EJBR2020v10i3art232-239 ISSN 2449-8955 European Journal of Biological Research Review Article European Journal of Biological Research 2020; 10(3): 232-239 DOI: http://dx.doi.org/10.5281/zenodo.3958220 Povidone-iodine in wound healing and prevention of wound infections Maksym K. Gmur1, Tomasz M. Karpiński2* 1 Student Scientific Club of Medical Microbiology, Chair and Department of Medical Microbiology, Poznań University of Medical Sciences, Wieniawskiego 3, 61-712, Poznań, Poland 2 Chair and Department of Medical Microbiology, Poznań University of Medical Sciences, Wieniawskiego 3, 61-712, Poznań, Poland *Correspondence: E-mail: maksymgmur@gmail.com; tkarpin@ump.edu.pl Received: 13 May 2020; Revised submission: 11 July 2020; Accepted: 23 July 2020 http://www.journals.tmkarpinski.com/index.php/ejbr Copyright: © The Author(s) 2020. Licensee Joanna Bródka, Poland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/) ABSTRACT: The wound infections caused by bacteria and fungi are a significant problem in healthcare. Therefore, an effective treatment and prevention seems to be essential. Povidone-iodine is one of the commercial antimicrobial agents used for skin disinfection, in surgery and for local anti-infective treatment. The broad activity spectrum of this compound includes numerous species of Gram-positive and Gram- negative bacteria, mycobacteria, fungi, protozoa and viruses. Povidone-iodine is recommended for acute wounds as well as lacerations, bruises and deep wounds due to its good tissue penetration. Keywords: Povidone-iodine; PVP-I; Antiseptic; Antimicrobial; Wound infection. 1. INTRODUCTION Bacteria are a part of the physiologic skin and mucous membranes flora and in that way wounds [1]. Additionally, non-pathogenic or potentially pathogenic microorganisms of transient flora reside the skin and mucous membranes for hours to weeks [2]. Exceeding the critical threshold of 105 bacteria (critical colonization) may cause an infection. Additionally, antibiotic-resistant strains can significantly impede wound healing [1]. Most chronic wounds comprise more than one bacterial species. Among them Staphylococcus aureus, S. epidermidis, Streptococcus agalactiae, Enterococcus faecalis, Corynebacterium spp., Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter baumannii, Escherichia coli, Proteus mirabilis, Serratia spp., Finegoldia magna, Propionibacterium acnes, Fusobacterium nucleatum, Prevotella spp., and Bacteroides fragilis are the most often. An increase in surgical site infections (SSIs) correlated with methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus were observed. Infections caused by fungi, such as Candida albicans and C. glabrata are also a significant problem. Moreover, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Staphylococcus aureus are capable to form biofilms that contribute to antibiotic resistance [2-4]. To reduce the risk of infection, antiseptic agents are used. Antiseptics are naturally occurring or synthetic organic substances intended for local, topical use, that destroy or inhibit the growth of Gmur & Karpiński Povidone-iodine in wound healing and prevention of wound infections 233 European Journal of Biological Research 2020; 10(3): 232-239 microorganisms on skin, mucous membranes or damaged tissue [4]. One of the commercial antimicrobial agent is the polyvinylpyrrolidone–iodine (povidone-iodine, PVP-I). PVP-I was introduced in 1956 [5] and its routinely used as a preparation for skin disinfection in combination with alcohol and intraoperatively as a dilute solution. Its efficacy against wide variety of Gram- positive and Gram-negative bacteria, fungi, protozoa, viruses, good tolerability and lack of resistance suggests the correctness of use PVP-I in wound healing and infection prevention [6-9]. 