An Asian Perspective on Povidone Iodine in Wound Healing

Antiseptics are defined as agents used to inhibit or kill microorganisms present within a wound or on intact skin [1,2] and have long been used on wounds to prevent or treat infections. Despite this, and in the absence of standardized practice and clinical study guidelines, there continues to be a great deal of debate and controversy on the appropriate use of antiseptics.

Iodine has been used as an antiseptic in the treatment of wounds for more than a century [3], yet questions are raised about the place of iodine-based agents in the management of wounds. With povidone iodine (PVP-I), there have been concerns about allergy, ineffective penetration, and toxic effects on host cells [4,5,6,7], but how justified are these concerns? There are reports which indicate that these concerns may be based on inappropriately performed in vitro cellular or in vivo animal studies with sometimes limited applicability to the clinical reality [3,8,9]. The objective of this paper is to discuss the efficacy and safety of PVP-I and to outline its place in wound care management based on an appraisal of the literature as well as clinical practice, particularly in an Asian context.

The Asian Working Group (AWG) on wound management includes 5 advisors from Asia (Singapore, the Philippines, Thailand, Korea, and Malaysia) and an advisor from Germany (to provide a global perspective). All advisors are recognized experts with vast experience in wound management in their respective countries.

The AWG convened in April 2016 to assess the available published evidence for PVP-I in conjunction with their own clinical experience of its use in the wound care environment in a research/clinical setting, and to develop consensus statements for PVP-I to support clinicians in Asia in making informed decisions. The topics for discussion included the current perceptions and clinical practice with regard to the role of antiseptics (PVP-I in particular) in the wound care setting in Asia, and the evidence available for PVP-I. Consensus was reached after discussions within the group.

Prior to the meeting, a search strategy was developed for identifying relevant literature for PVP-I. A PubMed search, using the keywords “wound” AND (“povidone iodine” OR “Betadine”) AND (“efficacy” OR “safety” OR “cytotoxicity”) was conducted, and the results were limited to those in the English language. The resulting papers were qualitatively assessed, and only those papers relevant to wound management and with the primary objective of comparing the different antiseptics including PVP-I were selected for discussion at the meeting.

Antiseptics act on multiple targets and have a broader spectrum of activity against different classes of viruses, fungi and bacteria, including multiresistant organisms, compared to antibiotics [1,10,11]. Furthermore, antibiotic use is associated with a high risk of resistance and cross-resistance [11,12] as well as allergies. In this context, antiseptics are important alternatives in the clinical setting to control the bioburden in wounds.

The properties of an ideal antimicrobial agent have been described in detail in several publications [1,11,13,14,15,16].The efficacy profile of an ideal antimicrobial agent for wound care should include a broad antimicrobial effect (antibacterial [Gram-positive and Gram-negative bacteria], antimycotic, and antiviral), good local penetration, stability in the presence of body fluids and wound exudates, and a low potential for acquired resistance. From a safety viewpoint, an ideal antiseptic should also have good local and systemic tolerability and low systemic absorption, be nonsensitizing/hypoallergenic, and cause no delay in the wound healing process [11,13,14,16].

Additionally, in the experience of the AWG, an ideal formulation of antiseptic should not penetrate the corneal layer of intact surrounding skin of the wound, but should have optimal activity on the wound where the skin barrier is lost, and should also easily penetrate into microbial biofilms. If the antiseptic penetrates into the granulation tissue, which is typically highly vascularized, it may cause systemic toxicity. Further, the AWG notes that antiseptics should act continuously over a long period of time, rather than be fast-acting. This ensures a constant and high enough concentration for antimicrobial efficacy and allows for infrequent dosing, providing patient comfort and contributing to cost savings in terms of the reduced nursing care required.

Low cost and acceptable cosmetic and esthetic qualities are believed to be important attributes of antiseptics [16]. The Asia-Pacific region comprises several countries, and given the diversity in the economic and health care systems, the AWG notes that the cost-efficacy balance of an ideal antiseptic should be optimized. Furthermore, cultural practices, beliefs, and perceptions vary in the different countries in Asia - while some patients find antiseptic staining of the wound and surrounding tissues concerning, others associate it with increased efficacy. The AWG also believes that the concentration and formulation of the active ingredient are important factors contributing to the efficacy of antiseptics. There is a lack of evidence around the concentration and formulation of antiseptics to be used in different kinds of wounds, especially in relation to locally made, readily available formulations. Local and country-specific guidelines could potentially address this issue, while offering guidance to the clinicians.

