Introduction

Wounds, especially chronic wounds, impose an important burden on the worldwide healthcare system, causing both economic costs to society [1, 2] and fatal harm to patients. Chronic wounds are non-healing wounds of multifactorial cause. Infection is one of the significant causes of delayed wound healing [3]; therefore, infection control should be a careful consideration in wound management. In order to control infection, wounds should be treated with aseptic technique, optimal debridement, and appropriate antimicrobial agents [4].

Due to the rise in antimicrobial resistance caused by antimicrobial abuse, especially from systemic antibiotic use, the roles of topical antimicrobials in wound therapy are increasing in importance [5,6,7]. Topical antimicrobials are directly applied to the wound, resulting in a high concentration at the wound site, low systemic side effects, and a low incidence of antimicrobial resistance. Topical antimicrobial agents, which consist of disinfectants, antiseptics, and antibiotics, are defined as agents that have the ability to kill, inhibit, or reduce the number of microorganisms [5, 8]. Disinfectants are agents that can eradicate all microorganisms, including spores; however, these agents cannot be applied on living tissue because of their toxicity. Antiseptics are chemical substances that can be used on intact skin, some open wounds, and mucous membranes in order to kill or inhibit the growth and development of microorganisms with non-specific activity or multiple microbial targets [3, 5]. However, they have some toxic effects on host tissues. Antibiotics, which are either naturally or synthetically produced, are chemical substances that have the ability to kill or inhibit microorganisms with specific cell targeting action, causing a narrower antimicrobial spectrum. Antibiotics are relatively non-cytotoxic; nonetheless, bacterial resistance to antibiotics is more common.

Although the antimicrobial efficacy of these substances has been determined in various studies, a summary of their adverse effects is lacking. Each antimicrobial has different adverse effects, which may limit their use in some populations. The adverse effects of antimicrobials can be separated into local and systemic effects. Local effects include pain, rash, and cytotoxic effects on the cells necessary for the wound healing process, such as epithelial cells, fibroblasts, endothelial and inflammatory cells, and others [9]. These effects occur only at the site of application. Systemic effects occur from the absorption of these substances into the systemic circulation, resulting in toxicity to the kidneys, liver, and other organs.

This paper aims to summarize the downside of topical antiseptics and antibiotics that are commonly used in wound care in order to indicate the possible adverse effects that can result from topical antimicrobial use and summarize the limitations of antimicrobial application in certain patients.

Adverse effects of antimicrobials

Antiseptics

Antiseptics exhibit a broad antimicrobial spectrum and residual anti-infective activity on wounds; however, they may be toxic to host cells or tissues (e.g., fibroblasts, keratinocytes, and possibly leukocytes) [9].

Biguanide compounds

Chlorhexidine

Chlorhexidine (CHX) is a biguanide antibacterial agent that has been in wide use since the 1950s in several products. The recommend concentration of CHX for use in wounds is 0.05% [10, 11]. However, the toxicity of CHX was reported depending on both concentration and time [12, 13]. The possible mechanisms underlying its cytotoxicity were indicated that CHX was able to: (i) increase cell permeability, which contribute to leakage of cell components; (ii) cause mitochondrial injury leading to ATP depletion; (iii) suppress DNA synthesis, resulting in decrease of cell proliferation; (iv) alter cytoskeletal organization followed by change of cells configuration; (v) disturb protein synthesis and accumulation; (vi) induce endoplasmic reticulum stress owing to some proteins accumulation; and (vii) increase intracellular calcium ion, which conduce to reactive oxygen species (ROS) over generation [12,13,14]. The ROS generation also cause endogenous DNA damage leading to genotoxicity of CHX to several cells [15]. Different effects were observed on various cells involved in the wound-healing process, including fibroblasts, endothelial cells, macrophages, and lymphocytes [12,13,14,15]. Moreover, CHX showed toxicity to human osteoblasts [16] and human cartilage, especially osteoarthritic cartilage [17] so CHX should be used with caution to irrigate exposed cartilage. Allergic reactions, including anaphylaxis from products containing CHX, have been also presented especially mucous membrane treatment [10, 18]. For systemic effect, the toxicity was rarely reported because CHX is poorly absorbed through intact skin [19, 20]. Only small amounts of CHX (1 to 460 ng/mL) was detected in human blood [21].

