Topical Antibacterials in Dermatology.

Topical antibacterials are commonly used for superficial pyodermas such as impetigo and treatment or prevention of infections following minor cuts, abrasions, burns, and surgical wounds. Several antibiotics and antiseptics are available for use in different indications. One of the major uses of topical antibacterials is acne in which benzoyl peroxide is the drug of the first choice either singly or in combination with antibiotics or retinoids. Mupirocin and fusidic acid are the two most commonly used antibiotics for the treatment of superficial pyodermas and eradication of staphylococcal carrier state. Bacterial resistance to topical antibiotics is a growing concern and topical antiseptics such as gentian violet are getting renewed interest as alternatives. Incidence of contact dermatitis is a limiting factor for the use of several topical antibacterials. Although many botanical products have demonstrated in vitro activities against skin pathogens, their clinical utilities remain to be established by good-quality clinical trials. Copyright:

Introduction

Normal, healthy skin offers a formidable natural barrier to invasion by pathogens. Impairment of this barrier may make an individual susceptible to infection. Thus, physical traumas in the form of abrasions, penetrations, cuts and burns, pre-existing dermatoses with impaired barrier states, undernutrition, diabetes mellitus, and various congenital and acquired immunodeficiency syndromes can all lead to cutaneous bacterial infections.

Staphylococcus aureus and group A Streptococci are the two most frequently encountered pathogens causing primary and secondary infections of the skin and minor skin wounds. Gram-negative organisms such as enteric bacilli (mainly Pseudomonas aeruginosa) are sometimes involved in cutaneous infections, particularly in the groin and the ear, foot ulcers, and intertriginous infections. Topical antibacterials are commonly used for the prevention and treatment of skin infections. Additionally, acne vulgaris, whose pathogenesis involves bacterial infection, is also treated with topical antibacterials.

Topical Antibacterial Use in Dermatology

Topicals antibacterials are eminently suitable for targeted drug delivery by taking the drug directly to the site of action, thus ensuring excellent bioavailability of antimicrobials at the infected tissue. The other advantages of topical usage of antimicrobials are the small amounts of drugs used, low cost, and non-interference with intestinal microbial flora.[1] Locally applied antimicrobials may however be associated with some local side effects and the development of contact dermatitis. The various advantages and disadvantages of topical antibacterials are shown in Table 1.

Table 1

Advantages and disadvantages of topical antibacterial therapy

Advantages

Disadvantages

Targeted delivery of a high concentration of drug to the site of infection Small amounts of drugs used Less potential for systemic side effects and toxicity Need for systemic antimicrobials may be avoided No interference with intestinal microbial flora Ease of administration particularly for children Low cost

Many agents associated with contact dermatitis Minimal depth of penetration, used for superficial infection only Concerns about impairment of wound healing Widespread and unrestricted use is likely to produce bacterial resistance Possibility of recurrent use and contamination after storage in patients’ home Potential for systemic absorption and toxicity if applied over a large area May be difficult for some patients to apply to larger surface areas or skin folds

Topical antibacterials are commonly used for superficial pyodermas such as impetigo and treatment or prevention of infections following minor cuts, abrasions, burns, and surgical wounds. Topical antibiotics are widely used for the treatment of folliculitides and furuncles, but their action may be very modest and limited to avoid the spreading of the infection from the primary lesion to the adjacent follicles.[1] Other pyodermas, such as carbuncles, ecthyma, cellulitis, or erysipelas, are best treated with appropriate systemic antibiotics. Topical antibiotics are used in the treatment of secondary bacterial infections of skin disorders like eczema and leg ulcers. Intranasal topical antibiotics are also indicated for the elimination of staphylococcal carrier state. Topical antibiotics are at times used following minor surgical procedures. However, topical antibacterials do not appear to aid healing or prevent infections of clean wounds made during minor surgery. Prophylactic topical therapy is often used for burns to prevent the complication of serious secondary infections. Additionally, topical antiseptics are universally used for hand hygiene and preoperative surgical scrubbing.

