resistant strains are aconstant threat. PVP-I is widely used in surgicalsettings to prevent infection by ensuring pre-operative decontamination. The aim of suchdecontamination is to reduce the risk of skinflora being introduced into sensitive areas oncethe skin barrier has been breached. Normal andinnocuous bacterial flora that usually colonisehealthy skin can become harmful in such set-tings, particularly for immuno-compromisedindividuals. A PVP-I surgical scrub with adetergent and foam booster is recommended forthe most effective preoperative sterilisation[11].

A comprehensive literature review by a jointcommittee consisting of representatives fromthe British Society of Antimicrobial Che-motherapy, the Hospital Infection Society, andthe Infection Control Nurses Association

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concluded that 7.5% povidone iodine or 2%triclosan is helpful for the eradication and sup-pression of skin colonisation for short periods,particularly in preoperative settings [19]. TheWorking Party recommended in its findingsthat patients bathe daily for 5 days with anappropriate antiseptic detergent. The skinshould be moistened, and an antiseptic deter-gent should be applied thoroughly to all areasbefore rinsing in the bath or shower. The use ofsuch antiseptics was also recommended for allother washing procedures and for bed bathing.

Patients requiring endotracheal intubationare at a higher risk of microbial infection bybacterial strains including nosocomial pneu-monia. In a study of hospital patients under-going oral intubation, it was found that garglingwith 25 ml (2.5 mg/ml) of PVP-I for 1 min,twice, reduced the presence of bacteria in thetrachea [28]. Prior to intubation, all 19 patientsin the control group (5 of whom had MRSA)who gargled tap water were found to have bac-teria contaminating the tip of the tracheal tubeupon removal. However, in the group that gar-gled PVP-I, general bacteria and MRSA wereeradicated from the pharynx prior to intuba-tion, as well as at the tip of the tracheal tubeafter removal. With proper use of PVP-I, surgicalsites can be effectively decontaminated, and therisk of postoperative infection greatly reduced.Indeed, postoperative infection rates are lowerwhen procedures include a sterilisation stepwith PVP-I [29]. Patients undergoing gastroin-testinal procedures are at a higher risk of post-operative wound infection due to the difficultyin removing enteric bacteria present in the gut.However, PVP-I formulations have also beenshown to be effective in preventing complica-tions arising from infections in such settings[30], resulting in an average of five fewer daysspent in hospital recovery. Additionally, the useof a PVP-I mouthwash prior to dental extractionprocedures has been shown to reduce gingivalbacteria, lowering the risk of bacteraemia [31].

Other sterilisation approaches can be con-sidered for use in combination with PVP-I.Microbial pathogens such as influenza andtuberculosis can spread by airborne pathways inhospital settings. Although UVC light is knownto inactivate such agents, even brief exposure to

this highly energetic light can damage humantissue. In an interesting recent study, research-ers used a UV-based sterilisation approachincorporating single-wavelength far-UVC lightgenerated by filtered excilamps, which wasfound to kill pathogenic microorganisms [32].Importantly, the wavelengths used cannotpenetrate human skin or eye tissue, and are notpowerful enough to cause biological damage tomammalian cells. Due to the considerablysmaller scales at which microbial structuresexist, the 222-nm far-UVC light was highlyeffective in inactivating the H1N1 strain ofinfluenza A virus. The viral particles were sus-pended in aerosolised droplets, simulatingthose generated by human coughing andbreathing. In addition to its affordability as anantiseptic approach, one major advantage ofUVC light is that it is likely to be effectiveagainst all airborne microbes. Like PVP-I, thisbroad spectrum of effect is particularly impor-tant considering the multidrug-resistant vari-ants of bacteria emerging in such settings.

PVP-I FOR HYGIENICINTERVENTIONS

It has long been known that hand washing,when performed properly, can significantlyreduce the carriage and spread of pathogens[33]. This has a direct effect on reducing patientmorbidity and mortality from nosocomialinfections. Hand washing is an important andestablished procedure for infection control withclinically-validated efficacy and a core compo-nent of protocols aimed at reducing infectiousoutbreaks [11]. The skin can act as a reservoir forinfectious agents, and the use of PVP-I for handdisinfection represents an alternative to alco-hol-based hand rubs, with medicated soapscontaining PVP-I now readily available. SuchPVP-I soaps have shown equivalent or superiorefficacy to alcohol-based hand sanitisers whentested against norovirus, a common cause ofgastroenteritis [20]. In contrast, chlorhexidineand triclosan-based hand washes, have beenshown to be inferior against norovirus in prac-tical application tests. Hand washing with PVP-I-based formulations have shown similar

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antimicrobial efficacy to an alcohol-based handrub, with both being preferable to the use ofsoap and water alone [34].

