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Topical antibiotics in dermatology for uses other than acne
Topical Antibiotics in Dermatology for Uses Other than Acne Elizabeth S. Dunlavey, MD
Topical antibiotics are widely used in medical and surgical dermatology for both prophylaxis and treatment of primary and secondary pyodermas. The ideal topical agent should have a broad spectrum of activity against common skin pathogens, such as Staphylococcus aureus and Streptococcus pyogenes (group A streptococcus) and have an acceptable side effect profile. Given the existence of multi-drug-resistant bacteria, the likelihood and impactof the development of antibiotic resistance should also be considered when choosing a topical antibiotic. The following text first reviews the characteristics of some of the more commonly used topical antibiotics and antiseptics and discusses their role in the treatment of several dermatologic conditions including impetigo, bacterial folliculitis, corynebacterial infections, and atopic dermatitis. A discussion follows on the prophylactic use of these agents in the management of patients with superficial cuts and abrasions, surgical wounds, chronic ulcerations, and burns. A final comment is made about the problem of the emergence of antibiotic-resistant bacteria and the implications this has for the future.
Topical antibiotic agents Knowledge of the range of antibacterial activity of topical antibiotics and their potential side effects is essential in directing treatment in specific dermatologic conditions. The mechanism of action, spectrum of bacterial coverage, and some of the potential side effects for a number of commonly used antibacterial agents are reviewed in Table 1.1-5 Topical antibiotics like gentamycin (inhibits Staphylococcus, Streptococcus, and aerobic gram negative [including P aeruginosa]), which have important systemic uses, are not included in the table because they are not "commonly" used in dermatology for topical therapy. The potential side effects listed in Table 1 for the selected topical agents deserve special mention. In general, systemic side effects such as nausea and diarrhea are seen more commonly with the systemic administration of these medicines. Their presence in the table is based on their inclusion in the Physicians' Desk Reference, 6 which includes even single case reports of 216
adverse events. One of the real advantages of topical therapy is the lack of serious or debilitating side effects. Antiseptic agents, used primarily for disinfection before surgical procedures, also have broad-spectrum antibacterial activity. Hexachlorophene, povidoneiodine, benzalkonium chloride, and chlorhexidine gluconate are those used most often in dermatologic surgery. 4 The majority of studies find chlorhexidine, with its widerange activity against gram-positive and gram-negative bacteria, yeast, and molds, to be the most effective of this group. 7 Topical silver in the form of silver sulfadiazine or silver nitrate is bactericidal to a number of different bacteria. These agents disrupt bacterial respiratory enzymes, the electron transport system, and interfere with other DNA functions. 8 Fusidic acid (currently not Food and Drug Administration-approved in the United States) is an antibiotic that has a steroid-like structure, but no steroid activity. Because of its steroid-like structure, fusidic acid readily penetrates the upper layers of skin, resulting in a high concentration of the antibiotic at the infection site. 9 This, along with the fact that it is highly effective against S aureus bacteria, makes it a useful antibiotic in the treatment of superficial skin infections.
Dermatologic conditions frequently treated with topical antibiotics Topical antibiotics are effective in a number of dermatologic conditions (including acne, rosacea, hidradenitis suppurativa, and perioral dermatitis) in which their effectiveness is likely related to both their antibacterial and their anti-inflammatory action.l°,ll This text focuses on the use of these agents in some of the more common non-acneiform skin conditions.
Impetigo Impetigo is a superficial infection that, in certain circumstances, may be adequately treated with topical antibiotics. Two percent mupirocin ointment applied 3 times daily for 7 to 10 days is proven to be effective in Curr Probl Dermatol, September/October 2000
TABLE 1. Antibacterial agent Bacitracin
Clindamycin
Erythromycin Metronidazole
Mupirocin
Neomycin
PolymyxJn
Mechanism of action Complexes with C55-prenol pyrophosphate (constituent of bacterial cell wall)
Spectrum of activity
Potential side effects
Gram+ cocci; some Neisseria
2% incidence of contact dermatitis (postoperative); common concomitant sensitizaion to neomycin; rare a phylaxis with prior pruritus and edema Binds 50S subunit of bacterial ribosome Group A Streptococcus; Rare reports of diarrhea, bloody diarrhea, (involved in protein synthesis); causes penJcillinase producing pseudomembranous colitis (more common dissociation of ribosome subunits staphylococci with systemic therapy); gram-folliculitis Binds 50S subunit of bacterial ribosome Primarily, Group A Xerosis, pruritus, burning sensations of the (involved in protein synthesis) Streptococcus skin and eyes Reduction causes production of free radicals Anaerobic bacteria (no aerobes); Xerosis, erythema; metallic taste, tingling/ that damage DNA and inhibit replication protozoa numbness of extremities, nausea (more common with systemic therapy) Inhibits bacterial isoleucyl tRNA synthetase Gram+ (except enterococci); Burning, stinging, pain, swelling, nausea in (involved in protein synthesis) inactive against many <1% of patients organisms of normal flora Binds 30S subunit of bacterial ribosome Gram- (except P aeruginosa); 1%-6% incidence of contact dermatitis (20%(involved in protein synthesis); interferes S aureus (not other gram+) 30% in patients with chronic leg ulcers); with bacterial DNA polymerase ototoxicity if significant systemic absorption (ie, application to large surface areas; reduced metabolism in renal failure) Acts as surfactant to disrupt cell membrane Gram- rods (except Proteus, Rare allergic contact dermatitis (possible cros~ Providencia, Serratia) reactivity with bacitracin)
the treatment of patients with limited numbers of lesions who do not have systemic signs of infection. ]2 Systemic therapy should be used in situations where there is widespread or deeper infection, fever, lymphadenopathy, or other signs of systemic disease. 13 Systemic therapy is also administered for the treatment of bullous impetigo and streptococcal pyodermas. In the case of streptococcal disease, penicillin may be able to prevent the infrequent but serious complication of poststreptococcal glomerulonephritis. 14 Scientific evidence does not appear to support the use of systemic agents over topical ones in either of these 2 conditions.
