Topical antimicrobial therapy of chronic wounds healing by secondary intention using iodine products

Abstract

All open wounds healing by secondary intention are contaminated by bacteria and in chronic wounds this can progress through colonisation to invasive infection. Iodine products reduce bacterial load and are active against most species of micro‐organisms, and certainly those encountered in chronic wound care. This review evaluates the use of iodine products in chronic wound care including povidone‐iodine solutions and cadexomer iodine. Antiseptics containing iodine are relatively cheap, resistance is unknown and concerns about systemic toxicity are probably overstated. More widespread use of these agents as topical anti‐microbials in chronic wound care should be considered to reduce the need for systemic antibiotics when colonisation has progressed to invasive infection with systemic signs.

Introduction

The history of topical antimicrobial therapy for open wounds, healing by secondary intention, is interesting. Some of the methods that have been used were clearly advantageous, others not so; in fact, sometimes hard to believe as they must have delayed healing, caused appreciable complications and even hastened death. This has been well documented in outstanding reviews and books 1, 2, 3. The Egyptians, Assyrians, Greeks and Romans all had well‐developed wound care plans, which involved the use of materials from animal, vegetable and mineral sources. The Roman gladiatorial surgeon, Galen, set progress back for several centuries with his aphorism of pus bonum et laudabile. He was an impressive physiologist and described, among many other discoveries, that localisation of pus (suppuration) in an infected wound was a desirable event, as spreading infection was probably then invariably fatal. This was misinterpreted, and many noxious substances were possibly introduced into wounds, to encourage suppuration, which would have healed uneventfully had they been left alone. There are isolated examples of good wound care throughout this time, but the real breakthroughs came with the recognition of bacteria as the cause of infection during the 19th century. This was accompanied by the introduction of antiseptic and aseptic surgery. The names of Robert Koch, Ignac Semmelweis, Louis Pasteur and Joseph Lister are legendary in the field. Antibiotics were to come later.

The chlorine‐releasing hypochlorites, like Lister’s phenol, are really disinfectants rather than antiseptics, and were used in wound care in the 18th–19th century as eau de Javel or eau Labbaraque. Later, the hypochlorites were found to have widespread use as Edinburgh University solution of lime, or as Milton, and as Dakin’s solution during the First World War (4). Although the hypochlorites, in many forms, have some adherents for their use in wound bed preparation prior to skin grafting, or as debriding agents, they have been largely excluded from modern open wound management 5, 6 because of their toxicity 7, 8, 9, 10, 11, 12. Alexander Fleming suggested as early as 1919 that topical agents should have toxicity to bacteria but not to underlying tissues, and ideally, they should also preserve or enhance host defence (13). The use of hypochlorite antiseptics remains controversial, but virtually all the evidence of their toxicity is based on experimental or laboratory‐based data.

Another halide, iodine, was discovered by Courtois in 1811. Within 30 years of this discovery, iodine was introduced into wound care as an iodide preparation (14). It was used during the American Civil War and became a household name for treating open wounds. There is a description of its use in Boris Pasternak’s Doctor Zhivago, portrayed later in David Lean’s film of the same name, when Lara applies iodine to her lover’s facial sabre wound. The pain caused to Pasha was surely a testament to its efficacy.

Some definitions

All open wounds, healing by secondary intention, are contaminated by bacteria. In chronic wounds, this may progress to colonisation, through a phase of hypothetical critical colonisation, to invasive infection (15). The recognition of infection can be surprisingly difficult, just as the effect of a delay in healing in the presence of bacteria or an increasing bioburden can be. This has been well summarised in two position documents from the European Wound Management Association 16, 17.

The definition of a chronic wound, the difference between an antiseptic and a disinfectant, has been recently addressed (18). A chronic wound is one that has not shown a 20–40% reduction in area after 2–4 weeks of optimal treatment. More simply, chronicity may be considered when there is not complete healing after 6 weeks or there is a poor response to a treatment change.