One of the major indications of topical antibacterials is acne vulgaris. Some agents such as benzoyl peroxide (BPO) and clindamycin are almost exclusively used for the treatment of acne. Topical antibacterials may also benefit some non-infective conditions such as rosacea, Grover's disease,[2] plasma cell balanitis[3] and gingivitis,[4] and confluent and reticulated papillomatosis.[5]

Types of Antibacterials Used Topically

Most topical antimicrobials can be divided into two major groups[6]:

Antiseptics are disinfectants that can be used on intact skin and some open wounds to kill or inhibit microorganisms. Antiseptics often have multiple mechanisms of action, a broad spectrum of antimicrobial activity, and residual antimicrobial action.

Antibiotic, for the purpose of this review, is loosely defined as natural (produced by microorganisms) or synthetic compounds that in low concentration inhibit the growth of microbes or kill them. They usually have one specific cell target and a narrower spectrum of activity. They are relatively nontoxic, and more susceptible to bacterial resistance.

In addition, botanicals or plant-derived natural products are also used as topical antibacterial agents. They usually contain essential oils, oleoresins, and other components used as medicine or for other purposes.

Topical Agents Used in the Treatment of Acne

Azelaic acid

Azelaic acid is a naturally occurring nine-carbon dicarboxylic acid having antibacterial, anti-inflammatory, and comedolytic properties.[7] The precise mechanism of its antibacterial activity is not clear; it may act by inhibition of bacterial protein synthesis. Azelaic acid is bacteriostatic against staphylococci, Propionibacterium, and some gram-negative organisms.

It is available as a 15%–20% cream and gel and used twice daily. As an antimicrobial and anti-inflammatory agent, it is used in the treatment of acne and rosacea. Azelaic acid is a competitive inhibitor of tyrosinase and may be used in the treatment of hypermelanosis. Because of its hypopigmentary property, azelaic acid may be particularly effective in acne with post-inflammatory hyperpigmentation, particularly in darker-skinned patients.[8] It is relatively non-irritating, non-photosensitizing, and shows little tendency for bacterial resistance. Adverse effects to azelaic acids are relatively mild and generally in the forms of dryness, scaling, pruritus, irritation, and erythema. Local reactions may be better tolerated with gradual initiation of application and application of soothing creams.

Benzoyl peroxide

Benzoyl peroxide or BPO is an organic peroxide derived from a byproduct of coal tar. The mechanism of its antibacterial activity is related to its strong oxidizing action by releasing highly reactive oxygen intermediates that oxidize bacterial cell membrane proteins. Despite decades of use, no bacterial resistance to BPO has been reported as bacteria cannot develop resistance to this mechanism of action. In addition to its strong bacteriostatic action against Propionibacterium acnes, BPO also has keratolytic and anti-inflammatory effects enhancing its efficacy in the treatment of acne. It is available in gels, creams, lotions, and washes in various concentrations from 2.5% to 10%; there appears to be little difference in efficacy between 2.5% and 10% BPO.[9]

Combination therapy using BPO and an antibiotic is more efficacious and better tolerated than treatment with either component alone. Moreover, the addition of BPO to antibiotic therapy is a recommended strategy for preventing the development of antibiotic-resistant P. acnes.[10] A fixed-dose combination of BPO and clindamycin has been demonstrated to have greater efficacy than the individual active ingredients and vehicle with a favorable safety and tolerability profile.[11] The combination of adapalene and BPO may also provide synergistic efficacy with an acceptable safety profile in the treatment of acne vulgaris.[12] Either as monotherapy or in combination with a topical antibiotic or a retinoid, BPO is currently recommended by most treatment guidelines as first-line therapy for mild to moderate acne vulgaris.[13] The adverse effects related to BPO occur usually in the form of skin irritation.

Clindamycin

Clindamycin is a semisynthetic derivative of lincomycin. It acts by inhibition of bacterial protein synthesis through its action on bacterial 50S ribosome. For its action against P. acnes, it is used as a topical anti-acne agent in various formulations such as gel, cream, lotion, and foam. Topical clindamycin may be as effective as oral tetracycline or minocycline in the treatment of acne. For better effect, combination therapy with BPO is often employed. Topical clindamycin has been reported to be effective in the treatment of erythrasma, folliculitis, Fox-Fordyce disease, periorificial facial dermatitis, and rosacea. Adverse reactions to topical clindamycin are usually mild and occur in the forms of dryness, itching, burning, and erythema. The incidence of contact sensitivity is very rare.