Polyhexamethylene biguanide

Polyhexamethylene biguanide (PHMB), also known as polyhexanide, is a biguanide substance. It is a strong base antimicrobial agent. At concentrations of > 20–50 μg/mL, PHMB binds to the plasma membrane, resulting in cell lysis, leakage of enzymes and cytokines, and eventually cell death by necrosis [22]. In addition, the cytotoxic effect of PHMB on chondrocytes may result from the inhibition of proteoglycan synthesis [23]. Several studies have indicated low antimicrobial cytotoxicity of PHMB [24, 25], whereas others have shown concentration- and time-dependent cytotoxic effects of PHMB on chondrocytes [26], endothelial cells [27], keratinocytes, fibroblasts, and osteoblasts [28]. Moreover, the concentrations at which PHMB negatively affect osteoblasts and endothelial cells are equal to or lower than the clinically recommended concentration [16, 27]. Besides the cytotoxicity of PHMB on cartilage [26, 29, 30], the efficacy of PHMB is suppressed in the presence of mucin and chondroitin sulfate, which can be found in nasal and joint fluid [29]. Accordingly, PHMB should be applied with caution on areas with exposed bone or cartilage [29]; however, this effect may be relieved by NaCl irrigation [30]. It should be noted that the combination of PHMB and additives with surface-tension-reducing properties can lead to higher cytotoxicity as well as antimicrobial efficacy of PHMB [29]. Furthermore, PHMB is incompatible with anionic detergents, soaps, alkyl sulfates, strong inorganic bases, and complex phosphates [29]. Lastly, severe anaphylaxis should be aware as it occurred after patients came into contact with PHMB used for cleaning surgical wounds [31] and PHMB-containing products [32].

Silver compounds

Silver has been used for infection control in wound care for centuries. The silver compounds that are well-known antiseptics in clinical practice are silver nitrate and silver nanoparticles.

Silver nitrate

Silver nitrate (AgNO3) is a traditional antimicrobial that has been used for burns for centuries [33]. It is a water-soluble salt in solution. This agent can stain the contacted area by turning black following exposure to light [34]. There are several mechanisms of silver nitrate leading to its toxicity or adverse effects. First, at concentrations lower than 0.5%, silver nitrate negatively affects mitochondrial function in a concentration- and time-dependent manner. Moreover, silver nitrate induces cell detachment, interacts with nuclear proteins, inhibits DNA synthesis, depletes intracellular ATP, and decreases cellular protein content [35]. Accordingly, silver nitrate showed cytotoxicity to fibroblasts [34,35,36], keratinocytes [36], and endothelial cells [35]; however, its cytotoxicity can be reduced by addition of fetal calf serum and testing on a more complex arrangement of cells, which more closely mimics physiological conditions [36]. Secondly, nitrate is a pro-inflammatory and toxic substance to wounds, and it can be converted into nitrite, an oxidant substance that induces cell damage and retards wound healing, by gram-negative bacteria [34]. Thirdly, as a result of the deposition of inert precipitates of silver selenide and silver sulfide, argyria, which is blue, gray, or black discoloration of the skin commonly found in light-exposed areas, also occurs from the long-term use of silver nitrate [37]. The causative mechanism of argyria is still unclear, but it is suspected to relate to imbalances in soluble and insoluble silver in the middle or upper dermis and the reductive process involving lysosomal reductase and solar energy [38]. Lastly, nitrate anion can induce conversion of ferrous hemoglobin to the ferric state (methemoglobin), which is incapable of normal oxygenation. Methemoglobinemia in burn patients using 0.5% silver nitrate solution has been reported. This complication may be life threatening, which can be restored by intravenous methylene blue therapy. However, this complication is rare [38,39,40]. Apart from the abovementioned, due to its rapid inactivation, silver nitrate has no sustained effect; therefore, it should be reapplied frequently (up to 12 times per day), and this poses a problem for both practitioners and patients [34]. Patients not only suffer from the pain of dressing changes but also from the possible exposure to excess silver from frequent application. Silver can be absorbed into the systemic circulation, resulting in silver deposition in various organs such as the brain, liver, and kidneys. These depositions may produce toxicity to the involved organs [34].

