Accepted Manuscript

Povidone iodine in wound healing: A review of current concepts and practices

Paul Lorenz Bigliardi, Syed Abdul Latiff Alsagoff, Hossam Yehia El-Kafrawi, Jai-
Kyong Pyon, Chad Tse Cheuk Wa, Martin Anthony Villa

PII: S1743-9191(17)30536-8
DOI: 10.1016/j.ijsu.2017.06.073
Reference: IJSU 3940

To appear in: International Journal of Surgery

Received Date: 6 March 2017

Revised Date: 31 May 2017
Accepted Date: 20 June 2017

Please cite this article as: Bigliardi PL, Latiff Alsagoff SA, El-Kafrawi HY, Pyon J-K, Cheuk Wa CT, Villa
MA, Povidone iodine in wound healing: A review of current concepts and practices, International Journal
of Surgery (2017), doi: 10.1016/j.ijsu.2017.06.073.

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 ACCEPTED MANUSCRIPT

POVIDONE IODINE IN WOUND HEALING: A REVIEW OF CURRENT

CONCEPTS AND PRACTICES

Authors: Paul Lorenz Bigliardia Syed Abdul Latiff Alsagoffb; Hossam Yehia El-

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Kafrawic; Jai-Kyong Pyond; Chad Tse Cheuk Wae; Martin Anthony Villaf

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Author affiliations: a[1National University of Singapore, YLL School of Medicine;
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National University Hospital, Division of Rheumatology, University Medicine Cluster,

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119228, Singapore; 3Experimental Dermatology, Institute of Medical Biology, Agency for

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Science Technology & Research (A*STAR), 138648, Singapore];bAmpang Puteri Specialist
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Hospital, Orthopaedic Surgery, Selangor, Malaysia; cDepartment of Plastic and

Reconstructive Surgery, University of Alexandria, Alexandria, Egypt; dDepartment of Plastic

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Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,

Republic of Korea; eUniversity of Hong Kong, Pokfulam, Hong Kong; fDivision of Vascular
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Surgery, Institute of Surgery, St. Luke's Medical Center, Quezon City, Philippines
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Corresponding author:
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Paul Lorenz Bigliardi

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Address: Medical Center National University Hospital, 3rd floor, 5 Lower Kent Ridge Road,
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Singapore 119074

Email: paul_bigliardi@nuhs.edu.sg

Telephone: +65 9137 2324

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Acknowledgements:

The authors thank Geraldine K Hosking for providing medical editorial support, which was

funded by Mundipharma Pte Ltd, Singapore.

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Figure 1. Mechanism of action of povidone iodine in equilibrium with free iodine

The active moiety is iodine, oxidising pathogen nucleotides and fatty/amino acids and thus deactivates

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proteins as well as DNA/RNA.

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Table 1. Properties of ideal antiseptics

• Antimicrobial activity against a wide range of micro-organisms [5, 6, 8] including

pathogens within biofilms [4]
• Limited inactivation by organic compounds [6]
• Good penetration, including into necrotic tissue and eschar [6, 8] with minimal systemic

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absorption [1]
• No risk of acquired microbial resistance [1, 5, 6, 8]

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• Good local and systemic tolerability [1, 5, 6, 8]
• Supportive effect through the suppression of excessive inflammation [5]

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• Facilitation of wound healing (desirable cosmetic and functional outcomes) [1]
• Low cost [1] and ease of application

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Table 2. Povidone iodine effects contributing to anti-inflammatory properties

Host parameters Pathogen parameters

• Modulation of redox potential • Inhibition of production and release of

(antioxidant/free radical scavenging bacterial exotoxins such as α-hemolysin,
activity) [18, 19] phospholipase C, and lipase [5]

• Inhibitory effect on human
inflammatory effector cells and
mediators of inflammation such as TNF-
α and β-galactosidase [5, 20]
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• Suppression of bacterial enzymes such as
elastase and β-glucuronidase [5]

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• Reduction in plasmin activity [20]
•

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Inhibition of metalloproteinase
production [14, 20]
• Enhancement of healing signals from

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proinflammatory cytokines by activation
of monocytes, T-lymphocytes, and
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macrophages [14]
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Table 3. Antimicrobial spectra for four commonly-used antiseptics

Vegetative bacteria
Antiseptic Spores Fungi Viruses
Gram- Gram-
Actinobacteria
positive negative

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Povidone BC +++, BC +++, FC +++,
BC ++ SC ++ VC ++, LS
iodine 10% LS LS LS

