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3.1. Mode of action

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 membranes, in addition to cytosolic enzymes involved in the respiratory chain, causing them to become denatured and deactivated (Fig. 1) [17]. However, the precise sequence of events occurring at the molecular level has yet to be fully elucidated [6], [14], [15], [18], [19]. Cytotoxicity studies have shown that the bactericidal effect occurs even before individual human cells are affected (see below).

3.2. Preclinical efficacy data

3.3. Non-clinical models

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 human skin and is therefore the most suitable non-human model. Rodent skin, in contrast, differs from humans considerably, as it is much thinner, the epidermis is synchronized to 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 in clinical settings, as human patients often have underlying medical conditions that complicate healing [1]. These issues warrant caution when attempting to extrapolate preclinical data to clinical settings, and suggest that non-clinical data should be considered in 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 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 processes [41].

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% povidone iodine solution was associated with an early but rapidly transient decrease in blood flow [51], [53]. However, in the 10% povidone iodine study mentioned earlier, wounds showed faster neovascularization with povidone iodine treatment compared with silver nitrate, sodium hypochlorite, and untreated controls [54]. Another rat model demonstrated no negative effects on capillary blood flow after up to 60 min exposure to a 1% povidone iodine solution [51].

Interestingly, a recent study has shown povidone iodine to enhance wound healing via TGF β, not only by increasing granulation but also enhancing neovascularization [55].

3.4. Data on povidone iodine safety

4.1. Prevention of surgical site infection

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 during surgery originate from the patient's own commensal flora, disinfection of the surgical site prior to incision is imperative [61]. A large American study in 7669 clean-contaminated surgical patients [61], as well as a recent Cochrane review [60], confirmed the value of preoperative skin antisepsis with povidone iodine as a feasible clinical option. While there appeared to be little benefit from the addition of alcohol to povidone iodine [60], [61], one 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 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 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% 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 pre-operative skin prepping, where full concentrations are needed to eliminate resident microflora.

4.2. Povidone iodine in acute wounds

Depending on severity, acute traumatic wounds may be subject to OTC treatment with clear guidance on when to invoke physician referral [68]. Such wounds may benefit from the use of povidone iodine, especially when contaminated or infected [69].

Dry powder sprays may be better tolerated in sensitive wounds while having a hemostaticeffect 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 and can be used in dry wounds or skin and to prevent adhesion, but it is less indicated if oozing or exudate is predominant.

4.3. Surgical wounds

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 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 adverse effects reported [69], [70].

In contaminated and dirty wounds requiring surgical attention (class III and IV), antisepsis (together with systemic antibiosis and a check on the tetanus immunization status) is warranted. Intense debridement and wound cleaning, together with suitable wound treatment devices such as polyurethane foams may facilitate long term healing. Dressing changes and 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 wounds allow differentiated treatment. Patients have reported the additional benefit of a cooling effect experienced from dry powder sprays, likely due to the evaporating propellant.

4.4. Burn wounds

The potential for microbial infection is high in burn wounds, and infection can cause partial thickness burns to progress to full thickness, with severe consequences [21]. Burns precipitate 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 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 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. The effect of povidone iodine on neutrophils [5] and oxygen radicals [20] is potentially of significant value in burns patients due to the limitations imposed by collateral tissue damage [71].

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 tolerated in an uncontrolled pediatric trial [73].

In another randomized trial involving 213 patients with partial thickness burns, treatment with a povidone iodine dressing was associated with reduced treatment times, lower analgesiarequirements, fewer hospital visits, and less time off work compared with chlorhexidine 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 population demonstrated faster wound healing and a more favorable cosmetic result with liposomal povidone iodine hydrogel versus silver sulfadiazine [75].

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 tissue repair, preventing wounds from healing as expected even after intense treatment for an extended amount of time [2], [4], [22].

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 bacteriaseems to occur with increasing chronicity of wounds [3].A lack of perfusion in these chronic wounds 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 systemic antibiotics should only be used in cases of established clinical infection [7], [78]. In addition, about half patients with chronic wounds develop allergic contact eczemas to topical products applied, particularly to preservatives, emollients, dressing adhesives, antibiotics (e.g. fucidic acid or neomycine) and antiseptics (e.g. chlorhexidine). Therefore, the use of 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 safety profile.

The benefits of povidone iodine in chronic wound healing, as in burn wounds [23], may extend beyond its antimicrobial properties [74].