Silver nanoparticles

Silver nanoparticles (SNP) range in size from 1 to 100 nm. Because of their small size and large surface area, SNP are expected to have high antimicrobial efficacy. At present, SNP are crucial substances for wound care, and SNP are impregnated in various advanced wound dressings. Despite having effective antimicrobial activity, SNP show cytotoxicity that result from cellular SNP uptake and subsequent oxidation of intracellular SNP by oxygen or other molecules, resulting in silver ion (Ag+), which is toxic to cells. Ag+ can cause oxidative stress via ROS production and damage to cellular components such as DNA, enzymes, antioxidant molecules, proteins, and cell membranes [41, 42]. In addition, the toxicity of SNP is dose and time dependent. Some studies have shown cytotoxic and genotoxic effects of SNP on several cell types [42], including fibroblasts [43] and keratinocytes [44]. Even Acticoat®, a novel dressing containing silver nanoparticles, showed a cytotoxic effect on keratinocytes [34] and fibroblasts [45]. It is noteworthy that a very low concentration of SNP can be absorbed through intact skin; however, absorption can increase in damaged skin [46]. Therefore, SNP application to wounds may lead to silver accumulation and toxicity to various cell lines, including lung, stomach, breast, and endothelial cells. Furthermore, in vivo studies found toxicity of SNP to the brain, lungs, liver, kidneys, and reproductive system [34, 42]. Although some studies showed that silver from SNP application was less absorbed than that from silver sulfadiazine (SSD) application [47, 48], abnormal liver function was documented in burn patients using dressing containing silver nanoparticles [49]. It is uncertain whether the increased liver enzyme levels were due to the silver nanoparticle dressing or to the burn itself [48]; therefore, the level of silver in plasma should be monitored in order to avoid the adverse systemic effects of silver nanoparticle application, especially in large wounds. Unlike other drugs, SNP have variation in physicochemical properties that can lead to variation in toxicity. The smaller size of SNP is suspected to result in higher toxicity. Regarding particle shape, spherical particles seem to induce less toxicity than wire-shaped and plate-shaped particles. Moreover, differently coated surfaces result in different toxicities of SNP due to differences in charge, aggregation, and surface functionalization. In addition, SNP can form complexes with protein in the circulation, resulting in changes in cellular uptake, stability, distribution, and toxicity. Biosynthesized SNP tends to exhibit less toxicity and higher specificity for normal cells than chemically synthesized SNP [42].

Iodine compounds

Povidone-iodine

Povidone-iodine (PVP-I) is a complex between polyvinylpyrrolidone and iodine. The most commonly used formulation contains 10% PVP-I (1% available iodine). Its antimicrobial effects result from the free iodine, that is, released from the PVP-I molecule [50]. Released iodine can be toxic to microorganisms by irreversible binding with tyrosine residues of proteins, interfering the formation of hydrogen bonding by some amino acids and nucleic acids, oxidizing sulfhydryl groups, and reacting with sites of unsaturation in lipids. Povidone-iodine has been indicated as an agent that delays wound healing [51] which may attribute to the inhibition of fibroblast aggregation [52], induction of epithelial cell death [53], and inhibition of leukocyte migration [50]. Exposure to a high concentration of PVP-I seems to cause necrosis, while exposure to a low concentration of PVP-I causes apoptosis [53]. However, recent studies showed no advantage or disadvantage of iodine compared with other products [4]. Moreover, the effects of iodine can be diminished after exposure to exudate [50]; thus, its toxicity and efficacy can differ between in vitro testing and clinical practice. Furthermore, as PVP-I contains iodine in its chemical makeup, the absorption of released iodine through the large wound, burned areas, vaginal mucosa, oral mucosa, and in children even with normal skin into the systemic circulation resulting in iodine toxicity should be considered [54]. Excess iodine can influence thyroid function [55] and cause both hypo- and hyperthyroidism (the latter is rarer) [56]. In most healthy patients, excess iodine can temporarily inhibit thyroid hormone secretion before spontaneously getting back to normal; however, remaining suppression of thyroid function in some patients because of unknown reasons can lead to hypothyroidism. Hyperthyroidism can be found in patients with goiters, after long-standing iodine deficiency, iodine-induced hyperthyroidism can occur because of sufficient iodine. Moreover, long standing of high iodine levels can result in classical thyroid autoimmunity (hypothyroidism and thyroiditis), so iodine-induced hyperthyroidism can also be an autoimmune pathogenesis [54, 56]. Iodine-induced nephrotoxicity is also reported in patients received topical povidone-iodine, which may lead to acute kidney injury (AKI), often in the form of tubular necrosis [57]. The pathogenesis has not been clearly understood; however, it may involve iodine-induced renal ischemia and tubular toxicity. As iodine is eliminated by the kidneys, problems of iodine excess may arise in patients with renal impairment, especially under conditions of metabolic acidosis. Moreover, thyroid functions should be carefully monitored in patients treated with PVP-I for a long time, especially in large wounds and children. In addition, iodides can cross placental barrier and also present in mother’s milk so the risk of neonatal hypothyroidism should be taken into consideration when using iodine products in pregnant and lactating women [50]. Therefore, this antimicrobial agent should be used with cautions in patients with renal and/or thyroid impairment, children, and pregnant and lactating women. Allergic reactions were also found with PVP-I use, especially in leg ulcer patients [58].