Bacterial Folliculitis S aureus folliculitis may be treated effectively with twice-daily application of topical clindamycin, topical erythromycin, or 3-times-daily application of mupirocin. The addition of antiseptic agents like chlorhexidine to the treatment regimen may be beneficial. Recalcitrant or extensive disease may require systemic therapy. The prophylactic use of topical medication in cases of recurrent episodes of Staphylococcus folliculitis, in which patients are frequently found to be nasal carriers of S aureus, is discussed later in this issue.
Corynebacterial Infections Erythrasma and pitted keratolysis are superficial bacterial infections caused by the gram-positive bacteria Curr Probl Dermatol, September/October 2000
Corynebacterium minutissimum. Topical agents have been directly compared to oral erythromycin in the treatment of erythrasma and have been found to be equally efficacious./5 Twice-daily application of clindamycin or erythromycin, alone or in combination with an antiseptic agent, is effective in eradicating the infection in both conditions. Trichomycosis, a corynebacterial infection of the axillary or pubic hair, may also be treated with clindamycin, although shaving the affected area generally results in resolution of the problem. 3
Atopic Dermatitis It is well known that eczematous skin is often colonized with S aureus. It is unclear whether or not this organism is a pathogen or if its only role is a colonizing agent. Studies have shown that exudative lesions have higher number of Staphylococcus organisms than erythematous or lichenified lesions of atopic dermatitis, but treatment of these exudative lesions with topical corticosteroids alone markedly decreased bacterial numbers. 16'17 Other studies have shown the use of a combination of topical corticosteroids and topical antibiotics in "infected eczema" to be superior to treatment with the corticosteroid alone.18 After an extensive review of the literature, Hirschmann 3 states that the discrepancies in the results obruined from well-controlled studies may relate to their failure to define clinical criteria for "infected eczema." 217
Bacteriologic data alone do not always support the clinical diagnosis of infection. 19 In his review, Hirschmann found that topical antibiotics alone usually offer no substantial clinical benefit over topical corticosteroids. A possible exception is fusidic acid, which, as previously noted, is currently not Food and Drug Administrationapproved for use in the United States. 9 It has also been suggested that "superantigens," which are substances that can stimulate lymphocytes by crosslinking T cell receptors and class II antigens, may have a role in the development of impetiginization. 2° If this is the case, then treatment of potential pathogenic S aureus organisms, regardless of their numbers, would likely be beneficial. Evidence for this theory is currently unsubstantiated.21,22
Prophylactic uses of topical antibiotics Topical antibiotics are commonly used in the prophylaxis of infection in a number of different situations in which the integrity of the skin has been compromised. These include superficial cuts and abrasions, surgical wounds, chronic leg ulcers, and burns. Topical antibiotics are also prophylactically able to reduce nasal Staphylococcus carriage in patients who have recurrent problems with folliculitis or who have a propensity for the development of other Staphylococcus pyodermas. Whenever medications are used for prophylaxis, the risk of potential side effects must be weighed against the potential benefits. Contact sensitization ("potential side effects" in Table 1) is a limitation to the use of these agents in many instances.
Superficial Cuts and Abrasions Combinations of topical antibiotics such as a bacitracin-neomycin-polymyxin are often used in the treatment of superficial cuts and abrasions. There is some evidence to support the use of these formulations because they have been found to reduce skin colonization with staphylococci and streptococci, which may prevent subsequent infection. 23,24 When they are used infrequently and for short periods Of time, the potential benefit may outweigh the risk of development of contact sensitization.