Sterilisation involves the complete killing or removal of all microbial forms and is used in the preparation of instruments in operative surgery, for example. A disinfectant has a broad‐spectrum effect on all vegetative forms of micro‐organisms, including spores, but usually has a toxic effect on tissues and is probably not suitable therefore for use in chronic wounds. An antiseptic also has a broad‐spectrum antimicrobial effect, but is relatively non toxic to tissues, and may have the effect of promoting healing. If the sequence of increasing bioburden through contamination, colonisation, critical colonisation and infection could be reduced by topical antimicrobials, then the need for antibiotic therapy, with all their attendant risks of resistance, emergence, allergy and toxicity, might be avoided. Unfortunately, some of the topical agents are rapidly inactivated after contact with organic matter, which includes body fluids, pus and necrotic tissue (19), although nanocrystalline silver is not (18). Preparations that could prolong the topical antibacterial effect would offer an obvious advantage, but the development of antimicrobial resistance is rare and has not yet been reported with the use of iodine‐containing products. The reason for this is that topical antiseptics are toxic to multiple components of bacterial cell metabolism rather than to the more specific sites of antibiotic action such as enzyme inhibition. Allergy to antiseptics is well known but is probably overstated (20).

Action and structure of iodine‐containing antiseptics

Iodine‐containing solutions have been used in aqueous and alcoholic preparations that are widely used in skin preparation and hand washing prior to surgery. This and their other uses are the basis for a separate review (21). Through bactericidal and bacteriostatic mechanisms, iodine products effectively reduce bacterial load 22, 23 and are active against most species, certainly those encountered in chronic wound care (24). Iodine denatures proteins by interacting with thiol and sulphydryl groups in proteins and inactivates enzymes, phospholipids and membrane structures by blocking hydrogen and bonding with amino acids 25, 26. The spectrum of antibacterial activity of iodine‐containing antiseptics is wide, is superior to most other antiseptics and includes action against the resistant strains found in health‐care‐associated infections (HAIs) 4, 27, 28, 29, 30, 31. Although cross‐resistance to other antiseptics and antibiotics has been described with chlorhexidine and triclosan, it has not been reported with iodine‐containing antiseptics 32, 33, 34, 35, 36. The unfounded concerns of iodine toxicity and allergy appear to have slowed down the more widespread take up of its use as an antiseptic since the early 1990s when it was widely advocated for use. Interestingly, a consensus meeting of the European Tissue Repair Society in 1997 suggested that this unpopularity was probably unfounded (37).

Iodine is made less toxic by its incorporation with surface active agents such as polyvinylpyrrolidone iodine (PVP‐I) complexes, which also make it more soluble and significantly less allergenic and irritating 38, 39. PVP‐I (povidone–iodine, Betadine) is available as a solution (alcoholic and aqueous), cream, ointment and spray, and has been incorporated into impregnated dressings. These iodophor solutions can be used as wound soaks and, although this is time‐consuming and needs some compliance and facilities, they may also be used for wound lavage to reduce surface bacteria in contaminated wounds and to aid debridement (40). Trial work is lacking to show that they are superior to tap water but because they are not expensive and have an, although short, antimicrobial activity, their use seems more logical.

Iodosorb (cadexomer iodine) is a three‐dimensional lattice of microspherical, hydrophilic, biodegradable starch beads, which contain 0·9% iodine. These dextrin–epichohydrin beads allow slower, and more sustained, iodine release. They are available as ointments, which are easier to place in open wounds, or as powders, which are difficult to retain in an open wound. Although some of the evidence is based on experimental and animal data, Iodosorb (now classified as a medical device), like PVP‐I, reduces bacterial load and infection rates and promotes healing 20, 22, 23, 41.

The safety of iodine‐containing antiseptics is controversial, being accepted by the Food and Drug Administration (FDA) but not by the US Department of Health and Human Services 20, 42, 43. Most recommendations are based on opinion and beliefs as there is no meta‐analysis or level I, evidence‐based medicine, such as a Cochrane review, available. Nevertheless, some clinical guidelines do exist for the use of iodine‐containing antiseptics in chronic wounds (44).

There are other composite dressings that permit sustained release of iodine into an open chronic wound. This can also be associated with a hypothetical release of oxygen into the wound from a hydrogel dressing (45). Povidone–iodine has also been incorporated into hydrosome preparations and found to improve the take of meshed skin grafts in a clinical burns study, in addition to its antiseptic effect (46). There is minimal evidence for the use of iodine‐releasing agents in acute wounds, and there is probably a case for further research and development of different delivery systems associated with slow release of iodine.