Dapsone

Dapsone or diamino-diphenyl sulphone has long been used in the treatment of severe acne vulgaris. A topical formulation of dapsone (5% and 7.5%) in an aqueous-based gel vehicle is available to deliver clinically effective doses of dapsone with minimal systemic absorption for the treatment of acne vulgaris. The 5% of formulation needs twice daily application, whereas the 7.5% of formulation is used once daily. The precise mechanism of action of dapsone in the treatment of acne has not been elucidated. Its anti-inflammatory and anti-neutrophil actions may be partially responsible for the action. Its activity against P. acnes remains poorly understood.[14] Results of two pivotal studies[1516] comparing 7.5% dapsone gel with placebo in the treatment of moderate acne in patients >12 years have shown that at week 12, mean reduction in inflammatory and noninflammatory lesion counts, and the percent reduction in lesion counts from baseline were significantly greater in dapsone than vehicle recipients. Side effects associated with topical dapsone are generally minor and include local stinging/burning, dryness, scaling, and erythema.[14] No clinical or laboratory evidence of drug-induced hemolytic anemia was noted.

Topical Agents for Wound Care and Pyoderma

Antibiotics

Fusidic acid

Fusidic acid is an antibiotic derived from the fungus Fusidium coccineum. Fusidic acid acts by inhibition of bacterial protein synthesis by preventing translocation of the elongation factor G (EF-G) from the ribosome. Fusidic acid has a steroid-like structure without the unwanted side effects of steroid. Fusidic acid penetrates normal, damaged, and avascular skin. Thus, topical administration of fusidic acid may result in much higher local concentrations than can be achieved with systemic administration and antimicrobial concentrations can be achieved even at deeper layers of the epidermis or dermis.[17]

Fusidic acid acts against gram-positive bacteria such as Staphylococcus species and Corynebacterium species. As ointments or creams containing 2% sodium fusidate, it is one of the most frequently prescribed topical agents for the treatment of impetigo. A Cochrane database of systematic reviews of interventions for impetigo has concluded that there was good evidence that topical mupirocin and topical fusidic acid are equally, or more, effective than oral antibacterials.[18] Fusidic acid can additionally be used in the treatment of erythrasma and pitted keratolysis.

Gentamicin

Gentamicin is an aminoglycoside antibiotic derived from Micromonospora purpurea. It works by inhibition of bacterial protein synthesis by irreversible binding with 30S ribosomal subunit. Gentamicin is a broad-spectrum bactericidal agent active against gram-negative organisms like Pseudomonas, Proteus, and Escherichia coli. Among gram-positive agents, it is active against S. aureus, but has no activity against Streptococci. Contact allergy may rarely occur with cross-reactivity with other aminoglycosides like neomycin.

Metronidazole

Metronidazole is a synthetic nitroimidazole antibacterial and antiprotozoal agent. Its spectrum of activity includes most anaerobic bacteria and protozoa. The nitro group of the drug is chemically reduced by the mitochondrial ferredoxin in the bacteria; the reduced metabolite inhibits nucleic acid synthesis by disrupting the DNA helical structure. A gel formulation containing 0.75%, metronidazole is widely used as an effective treatment of rosacea. The mechanisms by which it acts in rosacea are unknown, but appear to include an anti-inflammatory effect. Metronidazole is also used to treat malodorous benign and malignant ulcers including pressure sores infected with anaerobes.[19] Topical use of metronidazole may cause burning, skin irritation, and dryness.

Mupirocin

Mupirocin is derived from Pseudomonas fluorescens and structurally unrelated to any other topical or systemic antibiotics. It inhibits bacterial protein and RNA synthesis by reversibly binding to bacterial isoleucyl-tRNA synthetase. Because of its unique structure and mechanism of action, mupirocin has little, if any, potential for cross-resistance with other antibiotics. It is active against penicillinase-producing and methicillin-resistant strains of S. aureus. The drug is ineffective against most aerobic gram-negative bacteria and anaerobes.

Mupirocin is used for the treatment of impetigo and other skin and skin-structure infections such as secondarily infected eczema or infected skin wounds due to susceptible strains of S. aureus or Streptococcus pyogenes. It is also used for the eradication of nasal colonization of methicillin-resistant S. aureus (MRSA) in adult patients and healthcare workers. In patients who are nasal carriers, an intranasal application can significantly reduce the rate of staph infection.[20] Increased use is correlated to resistance development; therefore, routine decolonization is not prudent unless MRSA colonization is confirmed in the nares or other sites. The most frequently reported adverse reactions to topical use are skin irritation (burning, stinging, or pain) and pruritus.