Several antiseptic preparations are available for the prevention and treatment of infection in wound care, such as the iodophors polyvinylpyrrolidone-iodine and cadexomer-iodine, the biguanides chlorhexidine, octenidine, and polyhexanide, the bisphenols triclosan and hexachlorophene, silver compounds, benzalkonium chloride, and hydrogen peroxide.

Iodine has been extensively used for decades as an antiseptic. PVP-I, the most well-established iodophor, is a combination of molecular iodine and a polyvinylpyrrolidone surfactant/iodine complex which acts as a reservoir of free iodine [17,18]. The bactericidal component of PVP-I is the free iodine, the levels of which are dependent on the concentration of the PVP-I solution.

The polyvinylpyrrolidone component of PVP-I delivers the iodine directly to the microorganism cell surface; the free iodine penetrates into the cell wall and targets proteins, nucleotides, and fatty acids, resulting in cell death [3,18,19]. The free iodine concentration increases with increasing dilutions of PVP-I: dilution weakens the iodine linkage to the carrier, resulting in an increase in free iodine in the solution [19]. It is believed that the concentration of free iodine contributes to the bactericidal activity of PVP-I; this is thought to explain the paradoxical increase in the antibacterial action of PVP-I with increasing degree of dilution (0.1-1% solutions were reported to be more rapidly bactericidal than the 10% solution) [19].

Spectrum of Activity

PVP-I has demonstrated a broad spectrum of activity against Gram-positive (including methicillin-resistant Staphylococcus aureus [MRSA]) and Gram-negative bacteria, fungi, viruses, protozoa, and bacterial spores in several studies [11,17,18,20,21]. PVP-I has also shown high bactericidal activity against test strains comprising causative organisms of nosocomial infections (MRSA, Serratia marcescens, Pseudomonas aeruginosa, Burkholderia cepacia) after 30 s of exposure [22]. In addition, PVP-I proved to be the only antiseptic without the development of cross-resistance. A similar study confirmed the efficacy of PVP-I against two Gram-negative bacteria (Xanthomonas maltophilia and S. marcescens), including resistant strains of both species; both sensitive and resistant strains of both species were killed within 20 s of exposure to PVP-I [23].

Efficacy against Biofilms

Wound biofilms - bacterial communities living within a protective extracellular matrix - are often resistant to conventional treatment with antimicrobials and delay the wound healing process [20,24]. The sustained efficacy of PVP-I in wound healing in the presence of biofilms has been described in several studies [20,24,25]. Hill et al. [25] used an in vitro biofilm model closely mimicking chronic wound biofilms and demonstrated the complete eradication of an established 7-day mixed Pseudomonas and Staphylococcus biofilm by using iodine-based dressings. Furthermore, Hoekstra et al. [24] recently demonstrated the efficacy of PVP-I in the presence of biofilms grown in a mixed culture of MRSA and Candida albicans, even when diluted. However, these are studies conducted in an in vitro environment and do not conclusively prove the efficacy of PVP-I on biofilms.

Resistance

Increasing bacterial resistance to antibiotics is a major clinical and public health problem worldwide [9,11,26], and Asia is no exception [12,27].

Bacterial resistance to topical antimicrobial agents, such as vancomycin, mupirocin, fusidic acid, and gentamicin, has been widely reported [11,28,29]. Bacterial resistance to chlorhexidine, quaternary ammonium salts, triclosan, and silver has also been reported [11,22,23]. Furthermore, cross-resistance to other antibiotics and antiseptics has been documented with chlorhexidine and triclosan [30]. However, despite widespread and extensive use, no acquired or cross-resistance has ever been reported for iodine [11,22,23,30].