Surgical Wounds Despite the fact that the infection rate in clean surgical procedures is less than 3%, topical antibiotics are frequently prescribed as part of the postsurgical wound care treatment regimen. Studies on the use of systemic antibiotics in surgery have shown that the antibiotic 218
must be present during the time of bacterial contamination to have a beneficial effect. It has also been shown that significant contamination of surgical wounds occurs, for the most part, before wound closure. 24 If these principles were applied to topical antibiotics, it would seem that they would have little to offer in the treatment of infection in the postoperative period. There is also a theoretical risk that their use could actually have a deleterious effect. Studies done to access topical antibiotic use in the prophylaxis of infection in patients with intravenous catheters have shown that the use of these agents for longer than 1 week promotes the growth of yeast, which could further complicate or delay wound healing. 23 Optimistically, showering with chlorhexidine before excisional surgery suppresses skin colonization for several hours. It is unknown, however, whether or not this correlates with a decrease in the incidence of postoperative infections.7 Topical antibiotics have been used in the postoperative care of patients who have had chemical or laser peels and dermabrasion. In these open wounds, the antibiotics provide a bacteriostatic or bactericidal environment during wound healing, and at the same time act as emollients to reduce the time of reepithelialization. 26 Because of the increased incidence of contact dermatitis observed in the laser-treated patient population, especially to bacitracin-containing compounds, many clinicians are now using topical emollients alone. 27.28 Some clinicians do use topical antibiotics as prophylaxis for the development of gram-negative infections. Those described for use after laser resurfacing include 0.25% acetic acid, aluminum acetate, and silver sulfadiazine cream. 27
Leg Ulcers Treatment of chronic wounds requires an understanding of the underlying abnormality causing the ulceration as well as the pathophysiologic mechanisms of the wound-healing process, both of which are beyond the scope of this discussion. A concise review of these topics may be found in an article by Nwomeh et al. 29 The role played by bacteria in the persistence of chronic wounds is debated. Cultures often reflect only contamination by normal skin flora. Even the presence of high number of organisms (>10 organisms/gram of tissue) does not necessarily correlate with infection and may not adversely affect healing. 3°.31 Wound infection is perhaps best determined by clinical examination. Pyrexia, erythema, swelling, and purulence are clinical signs that may suggest infection.29 In these cases sysCurr Probl Dermatol, September/October 2000
temic, rather than topical, antibiotics and debridement are the treatments of choice. Leg ulcers, by nature, result in chronically compromised skin and require long-term treatment and repeat applications of topical agents, which predisposes the patient to the development of contact dermatitis. 2 Studies in patients with chronic venous insufficiency or stasis dermatitis treated with topical antibiotics have shown sensitization in up to 70%. 2 The cytotoxic properties of many disinfectants often prohibit their use as well, because they may cause a delay in re-epithelialization of chronic wounds. 4
Burns The prophylaxis of infection in patients with bums is extremely important because infection is a major cause of both morbidity and mortality. Topical agents used on even extensive bums may be the most effective means of preventing sepsis. 32 Systemic agents may not be as efficacious as topical ones because the ischemia around deep wounds prevents the agents from reaching bactericidal concentrations at the bum site. 4 Silver sulfadiazine is the topical agent most commonly used in the treatment of bums because it has excellent activity against the common flora that colonize bums, including Pseudomonas aeruginosa, S aureus, and yeasts, and it has an acceptable side effect profile. Serious, systemic adverse effects are not observed, even with repeated application; contact sensitization is rare; and the development of antibiotic resistance is also low. These characteristics make sulfadiazine a logical choice over other agents such as povidone-iodine (which may cause acidosis with increased absorption) and other topical antibiotics that have a higher incidence of contact sensitization. 32 The sulfadiazide compounds should, however, be avoided in patients with documented allergic reactions to sulfa medications. Mafenide acetate cream, a bacteriostatic agent that diffuses well through devasculadzed areas, is also mentioned as a potential treatment for burns.4
Staphylococcus aureus Nasal Carriage S aureus is found in approximately 20% to 40% of normal adults. 3 It is usually not a significant pathogen except in cases of recurrent Staphylococcus pyodermas, such as folliculitis, and in cases of carriers transmitting the organism to susceptible patients, as in nosocomial staphylococcal epidemics. In such situations, it would be advantageous to eliminate the carrier state. Many topical antibiotics and antiseptics, including Curr Probl Dermatol, September/October 2000
gentamycin, bacitracin, neomycin, chlorhexidine, tetracycline, and vancomycin, have been shown to eradicate S aureus from the nares, but none have resulted in longterm elimination of the bacteria. 3,33 Topical mupirocin has been shown to reduce both nasal and hand carriage of S aureus for up to a year when it is applied to the nares of health care workers daily for 5 consecutive days. 34 More controlled studies are needed, but at this point, mupirocin appears to be the most effective topical agent for prophylaxis in this setting. Although antibiotic resistance is presently uncommon, the benefits of prophylactic use over the risk of creating resistant pathogens should .always be considered. Presently, however, there are no specific contraindications for the chronic use of mupirocin.