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BC +++, BC +++,
Polihexanide NA NA FC ++, IS VC +, IS
LS LS

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BC +++,
Chlorhexidine BC +++, IS NA NA FC ++, IS VC +, IS
LS

Octenidine BC ++, LS BC ++, IS NA NA FC ++, IS VC +, IS

Ethanol 70% BC +, LS BC +, LS
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+: Weak; ++: Medium; +++: High.
BC: Bactericidal; FC: Fungicidal; IS: Incomplete spectrum; LS: Large spectrum; NA: No activity; SC: Sporicidal; VC:
Virucidal.
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Adapted from Reference [8]

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Table 4. Selected commercially-available formulations of povidone iodine and clinical

wound healing applications

High PU foam with PU foam Dry powder Dry powder

3% with 3% spray* spray*/solution
/solution
Level of exudation

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Medium PU foam with PU foam Dry powder Dry powder
3% with 3% spray*/solution spray*/solution

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Low Liposomal 3% Ointment Ointment 10% Ointment 10%
Hydrogel 10%

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Dry Liposomal 3% Ointment Ointment 10% Ointment 10%
Hydrogel 10%

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Contamination Colonization Critical Spreading/invasive
colonization infection (sepsis)
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Increasing level of infection
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[Footnotes]
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PU, polyurethane

*plus absorbant dressing

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Table 5. Use of PVP-I in burn wounds: clinical experience

Burn Treatment PVP-I Posology Dressing Frequency Comment

degree approach formulation (thickness) of change
used

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Superficial Conservative PVP- I Thick layer Vaseline Twice
second ointment gauze, and weekly
cotton

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dressing

Deep Conservative PVP- I Thick layer Vaseline 2 -3 times Optional

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second ointment gauze, and weekly addition of
cotton corticosteroid
dressing may hasten
healing

Third SSG PVP –I

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degree solution as dressing as preparation
soaked a debriding of the wound
packs method for grafting
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Table 6. Use of PVP-I in chronic wounds: clinical experience

Type of PVP-I Application Dressing Comments

ulcer (stage) product (thickness (frequency of change)
used etc.)

Clean PVP-I Thick layer Negative pressure

diabetic ointment dressing

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ulcer 2 times per week

Superficially PVP-I Irrigation/ PVP-I soaked gauze; Once good

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infected or solution disinfection hydrofiber/ granulation is
unhealed during hydropolymer achieved, change to
chronic dressing dressings; negative occlusive, moisture

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diabetic changes (not pressure dressings retentive dressings
ulcers normally left
Daily changes as
on wound
required, or at least 2

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surface) times per week
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Locally Liposomal Fine film of Gel covered with Wounds with biofilm
infected hydrogel gel hydrofiber and/or require initial
diabetic with 3% hydropolymer dressing debridement.
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ulcers with PVP-I 1-2 times per week Systemic antibiotic

biofilm after use is important.
wound
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debrideme Radiographic
nt examination to
explore access for
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drainage may be
important to prevent
sepsis.
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Pressure Diluted Twice daily After cleaning and

ulcers PVP-I for debridement, apply
(various solution disinfection negative pressure
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stages) (1:1 with (not usually dressings or those filled

saline) left on with hydrofibers or
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wounds) hydropolymers
with/without silver
2-3 times per week

Venous and PVP-I Typically Solution (optionally

arterio- solution twice weekly rinsed off before
venous

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ulcers Liposomal As needed dressing)

(locally PVP-I
Hydrogel covered with
infected) hydrogel
a polyurethane foam
and/or hydrofiber
dressing, optionally
thick layer applied
under VAC therapy

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Figure 2 Schematic representation of iodine pharmacokinetics after application of povidone

Absorption: Depends on site the site and area

of application, with an intact stratum

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corneum being the major barrier (thus higher
absorption from mucosa and wounds) [51,

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67]

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Distribution: Volume of distribution is
approximately 23 litres; biological half-life
approximately 2 days [51]; active uptake into

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the thyroid, intra thyroidal iodine has a half-
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life of 7 weeks

Metabolism: Iodine is rapidly converted into

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iodide. Iodide is is incorporated into

thyroxine (thyroid produces approx.
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100µg/dL)
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Excretion: 97% are excreted renally with a

half-life of 2 days [51]
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• In wound care, topical antiseptics may limit the potential for antibiotic resistance
• Povidone iodine is an effective antiseptic that does not impede wound healing
• Povidone iodine is bactericidal against Gram-positive and -negative organisms
• No acquired bacterial resistance or cross-resistance has been reported for iodine
• Povidone iodine aids healing in a range of acute and chronic wounds