Nadifloxacin

Nadifloxacin is a synthetic quinolone with broad-spectrum bactericidal activity. Nadifloxacin inhibits bacterial multiplication by blocking the enzyme DNA gyrase thus impairing DNA synthesis and replication. In vitro studies of nadifloxacin showed potent and broad-spectrum antibacterial activity against aerobic gram-positive, gram-negative, and anaerobic bacteria, including P. acnes and Staphylococcus epidermidis. Nadifloxacin is active against MRSA and has potential as an alternative for topical antibiotic treatment in bacterial skin infection.[21]

Efficacy of nadifloxacin in the treatment of acne vulgaris has been demonstrated in clinical trials.[22] Since exposure of pathogenic and colonizing bacteria to antibiotics results in drug resistance, it is not desirable to use a broad-spectrum antibiotic belonging to a class of valuable and widely used systemic agents, as a topical preparation. On this basis, nadifloxacin is not a good option for topical treatment of acne when other effective treatments are available.[23]

Neomycin

Neomycin is a bactericidal aminoglycoside antibiotic that acts by inhibition of bacterial protein synthesis. The commercial preparation of neomycin contains two active stereoisomers neomycin B and C. Neomycin B, also known as framycetin, is similar to neomycin sulfate in all respects. Neomycin acts mostly against gram-negative organisms like proteus, E. coli, serratia, and H. influenzae. It kills staphylococci but has weak activity against Streptococci. Allergic contact dermatitis (ACD) to neomycin appears to be relatively common and more frequently occurs with prolonged usage, particularly on leg ulcers. It potentially cross-reacts with other aminoglycosides like gentamicin.

Bacterial resistance is not uncommon and it is nearly always combined with antibiotics like bacitracin (for gram-positive coverage), and polymyxin (for activity against Pseudomonas) to broaden the microbiocidal spectrum. This triple combination formulation containing bacitracin, polymyxin, and neomycin is popularly used for the treatment of superficial pyodermas, minor wounds, and secondarily infected dermatitis.

Retapamulin

This semisynthetic antibiotic is the first agent in the new pleuromutilin class of antibacterials to become commercially available for clinical use. The mode of action involves high-affinity binding to a unique site on the 50S subunit of the bacterial ribosome leading to peptidyl transfer inhibition and impaired formation of active 50S ribosomal subunits. This novel mode of action may explain the lack of clinically relevant, target-specific cross-resistance of retapamulin with currently used antibacterials.[24]

In in vitro studies and clinical trials, retapamulin has shown potent activity against gram-positive aerobic bacteria including S. aureus (e.g., community- and hospital-acquired MRSA, vancomycin-resistant MRSA) and beta-hemolytic Streptococci.[2526] It has a broad spectrum of activity against anaerobic infections also.[27] The activity of retapamulin warrants its consideration as an alternative to mupirocin in MRSA decolonization regimens.

Retapamulin has shown efficacy against isolates resistant to existing therapies like beta-lactams, macrolides, quinolones, and topical fusidic acid and mupirocin. Retapamulin 1% ointment has been approved by the FDA for the treatment of impetigo and in Europe for the short-term treatment of impetigo and infected small lacerations, abrasions, and sutured wounds. The most frequently reported adverse reaction to topical retapamulin ointment is skin irritation at the site of application.[28]

Silver sulfadiazine

Silver sulfadiazine is a topical anti-infective agent used primarily for the prevention and treatment of wounds caused by second- and third-degree burns. It is available as a water-soluble cream containing 1% silver sulfadiazine. Silver sulfadiazine is also indicated for the treatment of mild infections such as Pseudomonas cellulitis, toe web infections, and ecthyma gangrenosum.[29] SS has also been used to control infections in the treatment of pressure ulcers, diabetic foot ulcers, and venous ulcers.[30]

The exact mechanism of antimicrobial action of silver sulfadiazine is unknown. This agent's main effect comes from the continuous dissociation and deposition of silver ions on the wound surface; the sulphadiazine component, while having a bacteriostatic effect, may play a secondary role.[31] Silver sulfadiazine has a wide spectrum of activity against both gram-positive and gram-negative organisms. Besides its antimicrobial effects, a positive effect on wound healing has been postulated.[32]

Pruritus, burning sensation, and brownish-grey discoloration of the skin, Stevens-Johnson syndrome, and photosensitivity can occur during therapy with silver sulfadiazine. Silver sulfadiazine is contraindicated in patients with sulfonamide hypersensitivity. It should not be used in neonates.

