Review article

Acta chir belg, 2003, 103, 241-247

The Role of Iodine in Antisepsis and Wound Management : A Reappraisal

G. Selvaggi, S. Monstrey, K. Van Landuyt, M. Hamdi, Ph. Blondeel Plastic Surgery Department, Gent University Hospital, Gent, Belgium.

Key words. Iodine ; povidone-iodine ; wound healing ; antisepsis. Abstract. For more than 150 years, iodine has been used for the prevention of infection and for the treatment of wounds. Nowadays a large amount of published evidence is available and, although it is generally in support of the use of iodine product, it is confused by being a mixture of laboratory, animals and human studies, often using different preparations. This makes interpretation and comparison difficult. After new developments and publications, the role of iodine in antisepsis and in wound management needs to be reevaluated. We mainly focused our review on the following problems : the role of the newly developed formulations of iodine preparations, its antimicrobial activity, the possibility of impairing the wound healing process, the role of iodine in the problem of growing resistance against antibiotics and antiseptics. New formulations seem to keep the same clinical efficacy, avoiding the problem of toxicity ; it seems that the antibacterial activity of iodine is superior compared to other products and, in contrast with antibiotics and other antiseptics, it seems to have no resistance problem. It seems that povidone-iodine has all the characteristics to become the first choice antiseptic in wound treatment.

Introduction For more than 150 years, iodine has been used for the prevention of infection and for the treatment of wounds. Use of its beneficial impact had even existed much earlier without any actual awareness of the active substance. Already in the Greek Age (4th century BC), Theophrastus, Aristotles pupil and first expert in medical plants, described the use of seaweeds and other plants in refreshing and relieving pain after sun burn wounds. During Napoleons Egyptian campaign (1798-1801), wounded soldiers were treated with extracts from seaweeds and other plants enriched with iodine at high concentrations from sea water (1). Also during the American Civil War (1863), the use of iodine for disinfections was widespread (2). Even if iodine-containing plants were well used before, the natural element iodine was only discovered in 1811 by the Dijon chemist Bernard Courtois. It was given its name from the Greek ioeides meaning violet coloured, because of the intensely violet colour of its vapours (1). Iodines bactericidal efficacy was first described scientifically by DAVAINE (3) in 1880 and it was only between the 19th and 20th century that surgeons started to use iodine as a preoperative disinfectant.

At that time, iodine was widely used as a particular iodine compound, called iodoform (triiodomethane, CHI3) and as ethylic iodine tincture with all the disadvantages of lacking stability and highly aggressive action on skin and mucosa (1). Already in 1919 Alexander Fleming stated that, in considering and estimating the value of an antiseptic it was probably more important to study the effect on tissues than on bacteria (4). It was the development of the iodophors (substances that can carry Iodium, e.g. povidone-iodine), and the detoxification of iodine by binding it to macromolecules by SCHELANSKI (5), which made the large-scale use of this highly effective microbiocidal possible. Despite a history spanning almost two centuries, a lot of old and new questions about the role of iodine still remain unanswered : 1. What is the role of the newly developed formulations of iodine preparations ? 2. How exactly do iodine-containing agents compare to the other antiseptics available nowadays in their antimicrobial activity ? 3. To what degree is iodine deleterious to normal living cells and does it impair the wound healing process ? 4. How does the problem of growing resistance against antibiotics affect the use of antiseptics in general and specifically of iodine-containing agents ?

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5. Are there specific situations in which PVP-I should better not be used or is even contraindicated ? The purpose of this article is to review the recent literature concerning iodine-containing agents in order to answer the above-mentioned questions. New developments and publications require that the role of iodine nowadays in antisepsis and in wound management needs to be reevaluated and redefined ! Discussion 1. Iodine formulations Elemental iodine is a violet-black non-metallic crystalline solid, with an atomic weight of 126.904, which readily sublimes to form a pungent irritating violet vapour. Its solubility in water is only 1:3000. Iodine, fluorine, chlorine, bromine comprise a group of elements called the halogens (from the Greek : salt formers). Iodine salts are widely distributed (sea water, fish, oysters and certain seaweeds). Commercially, iodine used to be obtained by burning seaweed (kelp), but it now comes mostly from Chile saltpetre, which contains small quantities of sodium iodate (6). Iodine is an essential nutrient required for synthesis of thyroid hormones and the body requires 100-200g iodine per day (6). Iodine compounds have diverse uses : potassium iodate and sodium iodide are used to treat iodine deficiency diseases, other iodine salts are used in expectorants and as diuretics (7). Iodine has traditionally been available in Solution 2%, Tincture 2%, Strong Solution 5% and Strong Tincture 7%. It has been demonstrated that, with these old formulations and in a normal solution at least seven iodine forms are present in a complex equilibrium with molecular iodine (I2), which is primarly responsible for the antimicrobial efficacy (8). This resulted in a high degree of instability of these solutions. These problems were overcome by the development of iodophors (iodine carriers or iodine releasing agents). Iodophors are complexes of iodine and a solubilizing agent or carrier, which acts as a reservoir of the active free iodine (8). The two most important iodophors used nowadays are povidone-iodine and cadexomer-iodine. 1) Povidone-iodine. Povidone-iodine (Polyvinil-Pyrrolidone-Iodine or PPI complex) is an iodophor containing a loose combination of iodine with a non-ionic surfactant in which some of the iodine may be available in its molecular form. The