Cadexomer iodine

Cadexomer iodine is 0.9% w/w iodine [58] contained in hydrophilic-modified starch. This substance can absorb exudate from the wound, swell, and release iodine into the wound in order to control infection [59]. Because cadexomer iodine also contains iodine in its chemical structure, the released and absorbed iodine can produce toxicities that are similar to those found from PVP-I. The cytotoxicity of cadexomer iodine to cells is still controversial as some studies found cytotoxicity at concentrations higher than 0.45% w/v cadexomer iodine [60], while others found benefits to wound healing [61, 62]. Moreover, some studies revealed transient pain after cadexomer iodine application [63,64,65]. Although some studies showed no toxicity from iodine absorption after cadexomer iodine application [61], cadexomer iodine should still be used with caution in pregnant and lactating women, patients with large wounds, systemic complications such as renal failure or thyroid dysfunction, and severely immunocompromised patients [66]. Lastly, cadexomer iodine should be used with caution on low-exudate wounds as this substance can absorb fluid, resulting in insufficient moisture in the wound.

Chlorine compounds

Sodium hypochlorite

Sodium hypochlorite (NaOCl) was introduced as a topical antiseptic for wounds in 1915 by Henry Dakin [67]. At concentrations between 0.5 and 5.25%, it is an alkaline solution with pH 11 to 13 that can eradicate microorganisms and also dissolve necrotic tissue. Hypochlorite solution contains two active compounds, hypochlorous acid (HOCl), an extremely active compound and hypochlorite ion (OCl−), a less active compound [68]. Because NaOCl is a strong oxidizing agent, it can damage healthy tissue and its components, including human stratum corneum, collagen, fibroblasts, and immunological cells such as macrophages [69]. The cytotoxic mechanisms of NaOCl consist of cellular energy metabolism impairment, DNA synthesis reduction, progressive mitochondrial dehydrogenase dysfunction, and subsequent cell death [70]. Moreover, hemolysis can be induced by hypochlorous acid through membrane protein modification [71]. The toxic effect of NaOCl depends on its concentration and the duration of exposure. Although NaOCl showed toxic effects in an in vitro model [72], the dilute concentrations used in clinical practice seem to result in extremely low toxicity to tissue [71, 73]. NaOCl is unstable when exposed to light, heat, acids, and metallic substances. It is immediately degraded after exposure to blood or proteins in an open wound; therefore, systemic toxicity occurring from topical application is not suspected [71, 74]. Common adverse effect resulting from NaOCl application is pain at the wound site [75].

Other antiseptics

Hydrogen peroxide

Hydrogen peroxide (H2O2) is an oxidizing agent used for wound irrigation and may be used to remove necrotic tissue from wounds. The concentration of hydrogen peroxide, that is, normally used for disinfection is 1–3% (324–972 mM) [76]. H2O2 is an important compound regularly found in the normal healing process. Moreover, its disinfectant effect is rapidly diminished because H2O2 is an unstable compound, that is, rapidly decomposed to water and oxygen. Hydrogen peroxide is a well-known oxidizing agent. It can generate hydroxyl radicals that induce lipid peroxidation leading to DNA damage and cell death. The toxicity effects of H2O2 can result from three mechanisms: corrosive damage, oxygen gas formation, and lipid peroxidation [77]. Some studies showed that applying a relatively low concentration of H2O2 can enhance healing (10–50 mM) [78, 79] and promote re-epithelialization (250–500 μM). However, these beneficial concentrations are much lower than those used in clinical practice [76]. The high concentrations of H2O2 do not only damage cells in the wound bed but also destroy the healthy cells in the surrounding wound [78, 79]. The cytotoxicity of H2O2 in fibroblasts [80] and keratinocytes [81] has been reported in several studies to result from oxidative stress. Moreover, using H2O2 to irrigate wounds located in closed body cavities or under pressure should be avoided as it may lead to oxygen gas embolism or emphysema [77], especially when a high volume that exceeds the oxygen solubility in the blood is used. Data on the H2O2 dermal penetration rate are not yet available. Even though H2O2 is absorbed through the skin, it is metabolized rapidly by the enzymes catalase and glutathione peroxidase. Because H2O2 is an unstable compound, it rarely has systemic effects [82].

Antibiotics

Because the mechanisms of action of most antibiotics are specific to one or a few targets, the spectrum of activity of antibiotics is narrower than that of antiseptics. Moreover, resistance to antibiotics is more frequently found than resistance to antiseptics, which affect multiple targets with less specificity. However, the cytotoxicity of antibiotics seems to be less than that of antiseptics [9].