Antiseptics

Alcohol

Alcohol-based antiseptics are widely used for surface disinfection and skin antisepsis and commonly found in many antibacterial hand washes, being one of the most important components of hospital hand hygiene practices. Antimicrobial effects of alcohols are short-lasting and they are often combined with agents such as chlorhexidine which display residual activity following evaporation of the alcohol. Ethyl alcohol, isopropyl alcohol, and n-propanol are the most widely used alcohols for antisepsis. Alcohols have rapid bactericidal activity and have a broad spectrum of activity. Alcohols act against vegetative bacteria (including mycobacteria), viruses, and fungi but not against bacterial spores.

The activities of both ethyl and isopropyl alcohols are highly dependent on the concentration used; the optimal bactericidal activity being achieved at a concentration of 60%–90%.[33]

The mechanism of antimicrobial action of alcohols is not well understood, but it may be related to protein denaturation or inhibition of mRNA and protein synthesis through direct effects on ribosomes and RNA polymerase with resultant membrane damage, interference with metabolic pathways, and a loss of cellular integrity. The incidence of allergic reactions due to alcohols is believed to be non-existent.[34]

Chlorhexidine

Chlorhexidine, a divalent cationic biguanide, is one of the most widely used antiseptics in the prevention of healthcare-associated infections. Antibacterial activity of chlorhexidine is mediated via its action on the cell membrane. The water-soluble form, chlorhexidine gluconate is incorporated into a variety of products for use on the body, such as hand rubs, body washes, and mouthwashes. Chlorhexidine is also impregnated into wound dressings and central line catheters and is generally regarded as an extremely safe topical agent.[35]

Chlorhexidine has a broad spectrum of activity and has a long-lasting residual activity in comparison to other antiseptics such as trichosan.[36] It is most active against gram-positive bacteria but also displays activity against gram-negative bacteria, some enveloped viruses, and fungi. However, it has no sporicidal action and mycobacteria are generally highly resistant.[37] A recent meta-analysis also preferentially recommended chlorhexidine over povidone-iodine for preoperative skin preparation in clean and clean-contaminated surgery.[38] Adverse effects of chlorhexidine are rare and include mild skin irritation and, more rarely, allergic reactions like severe anaphylaxis.[39]

Gentian violet

Gentian violet (GV), also known as crystal violet or methyl violet, is a triphenylmethane dye with antibacterial, antifungal, antihelminithic, antitrypanosomal, antiangiogenic, and antitumor properties.[40] GV is an inexpensive drug with a long history of topical use as an antibacterial and antifungal agent. The precise mechanism of action of GV is unknown but may include alteration in redox potential, inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, free radical formation, inhibition of protein synthesis, uncoupling of oxidative phosphorylation, and inhibition of formation of the bacterial cell wall.[40] Multiple clinical studies have documented the successful treatment of GV in the treatment of MRSA-colonized ulcers and pyodermas. Topical application of GV was also shown to be effective in the treatment of nasal carriage of MRSA[41] and impetiginous eczema.[42] GV has negligible side effects; staining of the areas treated may however be considered as a disadvantage.

In the face of emerging and continuing bacterial resistance, there has been a recent resurgence in interest and research on GV. For its stability, ease of application, low cost, and clinical efficacy, GV must be considered as a legitimate option for the treatment of skin and soft tissue infection.[43]

Hydrogen peroxide

It is a potent broad-spectrum antimicrobial that is active against all forms of microorganisms including bacteria, viruses, and protozoa. It is also active against bacterial spores, protozoal cysts, and prions. In liquid form, hydrogen peroxide can be used on the skin as an antiseptic at concentrations of 3%–6% (vol/vol). The mechanism of action of hydrogen peroxide is not fully understood but is thought to be associated primarily with its oxidizing activity, acquired bacterial resistance to hydrogen peroxide has not yet been reported. HP has synergistic activity with povidone-iodine.[44]