Antibiotic Resistance Ongoing studies of antibiotic susceptibilities of skin wound flora in hospitalized dermatology patients show an alarming trend toward resistance to several commonly used systemic antibiotics. 35 Changes occur in the antibiotic resistance patterns for a number of reasons that include the selection of chromosomally resistant bacterial variants, bacterial acquisition of a resistance plasmid, and the selection of new organisms as a result of antibacterial therapy.36 Topical use of antibiotics has often been implicated in the development of systemic resistance. The empiric use of topical agents in many clinical settings, the long-duration of use in chronic conditions, and the fact that topically applied medicines become wide-spread (by means of the hands) to other areas of the body (exposing large numbers of organisms to "therapy") all probably contribute to the development of resistance. The relatively new reports of the emergence of mupirocin resistance are alarming because this topical medication is the most effective treatment in many skin conditions (as noted previously in this discussion), as well as in the treatment of methicillin-resistant S aureus infections. 37 Several things may be done in the future to reverse these trends and to preserve the role of topical antibiotics in the treatment of prophylaxis of primary and secondary pyodermas. Well-designed case-controlled studies to evaluate the efficacy of topical medications, especially in the area of prophylactic use, are needed so that empiric therapy for undefined, often prolonged periods is not the rule. The development of topical-use-only antibiotics with unique mechanisms of action, like mupirocin, would help with the problem of cross-resistance and would decrease the resistance observed to important systemic 219
antibiotics that have historically also been used in a topical form. 36
A relatively new compound, pexiganan acetate, which is derived from the magainin family of skin peptides found in the African clawed frog, is being investigated for topical use. It is a membrane-active agent that causes pore formations in the cell membranes of microbial and some fungal organisms. The Food and Drug Administration recently ruled not to approve its use in the treatment of decubitus and diabetic food and leg ulcers, stating that more placebo-controlled studies are needed (Anti-infective Drugs Advisory Committee, March 4, 1999). However, such membrane active agents may have a bright future in topical therapy as the chance of the developing resistance is low. It is very difficult for bacteria to change their outer surface to avoid destruction by these agents. Finally, we should look for new roles for existing topical agents, such as silver, for which there is no documented evidence of cross-resistance patterns with antibiotics. 8 Responsibility should be the rule in the use of established therapies and in the development of new ones.
13. 14.
15.
16.
17.
18. 19. 20.
21.
REFERENCES 1. Bajaj A, Gupta S. Contact hypersensitivity to topical antibacterial agents. Int J Dermatol 1986;25:103-5. 2. Gallenkemper G, Rabe E, Bauer R. Contact sensitization in chronic venous insufficiency: modern wound dressings. Contact Dermatitis 1998;38:274-8. 3. Hirschmann J. Topical antibiotics in dermatology. Arch Dermatol 1998;124:1691-5. 4. Kaye E, Kaye K. Topical antibacterial agents. Infect Dis Clin North Am 1995;9:547-59. 5. Thestrup-Pedersen K. Bacteria and the skin: clinical practice and therapy update. Br J Dermatol 1998; 139(Suppl 53): 1-3. 6. Physicians' Desk Reference. Medical Economics Company, Inc. Montvale, New Jersey, 1999. p. 1052, 1305, 1934-35, 2464, 3034. 7. Kaul A, Jewett J. Agents and techniques for disinfection of the skin. Surg Gynecol Obstet 1981;152:677-85. 8. Wright B, Lain K, Burrell R. Wound management in an era of increasing bacterial antibiotic resistance: a role for topical silver treatment. Am J Infection Control 1998;26:572-7. 9. Wilkinson J. Fusidic acid in dermatology. Br J Dermatol 1998; 139(Suppl 53):37-40. 10. Jemec G, Wendelboe P. Topical clindamycin versus systemic tetracycline in the treatment of hidradenitis suppurativa. J Am Acad Dermatol 1998;39:971-4. 11. Toyoda M, Morohashi M. An overview of topical antibiotics for acne treatment. Dermatology 1998; 196:130-4. 12. Rajos R, Zaias N. The efficacy of Bactroban ointment in the treatment of impetigo as compared to its vehicle: a doubleblind comparative study. In: Dobson R, Leyden J, Nobel W, et
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25. 26. 27.
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29. 30.
31. 32.