In vitro studies with PVP-I have reported contradictory results [6,7,31,32]. The role of PVP-I in wound healing has also been investigated in animal studies, with varying results [17,33]. Most of these animal studies were published at least 2 decades ago, were conducted in beagles, rats, rabbits, and guinea pigs, and demonstrated that concentrations of up to 10% of PVP-I did not cause any inhibition in the granulation and epithelialization process [33]. Increased microcirculation is an important feature of the wound healing process. In experiments performed on wounds in male SKH1-hr hairless mice, PVP-I products (PVP-I liposomal hydrogel) showed a positive effect on dermal wound healing and wound microcirculation [34]. In full thickness wounds in mice, Kjolseth et al. [35] also demonstrated earlier and complete neovascularization with PVP-I versus other antiseptics.

Some human studies conducted in varying settings have established the efficacy of PVP-I in reducing the bacterial load in both acute and chronic wounds [8,9,17,36,37,38,39,40,41,42]. Gravett et al. [36] and Stringer et al. [37] reported that PVP-I in patients prior to suturing lacerations reduces the incidence of wound infection. Similarly, postoperative irrigation of surgical wounds with PVP-I resulted in a decrease in wound infection rates in another study [38]. Further, in a study of 294 pediatric surgical wounds, PVP-I did not impair wound healing rates [39]. PVP-I has also been demonstrated to be effective in reducing wound infection in pressure ulcers [40,41]. Fumal et al. [41] also demonstrated faster healing rates and a positive reduction in bioburden in venous ulcers with PVP-I. Daróczy [42] also showed similar results in chronic wounds.

Studies of PVP-I in patients with diabetic foot ulcers and patients with burns have also established its efficacy. In one study, 29% of the wounds achieved full closure and 45% achieved partial closure within 6 months of regular topical PVP-I application [43]. In another study evaluating PVP-I in patients with partial thickness burns, treatment with PVP-I dressing was associated with reduced treatment times, lower need for analgesia, fewer hospital visits, and less time off work; less pain and bleeding on the removal of the dressing was also observed [44]. In similar settings, faster healing times and a favorable cosmetic result was demonstrated by PVP-I [45]. Studies evaluating a PVP-I preparation in hydrogel (containing iodine in a 3% concentration) in patients receiving meshed skin grafts after burns or reconstructive procedures have also reported significantly improved epithelialization, decreased transplant loss, and improved healing [46,47].

Table 1 details some of the key studies investigating PVP-I in a variety of settings, including in vitro and human studies (burns, ulcers, skin trauma and lacerations, and pre- and postoperative antisepsis) [6,7,31,32,36,38,39,40,41,42,43,44,45,48,49,50,51,52,53,54,55,56,57,58,59,60,61].

There have been concerns about perceived cytotoxicity with PVP-I, and the potential detrimental effect of PVP-I on wound healing has been widely argued, with several in vitro studies demonstrating the dose-dependent cytotoxicity of PVP-I on cultures of granulocytes, monocytes, keratinocytes, and fibroblasts [6,62,63]. At the same time, questions have been raised on the clinical relevance and application of these in vitro reports of topical toxicity or impact on wound healing [30,33,62]. In vitro cell toxicity and toxicity in rodents with thinner skins could potentially be more marked than those seen in a human wound [30,33]. Isolated cells in cell cultures have no supportive matrix or vascular network, making them very susceptible to the slightest disturbances, in contrast to multiple layers of intact skin [33]. Experimental conditions also have a distinct impact on results, and as such the choice of experimental conditions for the assessment of cytotoxicity of antiseptics in cell culture has varied to a great extent [64]. The additives in the products being used or the formulation itself may produce variable degrees of toxicity in cell culture [33].

Whereas several in vitro studies report cytotoxicity, some in vivo human studies have demonstrated that PVP-I does not have a negative impact on wound healing [11,33,41,62,65]. As mentioned previously, Fumal et al. [41] described an increased healing rate and reduced time to healing by 2-9 weeks with PVP-I versus chlorhexidine in venous ulcers. Faster healing times with PVP-I have also been demonstrated in patients with burns [44,45]. Niedner [33] reviewed the cytotoxicity of PVP-I and reported that the course of wound healing is not influenced negatively by PVP-I. More standardized human studies are needed to address these disparities in evidence seen in in vitro and in vivo animal studies.