Bacitracin

Bacitracin is a mixture of polypeptide antibiotics produced by Bacillus subtilis. Complexing with zinc results in a stable form of bacitracin. Bacitracin is commonly combined with other antibiotics, such as neomycin and/or polymyxin, in order to increase the spectrum of their activity [83]. The adverse effects of topical application can be burning, itching, increased irritation, or rash. Allergic contact reactions were reported [84], with some variations among studies depending on the form of bacitracin and geographic location [85]. Due to the increasing use of bacitracin, the number of allergic contact reactions from bacitracin is also increasing [86]. Moreover, allergic reactions to bacitracin seem to be delayed (96 h). The physician should therefore be aware of previous allergic contact reactions to bacitracin before prescribing it. Bacitracin can cause a hypersensitivity reaction from both systemic and, less commonly, topical application. In rare cases, anaphylactic reactions from bacitracin ointment application have been reported [87, 88]. Moreover, systematic administration of bacitracin can cause severe nephrotoxicity, especially in patients with renal impairment [83, 89]; however, topically applied bacitracin is not significantly absorbed [90], so this adverse effect is rarely found. It is necessary to state that some patients who were allergic to neomycin also showed allergic reactions to bacitracin, despite the differing structures of these compounds and the absence of a relationship between neomycin and bacitracin allergies [84]. Because bacitracin is commonly combined with neomycin, and they sometimes have coincidental sensitization, the healthcare provider should determine which antibiotic is the real cause of the allergic reaction.

Mafenide acetate

Mafenide is a synthetic antibiotic structurally closely related to sulfonamides. The difference between mafenide and sulfonamide structure is its methylene group between the benzene ring and the amino nitrogen, which differs from the basic sulfonamide structure [91]. Mafenide is not antagonized by p-aminobenzoic acid (PABA), serum, or pus, unlike other sulfonamides [92]. Moreover, it has excellent tissue penetration, including eschar. The cytotoxic mechanism of mafenide involves selectively inhibition of the de novo base synthesis pathway. Mafenide might inactivate the folic acid transport system via indirectly inhibition of folic acid transport by changing the concentrations of hormones, expression of folate receptors or carrier, or pH in the wound [93]. According to its cytotoxicity, mafenide acetate may delay wound healing and reduce the breaking strength of healed wounds [94]. For systemic effects, some of the mafenide from topical application can be absorbed through the skin and metabolized rapidly into the inactive metabolite p-carboxybenzene sulfonamide; however, it can result in blood dyscrasias, including hemolytic anemia, bone marrow suppression, and methemoglobinemia [92]. Moreover, mafenide should be avoided in patients with glucose-6-phosphate dehydrogenase deficiency, as fatal hemolysis from topical mafenide application has been reported [95]. Hemolysis can be caused by oxidant drug such as sulfonamides as these drugs facilitate oxidation of hemoglobin, glutathione, and other compounds of the red cells [95]. Furthermore, mafenide and its acid metabolites can inhibit carbonic anhydrase in the renal tubules, resulting in metabolic acidosis, so it should be used with caution in patients with respiratory or renal dysfunction or large burns [96]. Pulmonary complications were also reported from mafenide cream application, but the mechanism is still unknown [97]. Furthermore, pain or burning resulting from topical mafenide application, which increased with increasing concentration, was the most frequent adverse effect [92, 96,97,98]. An allergic response to mafenide can result in rash, pruritus, facial edema, swelling, hives, blisters, erythema, and eosinophilia [92], as well as other skin reactions such as erythema multiforme and contact dermatitis [97]. There are some concerns to be noted before using mafenide. First of all, prolonged use of mafenide can lead to the growth of Candida albicans [94]. Secondly, mafenide should be avoided in patients with glucose-6-phosphate dehydrogenase deficiency. Thirdly, mafenide should be used with caution in patients with respiratory or renal dysfunction or large burns, and acid-base balance should be monitored in these patients. Last but not least, although cross sensitivity to other sulfonamides has not yet been confirmed, patients with known allergies to sulfonamides should avoid mafenide [92].

Mupirocin

Mupirocin is a short fatty acid side chain (9-hydroxynonanoic acid) linked to monic acid by an ester linkage produced by submerged fermentation of Pseudomonas fluorescens. It is a mixture of pseudomonic acids and is therefore classified as a pseudomonic acid. The major metabolite is pseudomonic acid A, which is responsible for most of the activity, while three other minor metabolites (pseudomonic acids B, C, and D) have similar chemical structures and antimicrobial spectra [99, 100]. Its activity can be decreased if the pH increases above the normal skin pH of 5.5 [101]. The cytotoxic mechanism of mupirocin has not been indicated; however, a study by Balin et al. showed growth inhibition of fibroblasts after 4–6 days exposure to 700 μg/mL mupirocin. The clinical concentration of mupirocin is 2% or 20,000 μg/mL, which is much higher than that used in the study; however, the concentration of mupirocin in tissue from topical application is still unknown [102]. A delayed healing effect of mupirocin was also reported [94]. Although topical mupirocin application is considered as well tolerated [103], there have been reports of local side effects such as burning, itching, reddening [104], and allergic contact dermatitis [105]. Conjunctival application is contraindicated as it may cause irritation. Irritation and an unpleasant or abnormal taste, which are minor side effects, have also been recorded from nasal application [101]. Mupirocin can be absorbed through the skin, especially when skin lesions are present. Because mupirocin is rapidly metabolized in plasma [99], the percutaneous absorption of mupirocin can be measured from its metabolite monic acid. Urinary monic acid was evaluated after repeated applications of mupirocin, and the measured concentration of monic acid was higher in children than in adult patients. However, no systemic adverse effects resulting from mupirocin administration were observed. In order to avoid adverse effect to infant, pregnant and lactating women should use mupirocin with cautions. Because mupirocin can be absorbed, it may be able to pass into breast milk and may affect the infant. Moreover, the polyethylene glycol from the ointment base can be absorbed through open wounds or damaged skin, resulting in renal toxicity [106, 107]; therefore, mupirocin ointment application may not be suitable for patients with a very large open wound or those with renal impairment. It is worth noting that mupirocin should not be applied for longer than 10 days in order to avoid the development of bacterial resistance [94].