al, editors. Bactroban (Mupirocin). Princeton (NJ): Excerpta Medica; 1985. p. 150-4. Dillon H. Topical and systemic therapy for pyodermas. Int J Dermatol 1980;19:443-51. Blumer J. Changing therapy for skin and soft tissue infections in children: Have we come full circle? Pediatr Infect Dis J 1987;6:117-22. Hamann K, Thorn P. Systemic or local treatment of erythrasma? A comparison between erythromycin tablets and Fucidin cream in general practice. Scand J Prim Health Care 1991;9: 35-9. Nilsson E, Henning C, Njorleifsson M. Density of the microflora in hand eczema before and after topical treatment with a potent corticosteroid. J Am Acad Dermatol 1986; 15:192-7. White M, Noble W. Consequences of colonization and infection by Staphylococcus aureus in atopic patients. Clin Exp Dermatol 1986;11:34-40. Leyden J, Kligman A. The case for steroid-antibioticcombinations. Br J Dermatol 1977;96:179-87. Tada J, Toi Y, Akiyama H, et al. Infra-auricular fissures in atopic dermatitis. Acta Dermatol Venereol 1994;74:129-31. Buslau M, Kappus R, Gerlach D, et al. Streptococcal and Staphylococcal superantigens (ETA, SEB): presentation by human epidermal cells and induction of autologous T cell proliferation in vitro. Acta Dermatol Venereol 1993;73:94-6. Tada J, Toi Y, Akiyama H, et al. Presence of specific IgE antibodies to staphylococcal enterotoxins in patients with atopic dermatitis. Eur J Dermatol 1996;6:552-4. Tokura Y, Ishi-Ginoza M, Seo N, et al. Streptococcal impetigo induces Thl preponderant activation of T lymphocytes with subsequent anergy to superantigenic exotoxins in patients with atopic dermatitis. Br J Dermatol 1998;138:357-8. Leyden J, Kligman A. Rationale for topical antibiotics. Curls 1978;22:515-20, 522-8. Maddox J, Ware J, Dillon H. The natural history of streptococcal skin infection: prevention with topical antibiotics. J Am Acad Dermatol 1985;13:207-12. Hirschmann J. Controversies in antimicrobial prophylaxis. Chemioterapia 1987;6:202-7. Peters W. The chemical peel. Ann Plast Surg 1991;26:564-71. Ross V, Amesbury E, Baffle A, et al. Incidence of postoperative infection or positive culture after facial laser resurfacing: a pilot study, a case report, and a proposal for a rational approach to antibiotic prophylaxis. J Am Acad Dermatol 1998;39:975-81. Fisher A. Lasers and allergic contact dermatitis to topical antibiotics, with particular reference to Bacitracin. Curls Oct 1996;58:252-4. Nwomeh B, Yager D, Cohen I. Physiology of the chronic wound. Clin Plast Surg 1998;25:341-56. Efiksson G, Eklund A, Kallings. L. The clinical significance of bacterial growth in venous leg ulcers. Scand J Infect Dis 1984; 16:175-80. Thomson P, Smith DJ Jr. What is infection? Am J Surg 1994; 167(Suppl):7-10. Monafo W, Freedman B. Topical therapy for bums. Surg Clin North Am 1987;67:133-45.
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33. Bradley S. Effectiveness of mupirocin in the control of methicillin-resistant Staphylococcus aureus. Infect Med 1993;10:23. 34. Doebbeling B, Reagan DR, Pfaller MA, et al. Long-term efficacy of intranasal mupirocin ointment. A prospective cohort study of Staphylococcus aureus carriage. Arch Intern Med 1994;154:1505-8. 35. Colsky A, Kirsner R, Kerdel F. Analysis of antibiotic suscepti-
Curr Probl Dermatol, September/October 2000
bilities of skin wound flora in hospitalized dermatology patients. Arch Dermatol 1998;134:1006-9. 36. Nobel W. Topical and systemic antibiotics: Is there a rationale? Semin Dermatol 1990;9:250-4. 37. Cookson B. The emergence of mupirocin resistance: a challenge of infection control and antibiotic prescribing practice. J Antimicrob Chemother 1998;41:11-8.
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Topical antibiotics are widely used in medical and surgical dermatology for both prophylaxis and treatment of primary and secondary pyodermas. The ideal topical agent should have a broad spectrum of activity against common skin pathogens, such as Staphylococcus aureus and Streptococcus pyogenes (group A streptococcus) and have an acceptable side effect profile. Given the existence of multi-drug-resistant bacteria, the likelihood and impactof the development of antibiotic resistance should also be considered when choosing a topical antibiotic. The following text first reviews the characteristics of some of the more commonly used topical antibiotics and antiseptics and discusses their role in the treatment of several dermatologic conditions including impetigo, bacterial folliculitis, corynebacterial infections, and atopic dermatitis. A discussion follows on the prophylactic use of these agents in the management of patients with superficial cuts and abrasions, surgical wounds, chronic ulcerations, and burns. A final comment is made about the problem of the emergence of antibiotic-resistant bacteria and the implications this has for the future.