In a direct comparison of the virucidalactivity of various hand sanitisers, includingantimicrobial soaps and alcohol-based sanitis-ers, it was found in a modified fingerpad testthat soap containing PVP-I was superior to theother soaps and sanitisers tested [35]. Threesanitisers were tested in the study, includingethanol, phosphoric acid, triclosan andchlorhexidine formulations. A modified testfollowing the EN 1500 standard showed thatthe soap containing PVP-I was able to inactivatemurine norovirus by approximately 4 log10steps. More recent hand-hygiene simulationstudies have been described to test the com-parative efficacy of different agents for handantisepsis. In one study, volunteers prewashedtheir hands before artificially contaminatingthem with either Escherichia coli (for bactericidaltesting) or murine norovirus (virucidal) [36].Antisepsis agents were then used in a ran-domised approach and the number of testorganisms released from the fingertips was cal-culated in terms of mean log10 reduction factoras per EN1499 guidelines. The direct compar-ison of PVP-I 7.5% and chlorhexidine 4% for-mulations showed a clear superiority of PVP-Iagainst the murine norovirus, while both PVP-Iand chlorhexidine were significantly betterthan soft soap against E. coli. Such experimentalmodels could be helpful in broader assessmentsof antisepsis agents.

The Association for Professionals in InfectionControl and Epidemiology (APIC) has publisheda series of guidelines for hand washing andhand antisepsis in healthcare settings to sup-plement those written by various other hygieneauthorities, including the US Food and DrugAdministration. The guidelines recommendformulations containing 7.5% iodine for use asa surgical hand scrub. Lower concentrations(0.05%) have good antimicrobial activity due tothe concentrations of free iodine increasing tosome extent as the solution is diluted [37].Thorough hand antisepsis, which can beachieved by hand washing or surgical scrubswith antimicrobial agents, is recommended insurgical settings before the performance of

invasive procedures such as the placement ofintravascular catheters, or in any scenario whereit is deemed necessary to reduce numbers ofresident skin flora and transient microorgan-isms on the skin.

With recent hospital reports of vancomycin-resistant E. faecium emerging [1], as well asalcohol tolerance in some strains, it may beadvisable to take new considerations intoaccount. In cases where infectious enterococciare identified (independent of vancomycinresistance), hand disinfection is almost cer-tainly recommendable (30 s). In cases where E.faecium has been confirmed, the extent towhich hand disinfectants are used in the con-text of other available active substances shouldbe considered. The disinfectants listed by theDisinfectants Commission of the Associationfor Applied Hygiene (VAH) also mentionsproducts with various other active ingredientsincluding n-propanols, peroxides, and iodineproducts. Combinations with quaternary com-pounds, phenol derivatives, guanidine deriva-tives or iodine-cleaving compounds can also beconsidered. For surface disinfection, approachesthat rely solely on alcohol disinfection shouldbe avoided and replaced with combinationapproaches with alcohol and other active sub-stances. For final disinfection of patient roomswhere E. faecium may be present, per com-pound-based preparations can be used.

PVP-I scrubs have better skin tolerance thansoap formulations of chlorhexidine and qua-ternary ammonium compounds [38]. Althoughthere is an urgent need for well-designed studiesdirectly comparing the clinical and economicprofiles of antiseptics in such settings, PVP-I canbe considered the antiseptic of choice for themanagement of superficial skin infections.

Mouthwashes and gargles are commonlyused in hospital settings to prevent respiratoryand endotracheal infections. In one hospital-based trial, adult subjects with chronic respira-tory diseases and repeat infections gargled aPVP-I formulation multiple times daily forextended durations up to 2 years [39]. Prior tothe initiation of the study, 14 patients experi-enced a total of 67 episodes of infections (with amean of 4.8 episodes). This was reduced to aremarkable mean number of 2.0 following PVP-I

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gargling, representing a 58% reduction in thenumber of episodes. The most common causa-tive strains were identified as H. influenzae, M.catarrhalis and pneumococci, with both influ-enza and MRSA reducing by 50%. Similarly,tests of PVP-I 7% gargle/mouthwash diluted toreflect real-life scenarios (1:30 dilution; equiva-lent to a concentration of 0.23% PVP-I)according to EN13727 standards showed rapidantimicrobial effects after just 15 s of exposure[36]. Effective and clinically-meaningful bacte-ricidal activity against Klebsiella pneumoniae andStreptococcus pneumoniae was observed undersuch conditions, as well as the inactivation ofcommon agents of serious respiratory tractinfections including SARS-CoV, MERSCoV,influenza virus A (H1N1) and rotavirus.