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BACKGROUND: Of the many antimicrobial agents available, iodophore-based formulations

such as povidone iodine have remained popular after decades of use for antisepsis and wound

healing applications due to their favorable efficacy and tolerability. Povidone iodine's broad

spectrum of activity, ability to penetrate biofilms, lack of associated resistance, anti-

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inflammatory properties, low cytotoxicity and good tolerability have been cited as important

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factors, and no negative effect on wound healing has been observed in clinical practice. Over

the past few decades, numerous reports on the use of povidone iodine have been published,

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however, many of these studies are of differing design, endpoints, and quality. More recent

data clearly supports its use in wound healing.

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METHODS: Based on data collected through PubMed using specified search criteria based on
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above topics and clinical experience of the authors, this article will review preclinical and
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clinical safety and efficacy data on the use of povidone iodine in wound healing and its
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implications for the control of infection and inflammation, together with the authors' advice

for the successful treatment of acute and chronic wounds.

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RESULTS AND CONCLUSION: Povidone iodine has many characteristics that position it
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extraordinarily well for wound healing, including its broad antimicrobial spectrum, lack of

resistance, efficacy against biofilms, good tolerability and its effect on excessive

inflammation. Due to its rapid, potent, broad-spectrum antimicrobial properties, and favorable

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risk/benefit profile, povidone iodine is expected to remain a highly effective treatment for

acute and chronic wounds in the foreseeable future.

1. Introduction

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Virtually all wounds are colonized with microorganisms, often without clinical consequence

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and the presence of some microorganisms may even aid healing [1, 2]. However,

contamination with pathogenic microbial flora can lead to infection and sepsis, which disrupts

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the healing continuum [3, 4]. The development of infection is determined by complex

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interactions between the host and microorganisms, and further influenced by the environment
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and therapeutic interventions [3, 5].

Although inflammation occurs as a physiological response to wounding and is required for the
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healing process, microbial infection can induce excessive inflammation [4]. Prolonged
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inflammation together with defective remodeling of the extracellular matrix and a failure of
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re-epithelialization are hallmark characteristics of chronic wounds [2]. Microbial colonies in

chronic wounds often produce biofilms that interact with host tissue in a parasitic manner [3,
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4]. The reduced metabolic state induced by biofilms can also enhance resistance to antibiotics

and aid the evasion of host defense mechanisms. Biofilms are found in approximately 60% of
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chronic wounds and 6% of acute wounds, with eradication of the resident bacteria remaining
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difficult [4]. Therefore, effective antiseptics for wound healing should ideally address both

inflammation and biofilm formation.

Few antimicrobial substances are generally considered for wound therapy. Of these, povidone

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iodine has continued to be broadly applied [7-9].

The aim of this article is to clarify the current role and use of povidone iodine in wound

healing from both diverse regional and specialist's perspectives.

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Data were collected through PubMed using specified search criteria based on preselected

topics. For e.g. clinical use, focus was put on model indications as surgical site infection,

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burns and chronic wounds e.g. diabetic foot ulcer. Articles from personal bibliography and the

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clinical experience of the authors were also taken into account, especially in areas of limited

published information.

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2. Importance of antibiotics and antiseptics in wound healing
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An increasing emergence of resistance to topical and systemic antibiotics is observed. [4, 6].
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Antiseptics, as an alternative for topical wound treatment, tend to be microbicidal and have a
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broader spectrum of antimicrobial activity than antibiotics [6]. Furthermore, in comparison to

most antibiotics, antiseptics reduce the likelihood of resistance emerging due to their multiple
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mechanisms of action targeting various aspects of cell biology in microbes [4]. Therefore, the

use of topical antibiotics should be discouraged if appropriate antiseptics are available [7].
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Furthermore, a recent WHO guideline advocates the use of good antisepsis peri-operatively
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while reducing the use of systemic antibiotics [8, 9].

Overall, the properties of an ideal antiseptic include a broad spectrum of activity [5, 6, 10],

the ability to penetrate biofilms [4], necrotic tissue, and eschar [4, 6, 10], a low potential for

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acquired resistance [1, 5, 6, 10], supportive effects for wound healing by impeding excessive

inflammation [5, 11], and good local tolerability [5, 6, 10] (Table 1). Few antiseptics remain

to be relevant for the prevention and treatment of infection in wound care. These include

iodine carriers (iodophores) with polyvinylpyrrolidone (PVP or povidone) iodine (which will

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be discussed in detail as the most prominent representative), as well as silver, chlorhexidine,

benzalkonium chloride, triclosan, octenidine, and polihexanide (PHMB) and selected dyes

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such as Eosine.