Topical antibiotic agents Knowledge of the range of antibacterial activity of topical antibiotics and their potential side effects is essential in directing treatment in specific dermatologic conditions. The mechanism of action, spectrum of bacterial coverage, and some of the potential side effects for a number of commonly used antibacterial agents are reviewed in Table 1.1-5 Topical antibiotics like gentamycin (inhibits Staphylococcus, Streptococcus, and aerobic gram negative [including P aeruginosa]), which have important systemic uses, are not included in the table because they are not "commonly" used in dermatology for topical therapy. The potential side effects listed in Table 1 for the selected topical agents deserve special mention. In general, systemic side effects such as nausea and diarrhea are seen more commonly with the systemic administration of these medicines. Their presence in the table is based on their inclusion in the Physicians' Desk Reference, 6 which includes even single case reports of 216
adverse events. One of the real advantages of topical therapy is the lack of serious or debilitating side effects. Antiseptic agents, used primarily for disinfection before surgical procedures, also have broad-spectrum antibacterial activity. Hexachlorophene, povidoneiodine, benzalkonium chloride, and chlorhexidine gluconate are those used most often in dermatologic surgery. 4 The majority of studies find chlorhexidine, with its widerange activity against gram-positive and gram-negative bacteria, yeast, and molds, to be the most effective of this group. 7 Topical silver in the form of silver sulfadiazine or silver nitrate is bactericidal to a number of different bacteria. These agents disrupt bacterial respiratory enzymes, the electron transport system, and interfere with other DNA functions. 8 Fusidic acid (currently not Food and Drug Administration-approved in the United States) is an antibiotic that has a steroid-like structure, but no steroid activity. Because of its steroid-like structure, fusidic acid readily penetrates the upper layers of skin, resulting in a high concentration of the antibiotic at the infection site. 9 This, along with the fact that it is highly effective against S aureus bacteria, makes it a useful antibiotic in the treatment of superficial skin infections.
Dermatologic conditions frequently treated with topical antibiotics Topical antibiotics are effective in a number of dermatologic conditions (including acne, rosacea, hidradenitis suppurativa, and perioral dermatitis) in which their effectiveness is likely related to both their antibacterial and their anti-inflammatory action.l°,ll This text focuses on the use of these agents in some of the more common non-acneiform skin conditions.
Impetigo Impetigo is a superficial infection that, in certain circumstances, may be adequately treated with topical antibiotics. Two percent mupirocin ointment applied 3 times daily for 7 to 10 days is proven to be effective in Curr Probl Dermatol, September/October 2000
TABLE 1. Antibacterial agent Bacitracin
Clindamycin
Erythromycin Metronidazole
Mupirocin
Neomycin
PolymyxJn
Mechanism of action Complexes with C55-prenol pyrophosphate (constituent of bacterial cell wall)
Spectrum of activity
Potential side effects
Gram+ cocci; some Neisseria
2% incidence of contact dermatitis (postoperative); common concomitant sensitizaion to neomycin; rare a phylaxis with prior pruritus and edema Binds 50S subunit of bacterial ribosome Group A Streptococcus; Rare reports of diarrhea, bloody diarrhea, (involved in protein synthesis); causes penJcillinase producing pseudomembranous colitis (more common dissociation of ribosome subunits staphylococci with systemic therapy); gram-folliculitis Binds 50S subunit of bacterial ribosome Primarily, Group A Xerosis, pruritus, burning sensations of the (involved in protein synthesis) Streptococcus skin and eyes Reduction causes production of free radicals Anaerobic bacteria (no aerobes); Xerosis, erythema; metallic taste, tingling/ that damage DNA and inhibit replication protozoa numbness of extremities, nausea (more common with systemic therapy) Inhibits bacterial isoleucyl tRNA synthetase Gram+ (except enterococci); Burning, stinging, pain, swelling, nausea in (involved in protein synthesis) inactive against many <1% of patients organisms of normal flora Binds 30S subunit of bacterial ribosome Gram- (except P aeruginosa); 1%-6% incidence of contact dermatitis (20%(involved in protein synthesis); interferes S aureus (not other gram+) 30% in patients with chronic leg ulcers); with bacterial DNA polymerase ototoxicity if significant systemic absorption (ie, application to large surface areas; reduced metabolism in renal failure) Acts as surfactant to disrupt cell membrane Gram- rods (except Proteus, Rare allergic contact dermatitis (possible cros~ Providencia, Serratia) reactivity with bacitracin)
the treatment of patients with limited numbers of lesions who do not have systemic signs of infection. ]2 Systemic therapy should be used in situations where there is widespread or deeper infection, fever, lymphadenopathy, or other signs of systemic disease. 13 Systemic therapy is also administered for the treatment of bullous impetigo and streptococcal pyodermas. In the case of streptococcal disease, penicillin may be able to prevent the infrequent but serious complication of poststreptococcal glomerulonephritis. 14 Scientific evidence does not appear to support the use of systemic agents over topical ones in either of these 2 conditions.
Bacterial Folliculitis S aureus folliculitis may be treated effectively with twice-daily application of topical clindamycin, topical erythromycin, or 3-times-daily application of mupirocin. The addition of antiseptic agents like chlorhexidine to the treatment regimen may be beneficial. Recalcitrant or extensive disease may require systemic therapy. The prophylactic use of topical medication in cases of recurrent episodes of Staphylococcus folliculitis, in which patients are frequently found to be nasal carriers of S aureus, is discussed later in this issue.