Seeking to investigate the efficacy of PVP-Igargle in non-hospital settings, a study of PVP-I,chlorhexidine gluconate (CHG), andcetylpiridium chloride (CPC) gargles was con-ducted, supported by a PVP-I study across eightmiddle schools in Japan [40]. PVP-I showed thehighest bactericidal rate against all test strainsobserved within 30 s of exposure. Middle schoolstudents were trained and encouraged to use thegargles, with comparisons of absenteeism madebetween the schools that encouraged the prac-tice and those that did not. In the middleschool using the PVP-I gargle, absenteeism dueto the common cold and influenza were signif-icantly lower compared to the schools using theother two agents. The authors concluded thatthe use of PVP-I gargle resulted in a decrease inabsenteeism due to cold and influenzainfections.

EFFICACY OF PVP-IIN COMPARISON TO OTHERANTISEPTIC AGENTS

It has been more than 60 years since PVP-I wasfirst marketed as an antibiotic/antiseptic agent.Since its introduction, various other agentsincluding triclosan and carbapenem have beenintroduced, although it has been 30 years sincea new class of antibiotic was last discovered.

According to recent reviews, there have beenno confirmed reports of resistance to PVP-I to

date [41]. Numerous studies have shown thatPVP-I has a broader antimicrobial spectrumthan other available antiseptics includingchloroxylenol, chlorhexidine, and quaternaryammonium compounds. Although alcohol-based antiseptics also have broad potency,unlike PVP-I formulations, they typically haveno effect on fungal or bacterial spores. Inter-estingly, honey and maggots have been shownto have antibacterial properties when applied intherapeutic wound-treatment settings,although their potency in comparison to iodineagainst viruses and endospores remains to bedetermined [42].

SAFETY AND TOLERABILITY

PVP-I is well tolerated by the majority ofpatients, particularly when applied to the skin[9]. In comparison to chlorhexidine, for exam-ple, PVP-I has rarely been associated with aller-gic contact dermatitis, while urticarial oranaphylactic reactions have been exceedinglyrare. The 2013 EU Safety Assessment ReportFindings assessed human data involving 6.9 g ofPVP-I applied to the hands and forearms for acontact time of less than 5 min and concludedthat the proposed use of iodine in hand disin-fection products is suitable for human health.Although PVP-I is generally seen as very safe,with long-term use, cases of thyroid dysfunc-tion induced by PVP-I have been reported. Forthis reason, patients receiving PVP-I treatmentfor extended periods of time should be carefullymonitored [43].

CONCLUSIONS

With recent reports of emerging resistance toantibiotics, including ampicillin and van-comycin, attention has turned to the use ofbroad-spectrum antiseptics in limiting hospital-based infectious outbreaks. Despite its longhistory of efficacious use, no significant cases ofresistance to iodine have emerged. This isthought to be due to its broad antimicrobialactivity, which has been confirmed by globalhealth authorities including the World Health

590 Infect Dis Ther (2019) 8:581–593

Organization and the European Wound Man-agement Association.

European guidelines for testing PVP-I for-mulations during hand washing and topicalapplications recommend a stepwise approach,combined with standardised tests using vali-dated test models. Formulations like Betadine�

antiseptic solution have demon-strated[99.99% activity against both envel-oped and non-enveloped viruses includingEbola, MERS, SARS coronavirus, influenza andHFMD viruses (Enterovirus 71 and Coxsack-ievirus A16). The potency and accessibility ofPVP-I formulations is therefore likely to be ofcontinuing and significant benefit for humanhealth on a global scale, particularly in thedeveloping world where ensuring affordableaccess to reliable antiseptic agents can bechallenging.

Furthermore, in comparison to most antibi-otics, the use of broad-spectrum antisepticsreduces the likelihood of resistance emergingdue to multiple mechanisms of action targetingdiverse aspects of cell biology and replicationmachinery. In contrast to PVP-I, bacterial resis-tance to chlorhexidine, quaternary ammoniumsalts, silver and triclosan has been documented.

The long track record of efficacious use ofPVP-I in clinical settings is also an advantage forfurther clinical investigation. The WHO rec-ommends decision-makers be guided by allavailable scientific evidence regarding theexpected benefits and risks of any therapeuticapplication. For this reason, the considerableunmet medical needs that still remain forinfectious diseases in home and healthcareenvironments call for the further investigationof PVP-I formulations in such settings.

ACKNOWLEDGEMENTS

Funding. Writing assistance and the RapidService Fees was funded by Mundipharma Sin-gapore Holding Pte Limited, Singapore, whoplayed no role in the study and collection,analysis, and interpretation of the data. Allauthors had full access to the articles reviewed

in this manuscript and take complete responsi-bility for the integrity and accuracy of thismanuscript.

Medical Writing and/or Editorial Assis-tance. Writing assistance was provided by LeeFarrand of Streamline Editing.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Authors’ Contributions. The author con-ducted a review of the literature, provideddirections in the writing of the manuscript,reviewed and approved the final manuscript.

Disclosures. Maren Eggers has been a con-sultant for Mundipharma Singapore HoldingPte Limited, and the scope of engagementincluded laboratory studies as well as scientificpresentations in conferences, for which shereceived honoraria and travel expenses.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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