2. CHEMICAL ASPECTS Povidone-iodine is a yellowish-brown chemical complex of 1-ethenylpyrrolidin-2-one and molecular iodine with a slight characteristic odor. The iodine content is from 9.0 to 12.0% (calculated on a dry basis). The substance has a molecular formula C6H9I2NO and a molecular weight 364.95 g/mol [10]. Figure 1 shows the chemical structure of the compound. Figure 1. Chemical structure of povidone-iodine. The solubility of PVP-I at water and alcohol is good and it is practically insoluble in acetone, chloroform, light petroleum or carbon tetrachloride. There are available different concentrations of PVP-I used depending on the purpose: as a 10%, 7.5%, 5%, 1.28%, 1% and also 0.45% formulation (as a throat spray) [10, 11].The 10% commercial formulation is composed of 90% water, 8.5% povidone and 1% iodine and iodide [12, 13]. Mixing povidone and iodine indicates a chemical reaction. It is considered that iodine is complexed by polyvinylpyrrolidone and iodide through a hydrogen bond between two pyrroles. As a result, povidone-iodine exists with a small amount of free iodine. It has been documented that exposure to organic substances like whole blood, pus or fat reduces a bactericidal activity of PVP-I. It is most likely caused by iodine complexing and chemical reactions, such as the reduction to iodide. Moreover, approximately 46 to 59 mg of iodine is bound by one gram of hemoglobin [6]. In addition, it is worth remembering that in chronic wounds, iodine compounds should not be combined with silver-containing dressings, also due to the precipitation of iodides [4]. 3. MODE OF ACTION The microbicidal activity of PVP-I is based on release the free iodine to the solution from the PVP-I complex. PVP provides iodine to cells membranes, but itself has no biocidal properties. There has been demonstrated the paradoxical behavior of substance; in contrast to other iodine preparations, the content of free iodine primitively increases with the increasing dilution, reaching a maximum value at about 0.1% formulation and decreasing on further dilution [14]. This translates into antimicrobial activity of compound [7]. The iodine effects on amino, thiol and phenolic hydroxyl groups of amino acids and nucleotides in biological structures. Additionally, iodine reacts with the double bonds of unsaturated fatty acids in the cell Gmur & Karpiński Povidone-iodine in wound healing and prevention of wound infections 234 European Journal of Biological Research 2020; 10(3): 232-239 wall and membranes of organelles [15]. This mode of action leads to disruption of pathogens metabolic pathways and irreversible damage of the cell membranes structural components. PVP-I also inhibits the production and secrete of bacterial exotoxins [3, 11, 16]. The virucidal mechanism of action is based on the inhibition of essential viral enzymes. The inactivation of neuraminidase prevents viral release from the host cell, making a further spread of the virus to uninfected cells impossible. Haemagglutinin is also inhibited by iodophor and attachment to host cell receptor is blocked [17]. 4. ANTIMICROBIAL ACTIVITY PVP-I has a broad spectrum of antimicrobial activity even after a short time of exposition [7]. It demonstrates efficacy against Gram-positive, Gram-negative, various spore-forming bacteria (Clostridium spp., Bacillus spp.), mycobacteria and also enveloped and non-enveloped viruses [8, 18]. Equally inactivation of antibiotic sensitive and resistant staphylococci and enterococci, such as methicillin-resistant Staphylococcus aureus and Enterococcus faecalis, by PVP-I was demonstrated [19-22]. Also Gram-negative bacteria, including Pseudomonas aeruginosa and Escherichia coli presented sensitivity on PVP-I [17, 20, 23]. Minimal inhibitory concentrations (MIC) of PVP-I against some bacterial and fungal species are presented in Table 1. Biofilms impede wound healing and increase resistance to antibiotics. Studies have shown the in vitro efficacious of PVP-I against S. epidermidis, S. aureus and Candida albicans growth, as well as the inhibition biofilm formation [8]. Moreover, the iodophor revealed fungicidal activity against Candida auris [24], Aspergillus flavus and Cryptococcus neoformans [6]. Table 1. MICs (minimal inhibitory concentrations) of PVP-I against bacterial and fungal species. Species MIC (µg/mL) References Staphylococcus aureus 0.24-512 [3, 25, 26] Methicillin-resistant S. aureus (MRSA) 7.81-5210 [9, 25, 27] S. epidermidis 781-5000 [28, 29] Streptococcus pyogenes 490-4688 [9, 27] Escherichia coli 4-1024 [25, 26, 30] Carbapenem-resistant E. coli (CREC) 4-128 [30] Klebsiella pneumoniae 4-64 [30] Carbapenem-resistant K. pneumoniae (CRKP) 8-128 [9, 30] Pseudomonas aeruginosa 125-8330 [3, 27] Chlamydia trachomatis 97-1562 [9, 31] Bacteroides fragilis 3130-4688 [9, 27] Candida albicans 256-5000 [25, 32, 33] C. glabrata 10-5000 [32, 33] Cryptococcus sp. 2500 [32] Viruses and chlamydia play a meaningful role in infections. PVP solutions indicate high effective against Herpes simplex virus and excellent efficacy against the enveloped influenza A virus. Adenovirus type Gmur & Karpiński Povidone-iodine in wound healing and prevention of wound infections 235 European Journal of Biological Research 2020; 10(3): 232-239 8 proved to be sensitive to PVP-I, although, contrary to Herpes simplex, a longer time of exposure was necessary to inactivation. Enteroviruses and Coxsackievirus were resistant to povidone-iodine [7, 17]. 