Corynebacterial Infections Erythrasma and pitted keratolysis are superficial bacterial infections caused by the gram-positive bacteria Curr Probl Dermatol, September/October 2000
Corynebacterium minutissimum. Topical agents have been directly compared to oral erythromycin in the treatment of erythrasma and have been found to be equally efficacious./5 Twice-daily application of clindamycin or erythromycin, alone or in combination with an antiseptic agent, is effective in eradicating the infection in both conditions. Trichomycosis, a corynebacterial infection of the axillary or pubic hair, may also be treated with clindamycin, although shaving the affected area generally results in resolution of the problem. 3
Atopic Dermatitis It is well known that eczematous skin is often colonized with S aureus. It is unclear whether or not this organism is a pathogen or if its only role is a colonizing agent. Studies have shown that exudative lesions have higher number of Staphylococcus organisms than erythematous or lichenified lesions of atopic dermatitis, but treatment of these exudative lesions with topical corticosteroids alone markedly decreased bacterial numbers. 16'17 Other studies have shown the use of a combination of topical corticosteroids and topical antibiotics in "infected eczema" to be superior to treatment with the corticosteroid alone.18 After an extensive review of the literature, Hirschmann 3 states that the discrepancies in the results obruined from well-controlled studies may relate to their failure to define clinical criteria for "infected eczema." 217
Bacteriologic data alone do not always support the clinical diagnosis of infection. 19 In his review, Hirschmann found that topical antibiotics alone usually offer no substantial clinical benefit over topical corticosteroids. A possible exception is fusidic acid, which, as previously noted, is currently not Food and Drug Administrationapproved for use in the United States. 9 It has also been suggested that "superantigens," which are substances that can stimulate lymphocytes by crosslinking T cell receptors and class II antigens, may have a role in the development of impetiginization. 2° If this is the case, then treatment of potential pathogenic S aureus organisms, regardless of their numbers, would likely be beneficial. Evidence for this theory is currently unsubstantiated.21,22
Prophylactic uses of topical antibiotics Topical antibiotics are commonly used in the prophylaxis of infection in a number of different situations in which the integrity of the skin has been compromised. These include superficial cuts and abrasions, surgical wounds, chronic leg ulcers, and burns. Topical antibiotics are also prophylactically able to reduce nasal Staphylococcus carriage in patients who have recurrent problems with folliculitis or who have a propensity for the development of other Staphylococcus pyodermas. Whenever medications are used for prophylaxis, the risk of potential side effects must be weighed against the potential benefits. Contact sensitization ("potential side effects" in Table 1) is a limitation to the use of these agents in many instances.
Superficial Cuts and Abrasions Combinations of topical antibiotics such as a bacitracin-neomycin-polymyxin are often used in the treatment of superficial cuts and abrasions. There is some evidence to support the use of these formulations because they have been found to reduce skin colonization with staphylococci and streptococci, which may prevent subsequent infection. 23,24 When they are used infrequently and for short periods Of time, the potential benefit may outweigh the risk of development of contact sensitization.
Surgical Wounds Despite the fact that the infection rate in clean surgical procedures is less than 3%, topical antibiotics are frequently prescribed as part of the postsurgical wound care treatment regimen. Studies on the use of systemic antibiotics in surgery have shown that the antibiotic 218
must be present during the time of bacterial contamination to have a beneficial effect. It has also been shown that significant contamination of surgical wounds occurs, for the most part, before wound closure. 24 If these principles were applied to topical antibiotics, it would seem that they would have little to offer in the treatment of infection in the postoperative period. There is also a theoretical risk that their use could actually have a deleterious effect. Studies done to access topical antibiotic use in the prophylaxis of infection in patients with intravenous catheters have shown that the use of these agents for longer than 1 week promotes the growth of yeast, which could further complicate or delay wound healing. 23 Optimistically, showering with chlorhexidine before excisional surgery suppresses skin colonization for several hours. It is unknown, however, whether or not this correlates with a decrease in the incidence of postoperative infections.7 Topical antibiotics have been used in the postoperative care of patients who have had chemical or laser peels and dermabrasion. In these open wounds, the antibiotics provide a bacteriostatic or bactericidal environment during wound healing, and at the same time act as emollients to reduce the time of reepithelialization. 26 Because of the increased incidence of contact dermatitis observed in the laser-treated patient population, especially to bacitracin-containing compounds, many clinicians are now using topical emollients alone. 27.28 Some clinicians do use topical antibiotics as prophylaxis for the development of gram-negative infections. Those described for use after laser resurfacing include 0.25% acetic acid, aluminum acetate, and silver sulfadiazine cream. 27
Leg Ulcers Treatment of chronic wounds requires an understanding of the underlying abnormality causing the ulceration as well as the pathophysiologic mechanisms of the wound-healing process, both of which are beyond the scope of this discussion. A concise review of these topics may be found in an article by Nwomeh et al. 29 The role played by bacteria in the persistence of chronic wounds is debated. Cultures often reflect only contamination by normal skin flora. Even the presence of high number of organisms (>10 organisms/gram of tissue) does not necessarily correlate with infection and may not adversely affect healing. 3°.31 Wound infection is perhaps best determined by clinical examination. Pyrexia, erythema, swelling, and purulence are clinical signs that may suggest infection.29 In these cases sysCurr Probl Dermatol, September/October 2000