Neomycin

Neomycin is one of aminoglycoside antibiotics. Neomycin fermented from Streptomyces fradiae consist of neomycin A, B, and C. The commercial product of neomycin is a mixture of neomycin B and neomycin C, supplied in sulfate form [108]. Contact allergy is the most common adverse effect of neomycin topical use. Rashes can be found in 6–8% of patients using topical neomycin [108]. Moreover, the risk factors for sensitization to neomycin include advanced age, leg dermatitis, and a high number of positive reactions to other allergens. In some countries where neomycin is an OTC drug, the frequency of exposure to neomycin is increased, resulting in an increased risk of sensitization to neomycin [109]. Neomycin can adversely affect the kidneys and auditory system. Topical application to wounds can result in hearing loss, especially in patients with renal impairment [108, 110] because neomycin, like other aminoglycosides, can cause apoptotic cell death of hair cells, mainly in the cochlea [111]. Therefore, neomycin should be avoided in patients with renal impairment. Systemic hypersensitivity reactions occurring from topical application were reported from both a neomycin-only formulation [112] and a combination neomycin–bacitracin formulation [113]. Because some patients who are allergic to neomycin are also allergic to bacitracin, hypersensitivity reactions should be carefully monitored, and the real cause of the adverse effect should be carefully determined, especially when using the combined formulation.

Silver sulfadiazine

Silver sulfadiazine is produced by combination of silver nitrate and sulfadiazine; therefore, its antimicrobial effects are a combination of the effects of silver and sulfadiazine [34]. This antimicrobial has been used for topical treatment of wounds since the 1970s, and it is the main antiseptic used for burn wounds instead of silver nitrate. The cytotoxicity mechanisms of silver are mentioned in silver nitrate and SNP part. Moreover, the mechanisms leading to delay healing may also attribute to alteration of cytokine expression and disturbance of macrophage recruitment and activation [114]. In vitro and in vivo cytotoxicity of SSD on both keratinocyte growth [115] and fibroblast proliferation were shown [116]. Furthermore, impairment of re-epithelialization by SSD, resulting in a delay in the healing process, has been reported [117]. In addition, prolonged and/or extensive topical SSD application can also produce argyria in patients [34, 118], similar to that produced by silver nitrate. Moreover, pseudo-eschar formation owing to the interaction of the drug with proteinaceous exudate in the wound after multiple applications of SSD can lead to difficulty estimating the depth of burn wounds [94, 119]. There is evidence of silver absorption and deposition after topical application of SSD [47, 120], resulting in toxicity to various organs such as the kidneys [121, 122], liver, and cornea [123]; therefore, the concentration of silver in the blood and/or urine should be monitored in patients using SSD, especially those with large burns, renal and hepatic impairment, and the prolonged and extensive use of SSD.

Due to SSD contains sulfadiazine, the adverse effects related to sulfonamide moiety should be aware. Firstly, it is important to note that dermatologic and allergic reactions, including anaphylaxis and life-threatening cutaneous reactions: Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and exfoliative dermatitis can occur in patients with sulfonamide allergies. Secondly, in patients with glucose-6-phosphate dehydrogenase deficiency, exposure to SSD which is oxidizing agent can cause hemolysis [37, 124]. Thirdly, as sulfadiazine is an oxidizing agent, it can convert the hemoglobin molecule from the ferrous reduced state to methemoglobin, the ferric oxidized state, resulting in methemoglobinemia [37]. In addition, leukopenia occurring after prolonged application of SSD has been reported [34]; however, some studies revealed that SSD is not the cause of this adverse effect [37]. Moreover, the mechanism of leukopenia is not well understood. Lastly, sulfa drugs can compete with bilirubin-binding sites on albumin, leading to increased free bilirubin and jaundice in the newborn, so SSD should not be used on females who are pregnant or lactating [125]. As the abovementioned, SSD should be avoided in patients with known allergic to sulfonamides, patients with glucose-6-phosphate dehydrogenase deficiency, and pregnant or lactating women. Moreover, SSD should be used with cautions in patients with renal and hepatic impairment.