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antibacterial activity of such iodine is identical to that of iodine dissolved in ethanol or solubilised in potassium iodide. The iodine in povidone-iodine has virtually no vapor pressure hence no iodine loss occurs and there is no significant odor (9). It stains the skin and clothing less than iodine solutions and is also less irritant under occlusive dressing, which simply reflects that there is less free iodine. The brown color imparted to the skin, fabrics and during its use can be readily removed (9), but loss of the brown color from povidone-iodine is always associated with loss of antibacterial properties (10). Some 30 years after the synthesis of povidone-iodine, a paradox in the behaviour of 10% solutions was reported : its antibacterial action increased with the degree of dilution (low concentrations, i.e. 0.1% to 1%, were more rapidly bactericidal than a full-strength, i.e. 10%, solution) (11). This effect, which is maximal between 1:10 and 1:100 dilutions, has been fully described, together with observations on povidone-iodines mechanism of action. One hypothesis is that the concentration of free iodine significantly contributes to the bactericidal activity of povidone-iodine solution : dilution of povidoneiodine results in weakening of the iodine linkage to the carrier polymer with a concomitant increase in the amount of elemental (free) iodine in solution (11, 12). Polyvinil-pyrrolidone-iodine newer vehicles include PVP-I Solution, PVP-I Ointment, PVP-I Cream (13) and PVP-I Gel Alcohol (14). In particular, PVP-I Gel Alcohol (this product does not exist in Belgium, while a PVP-I Hydroalcoholic solution is available) delivers rapid and persistent activity against a broad spectrum of bacteria as a skin preparation formulation : within 30 sec., all challenge microorganisms were reduced below detection level, while Betadine PVP-I Solution needed 5 minutes ; PVPI Gel Alcohol also showed a long-lasting effect up to 24 hours (14), while PVP-I showed a duration of action of about 14 hours (15). A more methodic investigation reported a different bactericidal kinetic of PVP-I dermal solution, showing a significant reduction of aerobic and aero-anaerobic bacteria even after 15 seconds (16). CALFEE found no significant difference in skin disinfection among 10% PVP-I, 70% isopropyl alcohol, tincture of iodine and PVP-I with 70% ethyl alcohol (Persist), although there was some evidence suggesting greater efficacy among the alcohol-containing antiseptics (17). This was confirmed in another study by ARATA et al. (18). Wiping aqueous PVP-I 10% off after 30 seconds of application did not show a significant difference in the reduction from baseline counts of skin flora at 5, 30, 60 and 120 min (19).

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Table I Antiseptics and activity against micro-organisms
Anti-septics Alcohol Iodium-derivates Acetic acids Chlorumderivates Chlorhexidine Quat. Amonium Hexamidine Hexetidine Speciality Ethanol 70 Iso-Betadine Crystacide Dakin Cooper Hibitane Cetavlon Hexomedine Hextril G+ XX XXX X XXX XXX XX X X GXX XXX X XXX XX X X X/O CNM XX XXX O XX O O O O Spores O XXX O XX O O O O Fungi X XXX X XX X X X X Virus +/XX X XX X O O O