temic, rather than topical, antibiotics and debridement are the treatments of choice. Leg ulcers, by nature, result in chronically compromised skin and require long-term treatment and repeat applications of topical agents, which predisposes the patient to the development of contact dermatitis. 2 Studies in patients with chronic venous insufficiency or stasis dermatitis treated with topical antibiotics have shown sensitization in up to 70%. 2 The cytotoxic properties of many disinfectants often prohibit their use as well, because they may cause a delay in re-epithelialization of chronic wounds. 4
Burns The prophylaxis of infection in patients with bums is extremely important because infection is a major cause of both morbidity and mortality. Topical agents used on even extensive bums may be the most effective means of preventing sepsis. 32 Systemic agents may not be as efficacious as topical ones because the ischemia around deep wounds prevents the agents from reaching bactericidal concentrations at the bum site. 4 Silver sulfadiazine is the topical agent most commonly used in the treatment of bums because it has excellent activity against the common flora that colonize bums, including Pseudomonas aeruginosa, S aureus, and yeasts, and it has an acceptable side effect profile. Serious, systemic adverse effects are not observed, even with repeated application; contact sensitization is rare; and the development of antibiotic resistance is also low. These characteristics make sulfadiazine a logical choice over other agents such as povidone-iodine (which may cause acidosis with increased absorption) and other topical antibiotics that have a higher incidence of contact sensitization. 32 The sulfadiazide compounds should, however, be avoided in patients with documented allergic reactions to sulfa medications. Mafenide acetate cream, a bacteriostatic agent that diffuses well through devasculadzed areas, is also mentioned as a potential treatment for burns.4
Staphylococcus aureus Nasal Carriage S aureus is found in approximately 20% to 40% of normal adults. 3 It is usually not a significant pathogen except in cases of recurrent Staphylococcus pyodermas, such as folliculitis, and in cases of carriers transmitting the organism to susceptible patients, as in nosocomial staphylococcal epidemics. In such situations, it would be advantageous to eliminate the carrier state. Many topical antibiotics and antiseptics, including Curr Probl Dermatol, September/October 2000
gentamycin, bacitracin, neomycin, chlorhexidine, tetracycline, and vancomycin, have been shown to eradicate S aureus from the nares, but none have resulted in longterm elimination of the bacteria. 3,33 Topical mupirocin has been shown to reduce both nasal and hand carriage of S aureus for up to a year when it is applied to the nares of health care workers daily for 5 consecutive days. 34 More controlled studies are needed, but at this point, mupirocin appears to be the most effective topical agent for prophylaxis in this setting. Although antibiotic resistance is presently uncommon, the benefits of prophylactic use over the risk of creating resistant pathogens should .always be considered. Presently, however, there are no specific contraindications for the chronic use of mupirocin.
Antibiotic Resistance Ongoing studies of antibiotic susceptibilities of skin wound flora in hospitalized dermatology patients show an alarming trend toward resistance to several commonly used systemic antibiotics. 35 Changes occur in the antibiotic resistance patterns for a number of reasons that include the selection of chromosomally resistant bacterial variants, bacterial acquisition of a resistance plasmid, and the selection of new organisms as a result of antibacterial therapy.36 Topical use of antibiotics has often been implicated in the development of systemic resistance. The empiric use of topical agents in many clinical settings, the long-duration of use in chronic conditions, and the fact that topically applied medicines become wide-spread (by means of the hands) to other areas of the body (exposing large numbers of organisms to "therapy") all probably contribute to the development of resistance. The relatively new reports of the emergence of mupirocin resistance are alarming because this topical medication is the most effective treatment in many skin conditions (as noted previously in this discussion), as well as in the treatment of methicillin-resistant S aureus infections. 37 Several things may be done in the future to reverse these trends and to preserve the role of topical antibiotics in the treatment of prophylaxis of primary and secondary pyodermas. Well-designed case-controlled studies to evaluate the efficacy of topical medications, especially in the area of prophylactic use, are needed so that empiric therapy for undefined, often prolonged periods is not the rule. The development of topical-use-only antibiotics with unique mechanisms of action, like mupirocin, would help with the problem of cross-resistance and would decrease the resistance observed to important systemic 219
antibiotics that have historically also been used in a topical form. 36
A relatively new compound, pexiganan acetate, which is derived from the magainin family of skin peptides found in the African clawed frog, is being investigated for topical use. It is a membrane-active agent that causes pore formations in the cell membranes of microbial and some fungal organisms. The Food and Drug Administration recently ruled not to approve its use in the treatment of decubitus and diabetic food and leg ulcers, stating that more placebo-controlled studies are needed (Anti-infective Drugs Advisory Committee, March 4, 1999). However, such membrane active agents may have a bright future in topical therapy as the chance of the developing resistance is low. It is very difficult for bacteria to change their outer surface to avoid destruction by these agents. Finally, we should look for new roles for existing topical agents, such as silver, for which there is no documented evidence of cross-resistance patterns with antibiotics. 8 Responsibility should be the rule in the use of established therapies and in the development of new ones.
13. 14.
15.
16.
17.
18. 19. 20.
21.
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