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3. Povidone iodine

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The role of iodine in wound care is primarily as an antimicrobial agent. Povidone iodine has

been used and tested in wound healing for many decades [4, 10]. As with other antiseptics, in
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vitro, animal, and clinical data using various formulations and concentrations in studies of

differing design, endpoints, and quality continuously accumulates, while some questions still
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remain to be answered [12, 13].

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In povidone iodine, iodine forms a complex with the synthetic carrier polymer povidone,
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which itself has no microbicidal activity [10]. In an aqueous medium, free iodine is released

into solution from the povidone iodine complex and an equilibrium is established, with more
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free iodine being released from the povidone iodine reservoir as iodine-consuming germicidal
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activity proceeds (Figure 1) [14, 15].

The formulation-, concentration- and temperature-dependent equilibrium of povidone-bound

iodine to free iodine serves to minimize safety and tolerability issues associated with skin

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exposure to earlier elemental iodine formulations [10], and appears to protect against

inhibition of granulation tissue formation [16].

3.1 Mode of action

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The microbicidal activity of iodine appears to involve the inhibition of vital bacterial cellular

mechanisms and structures, and oxidizes nucleotides fatty/amino acids in bacterial cell

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membranes, in addition to cytosolic enzymes involved in the respiratory chain, causing them

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to become denatured and deactivated (Figure 1) [17]. However, the precise sequence of

events occurring at the molecular level has yet to be fully elucidated [6, 14, 15, 18, 19].

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Cytotoxicity studies have shown that the bactericidal effect occurs even before individual
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human cells are affected (see below).
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In vitro evidence suggests that iodine not only has broad spectrum antibacterial effects, but
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also counteracts inflammation elicited by both pathogens and the host response [20]. These

anti-inflammatory effects appear to be multifactorial (Table 2) [5, 16, 21, -22] and have been
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shown to be clinically relevant [21, 23].

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3.2 Preclinical efficacy data

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3.2.1 Spectrum of activity

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Povidone iodine is one of the few topical antimicrobial shown to be effective against bacteria,

several viruses, fungi, spores, protozoa, and amoebic cysts (Tables 3) [6, 10, 11, 14, 24].

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In classical antimicrobial testing, povidone iodine has been shown to kill a variety of bacterial

strains known to commonly cause nosocomial infections, including methicillin-resistant

Staphylococcus aureus (MRSA) and other antibiotic-resistant strains within 20-30 seconds of

exposure [25, 27]. In contrast, comparators such as chlorhexidine require much longer

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exposure times, and residual bacteria persist for most species [25, 27].

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3.2.2 Resistance and cross-resistance

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The global prevalence of hospital- and community-acquired infections is rapidly increasing,

together with increasing resistance to topical antibiotics such as mupirocin, fusidic acid, and

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gentamicin, as well as systemic antibiotics [6, 28-30]. This poses a major medical challenge,
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and appears to be partially attributable to the overuse and misuse of antibiotics [31, 32].
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Most data exists on bacterial resistance and cross-resistance to antiseptics, including

chlorhexidine, quaternary ammonium salts, silver and triclosan, as reported in strains isolated
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from clinical settings [6, 16, 26, 27, 33]. Evidence of cross-resistance between antiseptics and
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antibiotics has also been documented [16, 34]. Furthermore, resistance to povidone iodine has
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not been induced in systematic testing to date [35]. Thus, in contrast to other antiseptics (with

the apparent exception of an absence of cross-resistance to silver), no acquired resistance or

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cross-resistance has been reported for iodine in over 150 years of use [6, 14, 16, 26, 27]. This
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lack of resistance is likely due to iodine’s multiple mechanisms of action [36].

3.2.3 Activity against biofilms

Biofilms are known to delay wound healing and can promote bacterial survival in the

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presence of antimicrobial therapies [37]. The sustained efficacy of povidone iodine on wound

healing in the presence of biofilms has been recently reviewed [38]. Studies have confirmed

the in vitro efficacy of povidone iodine against S. epidermidis and S. aureus growth, as well

as the inhibition of staphylococcal biofilm formation at sub-inhibitory concentrations [39].