A new formulation of hydrogen peroxide stabilized in monoglycerides cream was found to be as effective as BPO in reducing both inflammatory and noninflammatory acne lesions with a better local tolerability profile.[45]

Povidone-iodine

Povidone-iodine has the broadest of spectrum of activity among all antiseptics and it can kill bacteria, viruses, yeasts, molds, fungi, and protozoa. Povidone-iodine is a complex of triiodide and the organic polymer polyvinylpyrrolidone. By wrapping in a soluble polymer matrix, the problems of low solubility, poor chemical stability, and local toxicity of free iodine is circumvented.[46] Although the mechanism of action of povidone-iodine is ill understood, it is likely that free iodine inhibits electron transport and cellular respiration, destabilizes membrane integrity, inhibits protein synthesis, and denatures nucleic acids.[46]

The preparations of polyvinylpyrrolidone-iodine (PVP-I) commercially available are povidone-iodine solution, scrub, ointment, and foam; of these, the solution is the most commonly used.[47] In dermatology, 10% PVP-I remains a popular pre-surgical skin disinfectant. A variety of studies has proposed to use dilute PVP-I in chronic, non-healing wounds as a means of reducing bacterial colonization.[48]

Triclosan

Triclosan, a chlorinated bisphenol antiseptic, exhibits a broad spectrum of antimicrobial activity and is effective against gram-positive and most gram-negative bacteria but with poor activity against Pseudomonas spp. It is also active against some viruses and fungi. Triclosan acts by inhibiting bacterial fatty acid biosynthesis.[49]

It is used in numerous hygiene and healthcare products such as soaps, surgical scrubs, creams, toothpastes, and mouthwashes in concentrations of up to 2%. There have been isolated reports of contact dermatitis.[50]

Much recent work has demonstrated the lack of efficacy of triclosan in household soap products, prompting the US FDA to prohibit use of triclosan and 18 other biocidal chemicals in consumer antiseptic products.[51]

Botanicals

Concerns regarding bacterial resistance, and hypersensitivity to antibiotics and synthetic antibacterials have ignited interest in many plant-derived substances. Although the exact mechanisms of action are generally unknown, botanical agents have been used for centuries for the topical treatment of skin disease.

The role of essential oils as antibacterial agents is well documented.[52] Essential oils are aromatic oils extracted from several plants. Tea tree oil and thymol display a wide-ranging activity against bacteria including staphylococci.[5354] Neem oil, derived from the Indian Neem tree (Azadirachta indica), has a wide range of usage including skin and dental care as well as a larvicide and insect repellent. Neem oil may exhibit a bactericidal effect on MRSA and may find clinical application as a topical antibacterial agent.[55]

Products from other plants including olibanum (Boswellia serrata), beard lichen (U. barbata), rosemary (Rosmarinus officinalis), and sage (Salvia officinalis) have been shown to inhibit the growth of several gram-positive bacteria such as S. aureus including MRSA, P. acnes, and Corynebacterium species.[53] The successful use of medical grade honey has been reported for a multitude of wounds, including burns, surgical sites, infected surgical wounds, chronic ulcers, malignant wounds, and neonatal wounds, among others.[5657]

However, the current literature is limited on the detailed pharmacology of topical botanicals and the duration, dose, or course of treatment is not standardized. Thus, antibiotics and synthetic antibacterials have remained the first-line topical therapy for skin infections.

Contact Allergy to Topical Antibacterials

One of the limiting factors for the usage of topical antibacterials is the incidence of ACD. ACD to neomycin occurs commonly and the prevalence on the level of unselected population is approximately 1%.[58] Sensitization to fusidic acid may occur rarely. The frequency of ACD to neomycin was found to be 10 times more common than to fusidic acid.[59]