Povidone–iodine

Experimental and animal data may present a wide gap for interpretation into clinical practice. Nevertheless, the physiological pathways and action of PVP‐I on cells and intracellular systems have been well described (47). PVP‐I modulates redox potentials and contributes to a pro‐oxidant effect in healing (48); has been shown to be less toxic than silver sulphadiazine or chlorhexidine on histological appraisal of wound healing (49) and can enhance angiogenesis (50); modifies cellular mechanisms and enhances healing messages by activating monocytes, T lymphocytes and macrophages with enhancement of pro‐inflammatory cytokines 51, 52, 53 and may inhibit excessive protease levels in chronic, non healing wounds (54). There are data to show that PVP‐I does not inhibit epithelialisation, and may even accelerate it, nor does it seem to delay the formation of granulation tissue 11, 22, 40, 55, 56.

It can always be stated that more clinical trial work on chronic or open wounds is needed but that which is available does seem to confer an advantage to the use of PVP‐I. In an uncontrolled series of 50 patients with burns, there was a reported control of bacterial growth (57); in non infected venous ulcers, PVP‐I, mixed with a hydrocolloid, reduced vasculitis and inflammation in biopsies and improved healing in the first 4 weeks of treatment compared with a hydrocolloid alone (58); and in another uncontrolled, non comparative study, PVP‐I reduced infection and promoted healing in pressure sores and leg ulcers (59). This alleged benefit of iodine products to promote healing has been addressed in another article (Durani and Leaper, manuscript in preparation).

Iodosorb (cadexomer iodine)

The slow iodine release, ease of application, lack of toxicity and antibacterial properties of Iodosorb make it superior for use in chronic open wound care compared with PVP‐I solutions. Like PVP‐I, it has been found to be non toxic to fibroblasts in culture and to stimulate experimental epidermal regeneration and be able to stimulate healing clinically 22, 60, 61. It also retains antibacterial properties, importantly against Pseudomonas spp. and methicillin‐resistant Staphylococcus aureus (MRSA), which are common chronic open wound pathogens, and can destroy biofilms 20, 23, 41, 62, 63.

Clinical data on the use of Iodosorb are extensive, with a collective report of its use in over 40 studies (24). The majority of these studies involve chronic leg ulcers, predominantly of venous type. It is disappointing to note that not all these studies are randomised, although some report that very large numbers of patients were studied (64), and most compare cadexomer iodine with standard therapy rather than with a treatment that offered a genuine chance of clinical equipoise. Few are powered to show a difference and use rather superficial definitions with clinical data being usually based on simple categorical or linear analogue scale measurements. Recruitment in this type of study, powered to show a difference, has proved to be elusive: this is based on the prolonged times needed for study completion; cost, with the probable need for multicentre methodology and all its vagaries, and the difficulty of ensuring as homogeneous a group as possible is studied. In addition, the categories of pain, odour, oedema, exudate, necrotic tissue or slough, granulation tissue quality and epithelialisation are often measured with difficulty, being based on analogue scores, and infection expressed as qualitative colony counts or the clinical presence of pus or erythema. The opportunity to show clear differences is thereby lost. There have been relatively few studies since 1990, but those that are more recent do seem to show that cadexomer iodine is cost‐effective 65, 66.

Nevertheless, most of these studies involved a reasonable cohort of patients, which was achieved by some using multicentre recruitment. In an early multicentre comparison against standard therapy in leg ulcers, Iodosorb was alleged to have reduced pain, pus and infection involving the usual pathogens, odour and erythema (67). An improved rate of granulation tissue and healing was noted in the 93 patients treated with Iodosorb. In a crossover, single‐centre study in out‐patients, involving 61 patients over a 24‐week follow‐up, those treated with Iodosorb had better odour control and epithelialisation (68). Further studies, involving in patients (69) as well as out‐patients, some with crossover (70), but never involving more than 100 patients with one exception (66), have shown similar advantages for cadexomer iodine, which occasionally reached a statistically significant difference 66, 69, 70, 71, 72, 73. One of the larger studies did not show a difference compared with a non iodine‐containing comparator (74). Further reported advantages following the use of Iodosorb, in addition to a universally reported improved rate of healing, include being easy for dressing changes and good for control of infection in dirty ulcers. Its low allergenicity was stressed in one small study (39). There have also been reports involving pressure sores 75, 76 and diabetic ulcers (65), which have also claimed that its use improved healing and debridement, thereby facilitating nursing care.

The antibacterial effect has been specifically addressed in other reports, involving smaller numbers of patients. Reduction of the common, pathogenic chronic ulcer organisms Pseudomonas spp. (41) and S.  aureus (77) has been shown following the use of cadexomer iodine.