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Furthermore, in a CDC-reactor model, povidone iodine was efficacious in the presence of

biofilms grown in a mixed culture comprising MRSA and C. albicans, even at highly diluted

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concentrations [40]. The biofilm removal in this assay was greater than observed with e.g.

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PHMB, octenidine, chlorhexidine, mupirocin and fusidic acid [40].

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3.2.4 Toxicity, tolerability, and allergenicity
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A number of cytotoxicity studies have been conducted to investigate the potential detrimental

effects of povidone iodine and other antiseptics on wound healing typically fibroblasts,
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keratinocytes and other cell lines. While all antiseptics may have a measure of cytotoxicity
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due to nonspecific effects, this may not necessarily be clinically relevant to the wound healing
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process [41]. Cytotoxicity data from tests performed on isolated cells must be considered in

perspective. In vitro cytotoxicity can be more pronounced than in a biological system with a
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three-dimensional matrix and vascular system, and not necessarily reflective of in vivo or

clinical settings [16, 41]. Interestingly, recent cytotoxicity tests have shown that povidone
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iodine has very low cytotoxicity compared to other antiseptics when tested on skin (vs.
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PHMB, octenidine, chlorhexidine and hydrogen peroxide) [41] and oromucosal (same as

octenidine but superior to chlorhexidine) cell lines [42]. However, other studies have reached

different conclusions. The inconsistency in translation may be further due to the multitude of

protocols, cell types and species involved in the testing.

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Clinical experience reveals increasing contact allergies to topical antibiotics such as

neomycine [43] or fusidic acid [44], and antiseptics such as chlorhexidine [45, 46]. In

addition, sensitisation through topical applications of antibiotics can induce severe

generalized allergic reactions if these antibiotics are later used systemically and vice versa

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[47]. On the other hand proven allergies against povidone iodine or silver are rare [46] .

Sensitisations against PVP-I are sometimes cross-reacting to iodinated contrast media [48].

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However, these important cross-reactivities can be discovered by prick, intradermal and/or

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patch skin tests skin tests.

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3.3 Non-clinical models
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Animal models can sometimes lack clinical relevance, and appreciable differences exist

between the dermal architecture in animal and human skin. Pig skin can compare closest to
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human skin and is therefore the most suitable non-human model. Rodent skin, in contrast,
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differs from humans considerably, as it is much thinner, the epidermis is synchronized to

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follicular cycles in the furry skin and it heals mainly by contraction rather than by migration

of epidermal cells [49]. Animal models may further lack applicability to chronic wound care
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in clinical settings, as human patients often have underlying medical conditions that

complicate healing [1]. These issues warrant caution when attempting to extrapolate
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preclinical data to clinical settings, and suggest that non-clinical data should be considered in
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conjunction with robust clinical evidence.

While some in vitro studies have suggested that povidone iodine may have a measure of

cytotoxic effect [50], no consistent deleterious effects on various measures of wound healing

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have been demonstrated in in vivo studies, particularly at lower povidone iodine

concentrations [41, 51]. A number of animal studies of povidone iodine in wound healing

were published over thirty years ago [41, 52], and the majority demonstrated that

concentrations of up to 10% generally do not inhibit the granulation and epithelialization

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processes [41].

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Several animal studies have also investigated the effect of povidone iodine on wound

microcirculation, with inconsistent findings. In rabbit ear chamber wounds, the use of a 5%

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povidone iodine solution was associated with an early but rapidly transient decrease in blood

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flow [51, 53]. However, in the 10% povidone iodine study mentioned earlier, wounds showed
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faster neovascularization with povidone iodine treatment compared with silver nitrate, sodium

hypochlorite, and untreated controls [54]. Another rat model demonstrated no negative effects
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on capillary blood flow after up to 60 minutes exposure to a 1% povidone iodine solution [51].
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Interestingly, a recent study has shown povidone iodine to enhance wound healing via TGF β,
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not only by increasing granulation but also enhancing neovascularization [55].

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3.4 Data on povidone iodine safety

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Data on the systemic absorption of antiseptics are scant [1]. Iodine seems to be absorbed from
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the skin, but more so from mucosa [56]. However, the condition of the skin barrier will

determine transdermal iodine absorption. The absorption will be increased if the skin barrier

is broken as in wounds and also dependent on skin age and surface area of application

(Figure 2). Safety information in povidone iodine product labeling includes general warnings

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against use in patients allergic to povidone iodine or excipients, thyroid disorders, in very low

birth weight infants, and in patients receiving radio-iodine therapy [6, 57].