5. APPLICATION PVP-I has a wide range of applications. In 2014, European Chemicals Agency approved PVP-I as an existing active substance for use in biocidal products for types 1, 3, 4, and 22 (human hygiene, veterinary hygiene, food and feed area, and embalming and taxidermist fluids) [9]. Efficacy of wound infection treatment, prophylactic intraoperative wound irrigation, hand wash preparations, skin disinfection and topical antiseptic has been shown [13, 34-37]. Povidone-iodine is available in a pre- and postoperative skin desinfection [38, 39]. PVP-I as an antiseptic formulation is the first choice for stab, bite and gunshot wounds [3]. In difficult- to-heal wounds (including chronic wounds), it is not recommended due to its cytotoxicity, limitations of use, and the incompatibility between PVP-I and the silver-based dressings [40]. It is also useful in the care of surgical wounds, and in wounds such as the diabetic foot, as it can be used to rinse deep wounds with lack drainage [41-43]. The use of PVP-I as a vaginal antiseptic has also been demonstrated. Presurgical vaginal irrigation with PVP-I significantly reduces the risk of post-cesarean endometritis, wound infections and pyrexia in patients who underwent cesarean delivery [44, 45]. Some studies indicate that PVP-I formulations are effective in eradication pathogenic cultures of the external auditory canal after tympanoplasty [46], in intraocular injection, ophthalmic surgery, also as a cataract surgery [12], in treating the corneal ulcers [47] or preventing post-cystoscopy urinary tract infection (UTI) [48]. Moreover, PVP-I is used for mucosal antisepsis, in oral surgery and dental conditions [11]. Studies present the positive effects of PVP-I gargles/mouthwashes against Bordetella pertussis, Klebsiella pneumoniae and Streptococcus pneumoniae strains [18, 49]. However, an equally important factor conditioning the proper healing process is the low cytotoxicity of the antiseptic. The Biocompatibility Index (BI) may be helpful in choosing the right preparation (Table 2). Tabela 2. Biocompatibility index as a quotient of IC50 for L929 cells and the required MIC for a reduction factor of ≥3 log10 [40]. Compound Escherichia coli Staphylococcus aureus Octenidine 1,7 2,1 PHMB 1,5 1,4 PVP-I (aqueous solution, referring on I2) 0,9 1,0 Chlorhexidine 0,7 0,7 Triclosan 0,2 0,5 Ag-protein (referring on Ag+) 0,2 0,1 Ag(I)-sulfadiazine and silver nitrate not measurable The BI value >1 indicates that a given product has a broad spectrum against microorganisms and a low level of cytotoxicity against fibroblasts or keratinocytes, and therefore its use does not adversely affect the healing process. It is also important that the antiseptic preparation has a high degree of penetration through biofilm structures, does not induce resistance build-up, and does not cause incompatibility with other substances contained in dressings and has the ability to prolonged operation (residua effect). Currently, in Gmur & Karpiński Povidone-iodine in wound healing and prevention of wound infections 236 European Journal of Biological Research 2020; 10(3): 232-239 clinical practice, the most frequently chosen antispetics for the prevention and treatment of chronic wounds are octenidine and iodine-containing agents (such as iodine povidone) [4, 40, 50]. Sometimes, sensitizations against PVP-I cross-reacts to iodinated contrast media. However, these can be detected by a simple skin test. In addition, PVP-I allergies are relatively rare [8]. Hypersensitivity to the povidone-iodine, hyperthyroidism, toxic nodular goiter, herpes dermatitis syndrome, radioactive iodine therapy and peritoneal lavage are contraindications to povidone-iodine usage. Application during pregnancy and breastfeeding, as well as in patients under 12 years old is not recommended [3, 51]. 6. 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