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2) Cadexomer iodine Around 15 years ago, another iodine complex iodophor, cadexomer iodine, became available ; this is a polysaccharide, a three-dimensional starch lattice containing 0.9% iodine. Cadexomer iodine has a high absorptive capacity. When fluid is absorbed, iodine is slowly released. It is suggested that this permits maintenance of more constant and prolonged iodine levels in the wound bed whereas other forms of iodine are broken down more rapidly. However, there seems to be no information concerning either the rate of release of iodine from cadexomer iodine or the extent to which this iodine permeates beyond its carrier. Cadexomer iodine is a purposedesigned wound dressing ; being insoluble, it is unlikely to have other applications (20). In conclusion, the development of new formulations, such as iodophors, has resulted in a major break-through in the use of iodine containing agents : toxicity has been eliminated, the formulations are more stable and despite a lesser concentration of iodine, the same high level of clinical efficacy is maintained (13, 20). 2. Antiseptics properties As a general rule, less is known about the mode of action of antiseptic agents compared to antibiotics. Antiseptic agents usually have a broader spectrum of activity than antibiotics and, while the latter group tends to have specific intracellular targets, the former group may have multiple targets (7). Although the precise mechanism of iodine has not been completely determined, it has been suggested that the lethal effect of iodine on microorganisms can be explained as follows : iodine rapidly penetrates the cell wall and proceeds to dislocate protein synthesis, it disrupts the function of respiratory chain enzymes and interferes with lipid membrane and nucleic acid function through several diverse mechanisms of action (7, 21). Less is known about the antiviral action of iodine, but it has been demonstrated that nonlipid viruses and parvoviruses are less sensitive than lipid enveloped virus-

es (22). Similarly to bacteria, it is likely that iodine attacks the surface proteins of enveloped viruses, but they may also destabilize membrane fatty acids by reacting with unsatured carbon bonds (23). Concerning iodophors, they are considered to be less active against certain fungi and spores than tinctures, although the germicidal activity is maintained (24). Antimicrobial activity of antiseptics can be influenced by many factors such as formulation effects, presence of an organic load, synergy, temperature, dilution, and test method (24, 25). More than 100 articles have been written specifically about iodine and its antiseptic activity, comparing it to other antiseptics and antibiotics. The whole literature, a mixture of laboratory, animals and human studies, using a considerable number of different preparations at different concentrations, is stating without doubt the superiority of iodine, in topical antisepsis, compared to other substances. Iodine has been shown to be the only agent that is simultaneously active against gram+, gram-, spores, amoebic cysts, fungi, protozoa and yeasts (26, 27), and MRSA, while other antiseptic agents, as chlorhexidine, never achieved a total kill against all the strains tested (both in clinical and laboratory conditions) (28-30). In particular, GOLDENHEIM confirmed the high degree of effectiveness of PVP-I solution (10%) and cream (5%), compared to chlorhexidine, against MRSA in vitro (28). MCLURE had the same results on 33 clinical isolates of MRSA, against which chlorhexidine never achieved a total kill, and only killed three out of 33 strains (9% success), while PVP-I achieved full efficacy against all of them (100% success) (29). These results are summerized in the Table I (31). The time interval in antiseptics is also important : PVP-I showed high bactericidal activity against common bacteria after only 30 seconds of exposure (32). After PVP-I application, the time required by skin bacteria to return to usual concentration on the skin is about 6 to 8 hours (25). In conclusion, there is almost a universal agreement in the literature that the overall antibacterial activity of PVP-I is superior compared to other products.

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3. Effect on the wound healing process It is a common belief that, the stronger the bactericide effect of an antiseptic agent, the more deleterious is its effect on living tissue. Probably because of this belief, many surgeons and general practicioners have long been convinced that iodine preparations, because of their extreme bactericidal effect, did not really promote good wound healing. Indeed, older studies and preparations have shown impaired wound healing and reduced wound strength with the use of iodine (33, 34). However, newer literature has demonstrated that many of those older studies confused different study conditions : animal versus human research, in vivo versus in vitro conditions and differences in preparations of iodine at different concentrations. The recent literature has demonstrated that the conclusions of those older studies are not always reliable and comparable (35). Very recent articles seem to go even a step further, demonstrating not only the absence of a deleterious effect on the wound healing process, but also indicating the presence of a beneficial effect, based on a molucular explanation. Nowadays, new formulations seem to have reached a great improvement (not jeopardizing proliferation of fibroblasts and epithelial cells, neither collagen production) in wound healing, if compared to the old iodine containing agents (13). MAYER, in his review focused on in vivo and human studies, affirmed that newer vehicles, such as PVP-I ointment and cream, might actually enhance the healing process, especially when PVP-I ointment is used in conjunction with the newer gel-type occlusive dressings (13). Data from MOORE (36) proposed a mechanism additional to iodine anti-bacterial activity in wound healing. He demonstrated that the delivery of iodine to nonactived macrophages within the chronic wound may induce TNFa as a primary event. As a consequence, iodine induces a fresh influx of macrophages and Thelper cells, which are considered to play a positive role in modulating wound healing (36). BENNET, in 2001, proved that PVP-I significantly enhanced angiogenesis (37). Very recently, FUMAL showed how PVP-I increased significantly the healing rate and reduced the healing time by 2-9 weeks ; histologically, PVP-I applications did not alter the microvessels and did not significantly reduce the density in dendrocytes and fibroblasts (while other two agents tested, silver sulfadiazine and chlorhexidine digluconate, appeared to alter the superficial microvasculature inclunding the dendrocyte population) (38).