4. Clinical evidence of povidone iodine efficacy

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Human trials of povidone iodine in wound healing have varied widely in regards to inclusion

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criteria, demographic characteristics, underlying pathologies, medical interventions, and trial

endpoints [10, 52]. Povidone iodine products have been available in many countries without

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prescription for decades [56], and are generally considered to be effective antiseptics that do

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not impede wound healing [12, 52]. A range of povidone iodine products have been
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formulated to suit specific medical needs, with current uses and benefits for various

indications discussed below (summarized in Table 4) [10].

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The concentration of free iodine determines the germicidal action of povidone iodine [15],
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and the color of povidone iodine can be used as an indicator of maintenance of efficacy, and
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as a reminder to reapply the product [13]. In addition, color gradation can aid the practitioner

in distinguishing between superficial and deep burns to guide wound debridement [58]. The
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frequency of dressing changes and type of povidone iodine formulation needed are dependent

on the nature and behavior of the wound bed.

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In therapeutic use, treatment should stop when symptoms subside. However, wound healing is

more than antisepsis [2, 4] and a good choice of dressings and procedures is essential for the

outcome. Therefore, povidone iodine antisepsis is one important measure amongst others.

This includes good debridement, cleaning and choice of an appropriate dressing. Negative

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wound pressure therapy is getting increasingly popular, but also not a single solution as

infection is a constant threat. Povidone iodine can be used both prophylactically during

wound cleaning and therapeutically as leave-on application in contaminated chronic and acute

wounds. A typical regimen for cleaning is a soaking time of 20 minutes each, using cycle

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frequencies of four to eight cycles per day [59].

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4.1 Prevention of Surgical Site Infection

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Surgical site infections (SSI) continue to be a significant source of increased morbidity,

mortality, hospital length of stay, and care costs [60]. As the majority of infections acquired

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during surgery originate from the patient’s own commensal flora, disinfection of the surgical
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site prior to incision is imperative [61]. A large American study in 7,669 clean-contaminated

surgical patients [61], as well as a recent Cochrane review [60], confirmed the value of
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preoperative skin antisepsis with povidone iodine as a feasible clinical option. While there
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appeared to be little benefit from the addition of alcohol to povidone iodine [60, 61], one
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study of 200 healthy volunteers showed that the use of 70% isopropyl alcohol before or after

10% povidone iodine was more effective in reducing bacterial skin counts than disinfection
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with a single agent [62]. The recent WHO guideline prefers alcoholic chlorhexidine solution

over povidone iodine for pre-surgical use [8, 9] However, some recent studies [63] were
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possibly not included due to a cut-off date leading to a recommendation in contrast to recent

Cochrane Reviews.

As well as surgical site preparation, intraoperative flushing with povidone iodine has been

shown to reduce infection rates in sensitive indications including breast surgery (at a 4%

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dilution) [64], spinal surgery (0.35% dilution) [65], total joint arthroplasty (0.35% dilution)

[66], and intraperitoneal irrigation (1% dilution) during laparotomy [67]. Such wound

irrigation with diluted povidone iodine has been advocated by a recent WHO guideline [8, 9].

In some countries, the use of povidone iodine dilutions represents approved usage except for

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pre-operative skin prepping, where full concentrations are needed to eliminate resident

microflora.

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4.2 Povidone iodine in acute wounds

Depending on severity, acute traumatic wounds may be subject to OTC treatment with clear

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guidance on when to invoke physician referral [68]. Such wounds may benefit from the use
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of povidone iodine, especially when contaminated or infected [69].
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Dry powder sprays may be better tolerated in sensitive wounds while having a hemostatic
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effect on some superficial bleeding, and can be applied without the need for wound dressing.

However, ointments can increase the efficacy and absorption of Iodine by occlusion effects
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and can be used in dry wounds or skin and to prevent adhesion, but it is less indicated if
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oozing or exudate is predominant.

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4.3 Surgical wounds

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In a clinical trial of patients undergoing split skin grafts, the use of povidone iodine ointment

medicated gauze did not delay wound healing when compared to simple vaseline gauze, and

evidence for a possible earlier onset of epithelialization with povidone iodine was observed

[23]. In addition, wounds treated with povidone iodine trended toward lower bacterial counts

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in comparison to the gauze controls.

In graft wounds, the efficacy of liposomal povidone iodine hydrogel has been demonstrated to

significantly enhance antiseptic efficacy, wound epithelialization, healing quality, and graft

take when compared with chlorhexidine gauze, with no clinically-relevant topical or systemic

PT
adverse effects reported [69, 70].