Iodine toxicity

The unfounded but widely considered complication of pain, when using povidone or Iodosorb, may well have slowed down the acceptance of these products in the past. Another reason for their seemingly falling use in chronic wound management, or for indications in surgery or acute wounds being addressed in a separate communication (Durani and Leaper, manuscript in preparation), may relate to its perceived associated toxicity when used topically. There is some experimental evidence that iodine might reduce wound strength (78), although this would not be pertinent in the healing of chronic wounds. The toxicity of povidone–iodine to cells in culture is dose dependent. This has been shown in cultures of granulocytes, monocytes (79), keratinocytes (80) and fibroblasts 8, 9, 81. However, other reports have suggested that this topical toxicity is probably not of clinical relevance 5, 6, 7, 10, 11. No histological evidence of toxicity was found when compared with silver sulphadiazine or chlorhexidine (49). This has to be balanced against the clear antimicrobial effect of iodine products and their influence on biofilms, which is presented later in this article.

The systemic toxic effects of iodine products also need to be considered. There have been a small number of case study reports, which suggest that the topical use of iodine‐containing products may affect thyroid function. In a large review, there was no clear risk to fit patients (24). Other studies already alluded to in this review have measured thyroid function during studies of cadexomer iodine in chronic wound management 66, 67, 69. Only minor derangements were found, such as a rise in protein‐bound iodine, but there were no changes in thyroid function tests. Others have recommended that iodine products should not be used in extensive burn management (82) because of the theoretical risk of thyroid dysfunction, hyperthyroidism, in particular, or the risk of metabolic acidosis. Whereas the risk to normal patients is minimal, if any, those with known thyroid dysfunction or extensive burns, children, pregnant mothers or lactating mothers, caution should probably be advised.

Biofilms and iodine products

Biofilms are made up of bacterial communities that are encased in an extracellular polysaccharide matrix, or glycocalyx, which is produced by the bacteria and facilitates their attachment to a surface 83, 84. This includes conditioning films, such as plasma proteins, fibronectin, fibrinogen and collagen, and also dental plaque (85). Many bacteria have been found to produce biofilms that can permit a broad‐spectrum defence against the host response and to antibacterial agents 86, 87, 88. The glycocalyx is a complex structure that allows transfer of nutrients and waste products through water channels (89). It also permits passage of intercellular signalling molecules, by quorum sensing, between bacteria to influence growth of the glycocalyx, and add to resistance to host defences through the production of virulence factors and coordinated regulation of gene expression 90, 91.

Theoretically, chronic wounds offer ideal conditions for biofilm production as proteins (collagen, fibronectin and fibrinogen) and damaged tissues are present, which can allow attachment 92, 93. Most of the chronic wound pathogens, such as MRSA and Pseudomonas spp., are typical biofilm producers. Theoretically, enzymatic agents may work in debridement by removing biofilms (87), but there is, encouragingly, already evidence that some antimicrobials are active against biofilms. Silver may be effective by destabilising the glycocalyx (94), but Pseudomonas spp. may be more resistant to cadexomer iodine when in a biofilms (62). However, it has been shown that Iodosorb can destroy biofilms and thereby S.  aureus 28, 63, possibly by increasing host neutrophil invasion (95).

Evidence exists of the antibacterial activities of povidone and cadexomer iodine, particularly against common chronic wound pathogens such as Pseudomonas spp. and S.  aureus, while synchronously stimulating healing 20, 23, 41. The recognition of the importance of biofilms in chronic wound care has received some attention with regard to iodine product use. The presence of biofilms in chronic wounds is probably underdiagnosed as the identification of organisms that form biofilms using culture techniques is difficult (96). It is likely that many of the HAIs are related to biofilms, and the presence of coagulase‐negative staphylococci in relation to implanted medical devices and catheters is an example. MRSA is resistant even to hypochlorite solutions, which may be related to its occurrence with biofilms (97). If an antimicrobial agent could destroy biofilms containing bacteria, then it may be rendered more effective.

Conclusions and recommendations

The continued unjustified use of antibiotics will have to be addressed if the rise of resistant and emergent organisms is to be controlled. Topical antimicrobials, such as the antiseptics, could be used more often to avoid the need for antibiotics particularly in wound care and management protocols. Iodine‐containing products are ideal for this purpose in that resistance is unknown and systemic toxicity and topical allergy are probably overstated. Antiseptics containing iodine are relatively cheap and their more widespread use ought to be reconsidered, both for their topical antimicrobial use and as a potential barrier as silver dressings can be (18).