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SCHMIDT reported a possible additional mechanism : cadexomer iodine formulations may modulate the redox environment of wounds and hence contribute beneficially to wound healing (39). Finally, GILCHRIST in 97 wrote an important report of a consensus meeting on the use of iodine in wound care : the overall impression was that the product (especially cadexomer iodine) does have a role in enhancing healing in chronic wounds (35). In conclusion, the literature seems to have moved away from earlier criticism of iodine with reports of deleterious effect of iodine on the wound healing process, towards a much more positive attitude with an even beneficial stimulating effect on wound healing. 4. The growing problem of resistance Nowadays, the growing resistance against antibiotics (and antiseptics ?) has become a worldwide and increasing problem (21). In recent years, considerable progress has been made in understanding more fully the response of different types of bacteria (mycobacteria, nonsporulating bacteria, and bacterial spores) to antibacterial agents. The widespread use of antiseptics and disinfectant products has prompted some speculation on the development of microbial resistance, against antibiotics, antiseptics and disinfectants and in particular on the occurrence of cross-resistance among all these products (24, 25). The ways whereby bacteria circumvent drug action are many and varied, ranging from intrinsic impermeability to acquired resistance (involving plasmids, transposons and mutations). Resistance against antibiotics may be explained by the inability to reach susceptible target sites, they may be enzymatically inactivated, modified or expelled or mutations may arise such as to render the target sites insusceptible (40). Mechanisms of bacterial resistance to biocides are less well understood but cellular impermeability is a major factor (40). The problem of the cross-resistance between antiseptics and disinfectants and antibiotics has been questioned (31). Some biocides have the ability to select for antibiotic resistant mutants and vice versa (41). An association between resistance to antibiotics and biocides in Gram-negative bacteria has been observed (40). For Gordon (21), the possibility of an association between multiple-antibiotic resistance and antiseptic resistance exists : multiresistant strains of S. aureus (including MRSA) possess the pSK1 family of multiresistant plasmids which variously encode resistance to both antibiotics and antiseptics including chlorhexidine.

The Role of Iodine in Antisepsis

Table II Descending order of resistance to antiseptics and disinfectants
Prions Coccidia Spores Mycobacteria Cysts Small non-enveloped virus (polio-virus) Trophozoites Gram-negative bacteria (non sporulating) (Pseudomonas) Fungi Large non-enveloped viruses Gram positive bacteria (S. Aureus) Lipid enveloped virus (HIV, HBV)

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of all reported bacteraemias are caused by S. aureus with a treated mortality of around 30%. S. aureus is also a major nosocomial pathogen and its infections may jeopardize the success of surgery. Few works report the resistance of MRSA to iodine formulations, but these studies considered very specific situations (such as very long conservation period and unusual storage s temperature, and no in-vivo test was used) (44-46). In view of all these recent developments, it seems logic to conclude that a growing resistance against antiseptics and antibiotics in general should result in a growing use of iodine containing antiseptic agents (21). 5. Contraindications

Extensive and prolonged use of chlorhexidine might even promote the evolution and dissemination of multiple-antibiotic resistance in S. aureus and other hospital pathogens. He concluded stating that it might be prudent to restrict the widespread use of chlorhexidine in the hospital environment to preserve not only the useful life of this antiseptic agent but also the value of many antibiotics (21). For other authors, the problem of cross-resistance is not that relevant, compared to the normal antibiotic resistance (42) ; anyway, further studies are indicated. KUNISADA demonstrated experimentally the acquisition of resistance of clinical isolated strains against commonly used antiseptics (chlorhexidine and alkyldiaminoethylglycine hydrochloride) ; strains that acquired resistance against one antiseptic agent showed also cross-resistance to all antiseptics except for PVP-I (32). This absence of acquired resistance after a long-term use of PVP-I is also confirmed in other studies (43). Table II shows the descending order of resistance of different pathogenic species to antiseptics and disinfectants (31). Given that iodine containing antiseptic agents have been in extensive clinical use in hospital for over 150 years without development of resistance, it is tempting to hypothesize that it is the actual mechanism of action of iodine, which stops the evolution of resistance : these various iodine-directed mechanisms of action occur with such speed at different and dispersed target sites that even with the genetic versatility of S. aureus they prove indefensible and rapidly lethal. Perhaps the most probable defense mechanisms that might evolve would be the excretion of inactivating compounds or novel permeability resistance, but even these have an extreme low probability of evolution (21). The clinical significance of MRSA, its treatment, control policy and the importance of using PVP-I, have been illustrated by Gordon (21) : in the UK about 15%