RI
In contaminated and dirty wounds requiring surgical attention (class III and IV), antisepsis

SC
(together with systemic antibiosis and a check on the tetanus immunization status) is

warranted. Intense debridement and wound cleaning, together with suitable wound treatment

U
devices such as polyurethane foams may facilitate long term healing. Dressing changes and
AN
antisepsis can be delegated to family members, allowing for easier follow-up in countries with

slim medical infrastructure. Dry powder sprays for exuding wounds and ointments for drier
M

wounds allow differentiated treatment. Patients have reported the additional benefit of a
D

cooling effect experienced from dry powder sprays, likely due to the evaporating propellant.
TE

4.4. Burn wounds

EP

The potential for microbial infection is high in burn wounds, and infection can cause partial
C

thickness burns to progress to full thickness, with severe consequences [21]. Burns precipitate
AC

a mediator-induced response, with evidence of both local and systemic oxidative changes,

increased oxygen free radical activity, lipid peroxidation, and a reduction in antioxidant

scavenging capacity [21].

In a study of 38 patients with varying burn sizes, the addition of povidone iodine ointment to

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a standard hospital antibiotic protocol alone or in combination with daily systemic vitamins E

and C improved markers of oxidative stress and wound healing. These effects were

accompanied by a 15.3% decrease in the incidence of infection after 4 days of treatment

compared with zero time, a reduction in the mortality rate from 87.5% for those receiving

PT
standard care to 5.9% in povidone iodine-treated patients, a faster wound healing time, and

reduced hospital cost burden [21]. Furthermore, no adverse systemic effects were observed.

RI
The effect of povidone iodine on neutrophils [5] and oxygen radicals [20] is potentially of

SC
significant value in burns patients due to the limitations imposed by collateral tissue damage

[71].

U
AN
A 5% povidone iodine cream was reported to be superior to silver sulfadiazine in terms of

application and wound healing [72]. This formulation was also shown to be effective and well
M

tolerated in an uncontrolled pediatric trial [73].

D

In another randomized trial involving 213 patients with partial thickness burns, treatment with
TE

a povidone iodine dressing was associated with reduced treatment times, lower analgesia

requirements, fewer hospital visits, and less time off work compared with chlorhexidine
EP

dressing treatment [74]. Interestingly, a trend toward less pain and bleeding on dressing

removal was also observed with povidone iodine [74]. Another trial in a similar patient
C

population demonstrated faster wound healing and a more favorable cosmetic result with
AC

liposomal povidone iodine hydrogel versus silver sulfadiazine [75].

The authors’ clinical experience with the use of povidone iodine in patients with burn wounds

is detailed in Table 5.

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4.5 Povidone iodine in chronic wounds

Chronic skin wounds affect 1-3% of the population [76] and represent a significant clinical

and financial burden to healthcare systems [22], with approximately 50% of outpatients

requiring nursing services [77]. In most cases, chronic underlying disease undermines normal

PT
tissue repair, preventing wounds from healing as expected even after intense treatment for an

RI
extended amount of time [2, 4, 22].

SC
Chronic wounds often harbor biofilms that render the infection more difficult to detect,

diagnose and treat [4, 32, 37]. A shift towards anaerobic and gram negative bacteria seems to

U
occur with increasing chronicity of wounds [3].A lack of perfusion in these chronic wounds
AN
with insufficiency of the arterial and/or venous system does not support the routine use of

systemic antibiotics to promote the healing of chronic wounds. Consensus suggests that
M

systemic antibiotics should only be used in cases of established clinical infection [7, 78]. In
D

addition, about half patients with chronic wounds develop allergic contact eczemas to topical
TE

products applied, particularly to preservatives, emollients, dressing adhesives, antibiotics (e.g.

fucidic acid or neomycine) and antiseptics (e.g. chlorhexidine). Therefore, the use of
EP

hypoallergenic formulations and active ingredients are important to avoid sensibilisations

through the treatment of wounds. Povidone iodine and silver have in this aspect a very good
C

safety profile.
AC

The benefits of povidone iodine in chronic wound healing, as in burn wounds [23], may

extend beyond its antimicrobial properties [74].