There is much debate among dermatologists about the allergenic and irritant potential of PVP-I. All antiseptics have irritant properties when misused, particularly in skin conditions with a damaged skin barrier (e.g., eczematous skin), under inadequate occlusion, and at very high concentrations [66]. However, the sensitizing potential of PVP-I is very low and it is considered a weak allergen with a prevalence of allergenicity of 0.4% [67]. Furthermore, there appears to be no link between iodine-associated allergies (particularly allergic contact dermatitis) and anaphylactic, allergic, or intolerance reactions or delayed-type hypersensitivity against radiologic iodine-containing contrast media [11,68]. There are some rare case reports of immediate or delayed allergic reactions to PVP-I, with povidone or nonoxynol as the most likely sensitizing agents [69,70]. However, a more complete investigation into the allergenic potential of PVP-I is needed to evaluate the clinical relevance. Until there is irrefutable evidence for the nonallergenicity of PVP-I, the AWG advises caution in the use of PVP-I in patients who report a previous reaction to iodine products. It is important that toxic reactions to the inappropriate use of PVP-I should be clearly separated from real allergic reactions. In the case of toxic effects of PVP-I, it can still be used, with a change in the concentration and method of application. If there is a real allergic reaction to PVP-I or its additives, proven by prick tests if immediate or patch tests if delayed type, the PVP-I or the offending additives have to be avoided under all circumstances. In addition, PVP-I is contraindicated in patients with hyperthyroidism/thyroid cancer; it should be used with caution in pregnant and lactating women and infants.

Systemic toxicity does not seem to be a common occurrence with PVP-I. However, systemic absorption from large surface area wounds may be a concern. There have been reports of patients developing systemic iodine toxicity from wounds dressed with gauze soaked in PVP-I or when PVP-I solution was used as a continuous wound irrigant [62]. The use of PVP-I in children with a higher skin surface area per body weight and less developed skin barrier could also lead to increased penetration and systemic absorption.

Another concern with PVP-I appears to be the reduced activity reported in the presence of certain proteins in wound exudates or body fluids [71]. It is postulated that this could be due to the masking and inactivation of the iodine in the presence of organic matter in the wounds. This could potentially be a limiting factor in the activity of PVP-I. However, further studies to evaluate this in greater detail are required.

In Asia, PVP-I is widely used and the perception of PVP-I in health care practitioners centers on its efficacy, ease of use, and availability is good. PVP-I has been available in the region for several decades, but is still used primarily for acute wounds and not very commonly for chronic wounds. There is a need for a formulation of PVP-I that would last for a longer time for use in chronic wounds. Some members of the AWG report good results with PVP-I in chronic wounds, with daily dressing changes.

Studies reporting toxicity of PVP-I remain at the back of the minds of health care practitioners. While there is no doubt regarding the efficacy of PVP-I, the concentration required for different types of wounds and the recommended contact time with the tissue continue to remain contentious. Given the conflicting reports about cytotoxicity with PVP-I, the AWG reiterates that the only aspects of toxicity that may be of concern are systemic effects due to absorption and local tissue toxicity. It is generally believed that absorption from large surface area wounds may lead to systemic toxicity. According to the AWG, this concern can be addressed by limiting the contact time of PVP-I on large surface area wounds, such as large burns. Furthermore, in the clinical experience of the AWG, PVP-I causes no problems when used in a concentration appropriate for the type of wound. There is a need to educate clinicians on the different formulations of PVP-I, such as ointments and solutions, which are diluted to concentrations appropriate for antisepsis without being cytotoxic.

In Asia, as in the rest of the world, antibiotic resistance is showing a rising trend [12,27]. The AWG notes that antibiotic overuse is rampant in the region and contributes to the development of resistant strains. In this scenario, PVP-I, which has been in use for a long time without the development of resistance, becomes an important measure for antisepsis.

PVP-I is available in a range of antiseptic formulations - the most commonly used in the Asian region is the 10% aqueous/alcoholic solution. PVP-I is also available as a 7.5% surgical scrub, a 2.5% dry powder spray, and a 10% ointment. Some of the common clinical uses of PVP-I in Asia, as discussed by the AWG, are listed in Table 2.