In a study of 4384 patients suspected of having a contact allergy, allergy to topical antibiotics (neomycin sulfate, gentamycin, soframycin, and fusidic acid) was more common in patients over 70 years.[60] It is thought that the presence of an impaired skin barrier, prolonged use of topical antibiotics, and occlusion for extended periods predispose these patient populations to developing ACD.[61] BPO is well known to cause irritant contact dermatitis, but allergic sensitization, while rare, has also been reported. ACD to topical metronidazole is rare. Cross-reactivity can occur with imidazole antifungals.[62] Mupirocin allergy is very rare. Because of its unique mechanism of action and structure, mupirocin does not appear to cross-react with other antibiotics.[61] There are numerous case reports of allergy to botanical extracts. A high prevalence of contact dermatitis to botanicals have been reported in patients with clinical diagnosis of contact dermatitis.[63]

Bacterial Resistance to Topical Antibacterials

Development of bacterial resistance to topically applied antibiotics is a growing concern. In the context of anti-acne therapies, the emergence and spread of Propionibacteria resistant to clindamycin calls for serious rethinking about their long-term role as topical anti-acne agents. Judicious use of combination of clindamycin with agents like topical retinoid, BPO, or azelaic acid can preserve the utility of these antibiotics in the treatment of acne.[52]

In a study of susceptibility of 218 isolates of S. aureus, resistance was found to macrolide (48.6%), clindamycin (6%), and mupirocin (10.6%). Only one isolate (0.5%) was retapamulin resistant.[64]

In clinical usage, alcohol resistance in bacteria, such as Staphylococci and Streptococci, has not been reported; this may be reflective of the nonspecific mode of bactericidal action.[65]

Bacterial resistance to silver can develop and is a matter of concern regarding the treatment of burn wound with silver sulfadiazine.[30]

Widespread use of fusidic acid as a topical agent for the treatment of pyodermas and minor wounds has resulted in the emergence of fusidic acid-resistant strains of S. aureus (FRSA). There is an indication of the development of an FRSA reservoir in the community.[54] Resistance to mupirocin, another widely used topical antibiotic, is also increasing and one Canadian study has demonstrated that up to 50% of isolates of MRSA may be resistant to this antibiotic.[56] Results from an S. aureus surveillance study has shown that among the isolates screened, 9.5% exhibited retapamulin resistance, of which 57.9% were MRSA; 9.8% of isolates were found to have mupirocin resistance.[66]

Despite the widespread clinical use of povidone-iodine over many decades, as well as extensive testing of isolates, there have so far been no reports of resistance or increased tolerance to povidone-iodine in any laboratory-derived or clinical isolates.[46]

Bacterial resistance to triclosan has been documented and there is growing concern about the potential link between widespread triclosan usage and the selection of antibiotic-resistant bacterial strains. Triclosan and antibiotics share multidrug efflux systems as a common mechanism of resistance.[50]

It is commonly assumed that bacteria will have difficulty developing resistance to botanical extracts which potentially contains thousands of active ingredients.[67] A recent study, however, has documented resistance of S. aureus to several botanical extracts commonly used for their antimicrobial properties including tree tea oil.[68]

Conclusion

Topical antibacterials are generally the preferred agents for the treatment of superficial pyodermas and the treatment and prevention of infection of minor wounds for their obvious advantages over systemic agents. A large number of topical antibiotic formulations are available for the treatment of acne and skin and skin-structure infections. BPO is established as a first-line therapy for acne. For superficial pyodermas and preventions of infection of minor wounds, mupirocin and fusidic acid are the most frequent choice among dermatologists. Silver sulphadiazine is the preferred agent for local treatment of first and second-degree burns. Bacterial resistance to fusidic acid, mupirocin, and retapamulin is increasing. Strategies to combat bacterial resistance to topical antibacterials include their judicious use as short-term therapy and the use of alternative agents such as antiseptics like GV. Bacterial resistance is constantly evolving, and patterns of resistance vary between settings and geographical regions. Hence, it is important that prescribers are aware of location-specific data on prevailing patterns of resistance to ensure appropriate treatment.[69]

Regular and systematic surveillance in this regard is needed.

Contact dermatitis to topical antibiotics is not uncommon. Physicians should be aware of high-risk groups, including patients who have an impaired skin barrier. Further research is needed regarding the cross-reactivity and prevalence of contact allergy to specific topical antibacterial agents. Although many botanical products have demonstrated in vitro activities against skin pathogens, their clinical utilities remain to be established by good-quality clinical trials. Many antibiotics used topically are also used systemically for severe infections; therefore, to minimize the development of resistant organisms, it is prudent to limit the choice of antibiotics applied topically to those not used systemically.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.