Natural antimicrobials

Curcumin

Curcumin is a yellow-orange phenolic compound contained in the herb Curcumin longa, which has been used as a coloring agent, food additive, and traditional medicine since ancient times [126]. The efficacy of curcumin on wound healing has also been established [127, 128]. Although curcumin has been in use for a long time, its safety is not guaranteed. Due to its poor solubility in aqueous solution (it is a hydrophobic compound), low bioavailability, and rapid metabolism [129], the effects of curcumin are in doubt and seem to be local. The current development of formulations such as nanoscale formulations, complexation with a carrier [130], and encapsulation [127] may improve its properties, but it may also result in a higher possibility of adverse effects. The cytotoxicity of curcumin is still controversial. At low concentrations, curcumin acts like an antioxidant, whereas at high concentrations, curcumin can induce ROS production leading to damage to enzymes and DNA. Moreover, some studies showed that curcumin can decrease the cell viability of fibroblasts via several pathways [131, 132]; therefore, curcumin should be used with caution in wound care, especially at high concentrations. However, some studies showed the safety of curcumin on normal cells [133, 134]. Topically, applied curcumin is rarely absorbed into the systematic circulation because of the poor permeability of the skin to curcumin. The systemic adverse effects of topical use should be scarce; however, novel formulations and high concentrations of curcumin may lead to greater adverse effects. It is considerable to define that curcumin is a natural compound that may be contaminated with microorganisms; therefore, using raw curcumin as a traditional medicine without suitable sterilization may lead to wound infection.

Honey

Honey is a viscous, hygroscopic fluid with a low pH, and high osmolarity, containing a high concentration of sugar and numerous natural substances produced by Apis mellifera (A. mellifera). It is one of the oldest traditional medicines in the world. Because honey is a natural product, its physicochemical properties, efficacy, and safety can differ depending on the type of plant, collecting season, age of the bees, storage condition, geographical location, and other factors [135, 136]. The antimicrobial activity of honey is derived from both peroxide and non-peroxide activities, which can also vary among products; therefore, quality control of its activity is important. Methylglyoxal (MGO) and defensing-1 are the active components of non-peroxide activity in honey. In spite of its antimicrobial properties, MGO is suspected to delay the healing effect by inducing rapid non-enzymatic modification of the free amino groups of lysine and arginine residues of proteins and peptides, leading to the generation of advanced glycation end products (AGEs), which are the cause of complications in diabetes [137]. Moreover, the time-dependent cytotoxicity of honey to human cell lines has also been reported [28]. Furthermore, stinging pain at the site of application is a common adverse effect of topically applied honey [138, 139], and atopic reactions are also found in some patients [139]. Allergies to honey may occur caused by pollens contained in honey; however, those pollens are removed from medical-grade honey, and there are still no reports of significant allergic reactions [140]. Contamination by microorganisms and their spores, such as Clostridium botulinum (C. botulinum), fungi, and yeast, in honey should be a concern, and there have been reports of contamination in several countries [141]. The proliferation of spores can produce botulinum toxin in the wound, which can result in systemic adverse effects of the toxin. Using medical-grade honey can diminish the risk of infection and adverse effects from toxin because contaminating spores in honey are inactivated by gamma irradiation in the final process [139]. Honey showed no systemic absorption from topical application, so it is not expected to affect blood glucose in diabetic patients [139]. Aside from abovementioned, honey should be avoided in immunocompromised patients and those with known allergies to bee venom.

Antimicrobial selection

There are several lines of evidence indicating toxic effects of antimicrobial application; therefore, the decision to select an antimicrobial should be performed by balancing its advantages and disadvantages. Moreover, the choice of an optimized concentration of each antimicrobial is also important in order to both suitably control infection and avoid toxicity from antimicrobial application. Due to the complexity of the wound-healing process, results from in vitro cytotoxicity tests may not represent the clinical situation. The cytotoxic effect of each antimicrobial can depend on the type of cell culture, number of cells, evaluation method, time of exposure, concentration of the antimicrobial, and other factors used in each experiment. However, in vitro assessment has been proven a useful method for characterizing cell toxicity mechanisms of topical antimicrobials [35], which may be difficult and complicated to perform with in vivo and clinical studies. Furthermore, clinical studies seem to focus on the efficacy rather than the safety of antimicrobials. Accordingly, the safety of antimicrobials should be determined from the results of entire studies. In addition, the formulation of antimicrobials may influence their toxicity, as some formulations can enhance absorption and/or provide sustained release. Furthermore, as drug coated on medical devices can be released and present in systemic circulation, there is possibility for these drugs to cause adverse effects as same as the drug absorbed from topical application.