The members of the AWG considered the literature available for PVP-I, in conjunction with their own clinical experience of using PVP-I in the management of wounds, to postulate consensus statements to guide the use of PVP-I in an Asian context.

The AWG believes and reiterates that there are no questions about the efficacy of PVP-I. It is fairly well accepted in the Asia-Pacific region that PVP-I is efficacious, with a broad spectrum of activity and demonstrated activity against biofilms, with no risk of resistance. However, concerns of cytotoxicity have yet to be addressed adequately. It is noteworthy that the pronounced cytotoxicity demonstrated in certain in vitro studies has not been confirmed in human studies, where PVP-I has been found to be safe in appropriate concentrations. The concentration and formulation of PVP-I has to be tailored and personalized according to the area and location (skin, mucus membranes) of application, skin condition, indication of use, and microbial load. It is important to know and understand the various formulations and concentrations of PVP-I and to adapt them to the scope of application. This necessitates access to updated information and regular training.

In an era of growing issues with antibiotic resistance, antiseptics (including PVP-I) are important viable alternatives; they do not lead to the development of drug-resistant bacteria and have a broader antimicrobial spectrum. Additionally, to combat the growing menace of antimicrobial resistance, the AWG recommends a more aggressive and methodical adoption of Antibiotic Stewardship Programs (ASPs) in the Asian region. The interventions in an ASP are targeted towards improving and monitoring appropriate antimicrobial use [72,73].

Given the wide disparity in the experimental settings evaluating the efficacy and safety of antiseptics as well as the conflicting results observed over the years, the AWG believes that new standardized and clinically relevant studies, using in vitro and in vivo models, along with novel noninvasive measurement systems, to compare antimicrobial efficacy and toxicology are the need of the day. Some tools to study in vitro and in vivo absorption and distribution of various compounds in wounds, which are currently being investigated, include in vitro skin-on-a-chip microfluidics and in vivo Raman spectroscopy and photoacoustics [74]. The differences in the study parameters under evaluation - assessment times, antiseptic concentrations and formulations, and the wound models - impact the results of the studies and should be carefully considered when arriving at conclusions. While in vivo studies are more relevant than in vitro studies, overall the research should be focused at comparing various antiseptics with regard to their toxicology in relation to the antimicrobial efficacy. Some of the elements that should be considered in designing toxicology research are listed in Table 3.

The AWG has developed consensus statements for PVP-I based on the evidence reviewed and their discussions (Table 4). These consensus statements are based on a critical appraisal of evidence for PVP-I available in the literature, albeit from in vitro and in vivo animal research, as well as the experience and opinion of the members of AWG of using PVP-I and other antiseptics in their clinical practice. These statements will not only support clinicians in Asia in making decisions for wound management, but could potentially guide future research in the field of antiseptics.

The use of PVP-I as an effective and safe antiseptic to prevent and address the bioburden in wounds is supported by several in vitro and in vivo studies. It has a broad spectrum of activity, the ability to penetrate biofilms, and a lack of development of bacterial resistance. Although PVP-I is used globally, questions about allergy and cytotoxicity are often raised based on data from in vitro cellular or in vivo animal studies. Furthermore, evidence from research investigating the comparative efficacy of antiseptics is limited by the disparity in elements such as the study design, the wound model, and the formulation and concentration of the antiseptics evaluated. Additional well-designed clinical studies in human wounds could potentially provide further evidence for the efficacy and safety of PVP-I.

The Asian Working Group presents consensus statements for povidone iodine based on evidence and their experience.

Medical writing assistance for the preparation of the manuscript was provided by Dr. Shilpa Mudgal of In Vivo Communications (Asia) Pte Ltd. Support for this assistance as well as the AWG advisory board meeting was provided by an independent medical education grant funded by Mundipharma, Singapore.

Paul Bigliardi has given presentations for Mundipharma GmbH and has received some support for an investigator-initiated clinical trial comparing a Mundipharma iodine product with silver dressing. Stefan Langer has given presentations for Mundipharma GmbH, Germany, and has received support for preclinical studies with Mundipharma research products. Jose Joven Cruz, Sang Wha Kim, Harikrishna Nair, and Gulapar Srisawasdi report no conflicts of interest.