Adverse effects of povidone-iodine have been rarely published in the literature and only in sporadic case reports. These side effects include : reversible kidney failure (47), convulsions with central nervous system involvement (48), peritonitis after mediastinal lavage with PVPI (49). There have also been reports on the disturbances on thyroid function tests with no clinical signs in premature infants after extensive use of PVP-I-containing compounds (50), but there was no correlation between their use and neonatal thyroid dysfunctions in controlled trials (51). A metabolic acidosis and fatal kidney failure has also been reported in an extensively burnt patient : it was attributed to the prolonged use of PVP-I over a large Total Body Surface Area, but in this case the simultaneous sepsis and the deteriorating general condition of the patient should be considered (52). Irritative contact dermatitis (53) and acute allergic reactions (54) caused by PVP-I have been reported. Epicutaneous testing revealed hypersensitivity against PVP-I in less than 1% of 6000 tested patients (55), while other authors never noted allergy towards povidoneiodine during many years of use (56). It should be stressed that all publications on adverse effects or possible contraindications for povidone-iodine are sporadic case reports often with a questionable clinical relevance. Conclusion For more than 2000 years, iodine-containing plants (first) and iodine extracts and preparations (later) have been used for the prevention of infection and the treatment of wounds. A large amount of published evidence is actually available and, although it is generally in support of the use of iodine product, it is confused by being a mixture

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of laboratory, animals and human studies, often using not always reliable and/or comparable methods, or using a considerable number of different preparations. This makes interpretation and comparison difficult. It is further complicated by the lack of good controls and the absence in many case of appropriate bacteriological investigation (4, 36). The purpose of this literature study is to review specifically the recent literature and the new developments concerning iodine-containing agents. In answer to the four key questions mentioned in the introduction, the following conclusion can be drawn out of the recent literature : 1. The availability of newer iodine-containing formulations has stimulated a new interest on these products : these formulations, despite a lower concentration of iodine, keep the same clinical efficacy, avoiding the problem of toxicity (13, 20). 2. As to the bactericidal activity, few, if any, alternative antiseptics have such ubiquitous clinical applications as iodine-derivated products. There seems to be an almost universal agreement in the literature that the antibacterial activity of PVP-I is superior compared to other products. In most of the studies, it proved to be superior to chlorhexidine and to other antiseptics in assessments of disinfection performance against MRSA, fungi and viruses, being the only one able to eradicate spores (26, 31). 3. It was a common belief, due to some old studies, that iodine preparations could be deleterious to the wound healing process. Many of the concerns about iodine are based on the toxicity against different cells (epithelial cells and fibroblasts, immunitary system cells and endothelial cells) of older formulations containing elemental iodine or arise from in vitro studies, which may not necessarily be relevant to in vivo situation. The advent of povidone-iodine overcame the problems of irritancy associated with other iodine preparations when used on raw surfaces. Newer preparations appear to be safe, still maintaining the same antimicrobial properties (36). Moreover, the possibility that iodine may have beneficial effects on wound healing (by modulating the secretion of cytokines) independent of any antimicrobial activity has generated much interest and a new avenue for research (36, 39). 4. In contrast with antibiotics and other antiseptics, povidone-iodine seems to have no real resistance problem. However, several authors concluded that the problem of growing resistance against other antiseptics and

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antibiotics (21) and the existence of cross-resistance among these (24, 25, 40), with the exception of PVP-I, should turn us to use more and more iodine preparations (21, 31, 43). 5. As other authors (57), we agree that caution is advised against extensive use of PVP-I in neonates due to the increased permeability of their skin, also in burned patients with very extensive burn injuries, and in individuals with known thyroid or renal dysfunction. A regular check-up of the thyroid function and renal function can let the physicians to avoid the mentioned problems. After reviewing the literature, we can reply to the above-mentioned questions, and maybe we can redefine the role of iodine nowadays in antisepsis and in wound management : it seems that PVP-I has all the characteristics to become the first choice antiseptic in wound treatment.

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