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4.5.1 Venous and arterio-venous leg ulcers

In an intra-individual comparison study, 51 patients with at least two similar chronic leg

ulcers were treated with hydrocolloid dressings. One ulcer in each patient received additional

topical application of povidone iodine, silver sulfadiazine, or chlorhexidine. While

PT
comparable antimicrobial activity was observed with all three agents, povidone iodine

RI
exposure resulted in a highly significant 2-9 week improvement in healing time, with superior

microvascularity and dendrocyte density [79]. In another study of female patients with at least

SC
two chronic venous leg ulcers treated with hydrocolloid dressings, daily application of

povidone iodine solution resulted in a faster reduction in ulcer size, a lower bacterial load, and

U
less pronounced inflammatory effects versus hydrocolloid dressing alone [80]. Long-term
AN
local application of povidone iodine solution and ointment in a study of 25 patients with
M

venous leg ulcers (VLUs) secondary to chronic primary lymphedema also resulted in

excellent local tolerability and clinical efficacy, with no evidence of resistance [81].
D
TE

In a further study of 63 patients with VLUs, 42 had compression bandages applied, of whom

21 with superficial infection were treated locally with povidone iodine, and 21 received
EP

systemic antibiotics [76]. The remaining 21 patients were treated locally with povidone iodine

without compression. Unsurprisingly, compression increased the ulcer healing rate;

C

furthermore, healing rates among patients receiving systemic antibiotics were comparable to
AC

those treated with topical povidone iodine, but the use of systemic antibiotics increased the

risk of relapse with superficial bacterial infections (impetigo and folliculitis) compared with

local povidone iodine application (32% vs. 11%, respectively).

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4.5.2 Diabetic foot ulcers

In a retrospective study of 30 patients with a total of 42 wounds, primarily diabetic foot ulcers,

29% of wounds achieved full closure and 45% achieved partial closure within 6 months with

regular topical povidone iodine application [77]. Another study in ulcer patients (the majority

PT
being diabetic) revealed less pain associated with povidone iodine dressings compared with

RI
cadexomer-iodine and silver dressings [82]. Under some conditions, diabetic foot ulcers may

be treated by split thickness skin grafting or allografts, and povidone iodine antisepsis can

SC
help ensure graft success by reducing the bacterial load in cost-sensitive environments [83].

However, the detailed effects of these antiseptics on skin grafts require further evaluation in

standardized clinical trials.

U
AN
4.5.3 Pressure ulcers
M

In a randomized study of 27 spinal cord injury patients with pressure ulcers, 84% of ulcers
D

treated with povidone iodine hydrogel achieved re-epithelialization, versus 54% treated with
TE

povidone iodine solution and gauze; however, there was no significant difference in the speed

of healing (measured in cm2/day) between the two groups. The authors concluded that the
EP

moist environment created by the hydrogel, rather than the use of a dry gauze dressing, was
C

the most likely reason for the higher rate of epithelialization raising questions with respect to
AC

the experimental design [84]. In another study, 18 outpatients with pressure ulcers and stasis

ulcers received daily application of povidone iodine ointment under and within the dressing,

which resulted in a reduced level of infection and inflammation, and apparent promotion of

healing [85].

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The authors’ general clinical experiences with povidone iodine use in the treatment of chronic

wounds have been summarized in Table 6. It is acknowledged that an individualized

approach should be taken, depending upon specific wound and patient characteristics.

PT
5. Summary

RI
Mounting evidence suggests that antiseptics should be used in preference to topical and

systemic antibiotics for localized skin infections. Povidone iodine, the most commonly used

SC
iodophor, has many characteristics that position it extraordinarily well for wound healing,

U
including its broad antimicrobial spectrum, lack of resistance, efficacy against biofilms, good
AN
tolerability and its effect on excessive inflammation. Clinical alternatives include

chlorhexidine, silver-containing products, PHMB, octenidine and the old antiseptic dyes,
M

although they all have different overall profiles that must be taken into consideration when

making a chosing an antiseptic. Of clinical relevance, wound healing in clean wounds is not
D

impeded and in colonised wounds is supported [22, 67]. Its use is especially important for
TE

sensitive and difficult to treat wounds and in the case of chronic wounds where an extended
EP

duration of therapy is likely. Some combinations as medicated gauzes make known

formulations easier to apply. Newer application methods and formulations, such as inclusion
C

in wound healing devices or carrier systems such as liposomes have extended the reach of
AC

existing formulations by combining iodine with modern wound treatment concepts. Due to its

rapid, potent, broad-spectrum antimicrobial properties, and favorable risk/benefit profile,

povidone iodine is expected to remain a highly effective treatment for acute and chronic

wounds in the foreseeable future.

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