In order to select an antimicrobial for an individual patient, there are some points that should be considered aside from the size, location, causes of wound, and characteristics of wounds (color, odor, exudate, and pain) which are important factors in antimicrobial selection. Firstly, the spectrum of antimicrobial activity should be appropriate for the strain of microorganisms that are possibly found in a particular wound. The spectrum of activity of each antimicrobial is summarized in Table 1. Some antimicrobials may show cytotoxicity to cells; however, those antimicrobials may be necessary for wounds with a high risk of resistant bacterial contamination. The biocompatibility index (BI), which compares the antibacterial activity with the cytotoxicity of antimicrobials, may provide more information for antimicrobial selection. The rank order of the BI of antimicrobials was PHMB > CHX > PVP-I; however, BI was calculated from the IC50 of each antimicrobial, which are considerably lower than the concentrations generally applied in clinical practice [24]. Therefore, the BI can be used as supplementary information. Other factors that may impact adverse effects of antimicrobials are discussed below.

Table 1 Summary of commonly antimicrobials properties and products for wound care
Full size table

Types of wounds

Different types of wounds might not directly impact adverse effects; however, the factors that influence adverse events are more likely to be size, depth, and location of wounds. Due to burns are commonly extensive wounds, and an increased surface area leads to increased absorption of drugs, adverse events are frequently reported in burns. Moreover, patients with chronic ulcer such as venous leg ulcers have a higher chance of sensitization to topical medications than patients with acute wounds [158].

Age of patients

In addition, the structure of skin varies with age. Infant skin can easily absorb substance because of the high proportion of water and the thin epidermis layer. Moreover, the ratios of surface area to weight in children are higher than those in adults, resulting in higher absorption. Children may require more attention to safety monitoring than adults, and antimicrobials with low absorption into the systemic circulation should be considered for children, especially for infants. According to their low systemic absorption, antimicrobials such as CHX [159, 160], Dakin’s solution [71, 74] and bacitracin [90] seem to be suitable for pediatric patients. However, further investigations into their safety in pediatric patients are still needed. Moreover, the ease and frequency of application should be taken into account for pediatric patients, so advanced dressings with controlled release of antimicrobials, such as the SNP dressing, may also be a suitable choice [161]. In elderly, the differences in absorption of drugs between adult and elderly may not play an important role; however, other pharmacokinetics including drug metabolism and excretion may be altered due to reduction in the function of some organs. Therefore, antimicrobial selection should be considered from the capability of each function or patients’ condition.

Patients’ condition

Patient comorbidities and/or conditions should be considered because certain adverse effects can occur in particular patients. Impairment of renal and hepatic function could lead to decrease of drug elimination and increase of drug accumulation, so the risk of drug toxicity is enhanced. Moreover, as iodine is an element that influences production of thyroid hormone, patients with thyroid impairment should be aware for possible adverse effects from iodine containing products. As mafenide and its acid metabolites can inhibit carbonic anhydrase resulting in metabolic acidosis, it should be used with caution in patients with respiratory dysfunction. Furthermore, glucose-6-phosphate dehydrogenase (G6PD) is the enzyme responsible for generation of nicotinamide–adenine dinucleotide phosphate (NADPH) needed for glutathione reduction in order to act as a scavenger for oxidative substances. G6PD deficiency is a genetic disorder caused by a lack of the G6PD enzyme so the adverse effects from some oxidant drugs can be induced in G6PD deficiency patients. Therefore, drugs with oxidizing properties may be not suitable for G6PD deficiency patients. Antimicrobials that can be absorbed into systemic circulation should be avoided in pregnancy and lactation as drugs may negatively affect fetus or infants. Antimicrobials that should be avoided in particular patients are summarized in Table 2.

Table 2 Patient comorbidities/condition and inadvisable topical antimicrobials
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Conclusion

Each antimicrobial shows different adverse effects, both local and systemic. For local effects, most antiseptics show cytotoxic effects on the key cellular participants in the wound-healing process, such as keratinocytes, epithelial cells, fibroblasts, and endothelial cells, which can lead to a delay in wound healing. The cytotoxic effects on various cells mostly depend on concentration and time of exposure.

Systemic adverse effects also differ between antimicrobials. Besides concentration and exposure time, systemic effects also depend on the physicochemical properties of each substance, which influence absorption, distribution, elimination, and accumulation in the body. Moreover, the size and condition of applied area also affects the toxicity of each antimicrobial. From this review, some antimicrobials showed various levels of systemic toxicity, while others showed rare toxicity. However, toxicity to the liver, kidneys, and other organ functions should be monitored after any antimicrobial application, especially for large wounds and long durations of use. Patients’ characteristics may impact the adverse effects of antimicrobials which may attribute to elimination of drug or specific mechanisms to some organs.