Mupirocin Ointment

The Journal of Emergency Medicine, Vol 17, No 1, pp 213–220, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679/99 $–see front matter

PII S0736-4679(98)00148-6

Antimicrobial Wound Management in the Emergency Department: An Educational Supplement

OPPORTUNITIES FOR MUPIROCIN CALCIUM CREAM IN THE EMERGENCY DEPARTMENT Phillip M. Williford,

MD

Department of Dermatology, Bowman Gray School of Medicine, Winston Salem, North Carolina Reprint Address: Phillip M. Williford, MD, Department of Dermatology, Bowman Gray School of Medicine, Winston Salem, NC

e Abstract—Mupirocin calcium cream is a newly reformulated topical antibiotic with a bactericidal spectrum specific for the pathogens that frequently cause secondary infections in superficial wounds. Both the calcium cream and ointment formulations have demonstrated efficacy in the treatment of secondarily infected traumatic lesions and dermatoses, including eczema, burns, wounds, bites, and ulcers. Mupirocin has a low risk of systemic and topical complications. To date, antimicrobial resistance is rare among target pathogens. The use of mupirocin to treat secondary wound infection has a profile of high efficacy and does not impair the normal healing in traumatized skin. © 1999 Elsevier Science Inc.

THE PHYSIOLOGY OF WOUND HEALING To understand the role of mupirocin in the treatment of SITLs and dermatoses, one must review the basic physiology of wound repair. Wound healing involves a complex interplay among many cell types, cytokines, and the extracellular matrix that can be divided into three phases. These designations are somewhat arbitrary and progress continuously from one to another. (2,3) The inflammatory phase, beginning with the injury and continuing for several days, is characterized by the influx of platelets, neutrophils, and monocytes and the release of their cytokines. Chemotactic factors released as part of the coagulation cascade facilitate diapedesis of neutrophils through up-regulation of adhesion molecules on the surface of epithelial cells (4). The interaction of these blood-borne cells mediates decontamination of the wound, removal of necrotic debris, and initiation of angiogenesis (2). The proliferative phase begins with the formation of granulation tissue, and the incipient reepithelialization of the wound. A matrix composed of fibrin, fibronectin, and type V collagen covers the wound bed and allows keratinocyte migration (2). Keratinocytes progress in sheets inward from the wound edge within 24 h of injury (2,5). Growth factors released from macrophages play a role in the direction and control of keratinocyte migration. Wound fibroblasts form new connective tissue composed initially of type III collagen, glycosaminoglycans, and proteoglycans. The wound subsequently contracts due to contractile proteins contained within myofibroblasts (2). The remodeling phase occurs for up to 18 months after the restoration of a functional epidermal barrier (3).

e Keywords—mupirocin; mupirocin calcium cream; skin diseases; infectious; wound infection; secondarily infected traumatic lesions; Staphylococcus aureus

INTRODUCTION Secondarily infected traumatic lesions (SITLs) arise when a preexisting wound or skin lesion becomes infected (1). Antibiotic treatment is often integral to proper healing. Recently, mupirocin was reformulated into mupirocin calcium cream to target SITLs. This article will focus on the treatment of SITLs and dermatoses, comparing the utility and the safety of the topical antibiotic mupirocin calcium cream and mupirocin ointment with that of oral antibiotics.

Grant Support: SmithKline Beecham. 213

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During this phase, type III collagen is replaced by type I collagen (2). Continued modification of fibronectin and proteoglycans also occurs. The remodeling phase results in the near recovery of preinjury tensile strength, which at its maximum is approximately 80% of preexisting strength (2,6). During the process of recreating the functional epidermal barrier after injury, secondary infection may intervene in efficient recovery. Whether this process occurs is dependent on a number of supervening factors.

DOES WOUND HEALING ALWAYS REQUIRE AN ANTIBIOTIC? Most wounds, particularly nonpenetrating wounds, heal well without the need for antibiotic treatment (7). Although debate continues regarding the timing of wound closure, choice of suture materials, and utilization of various scrub solutions and irrigants, it is clear that management generally revolves around cleaning the wound, irrigating it, and applying an appropriate dressing. Antiseptic scrub solutions probably should be avoided, although povidone solution 1% does not appear to be toxic to tissue and may improve outcome, though the assertion is open to dispute. Local anesthesia, when needed, should be administered without epinephrine, as the use of epinephrine is associated with increased risk of infection in contaminated wounds because of alterations in blood flow to injured areas. Avoidance of buried sutures is likewise recommended. The impact of topical antibacterial ointments on the healing of uninfected wounds is somewhat controversial. Kirsner and Eaglstein maintain that antimicrobial agents do not convincingly speed healing (2). Some authors decry the routine use of topical antibiotics in seemingly clean wounds, citing a low incidence of infection (8). However, most superficial traumatic wounds are contaminated by foreign material, whether iatrogenic (e.g., sutures) or otherwise, that alter the probability of infection and the subsequent usefulness of topical or systemic antibiotic therapy (9). One study found that topical application of neosporin or bacitracin to suture lines decreased the risk of infection compared to petrolatum controls (10). Other evidence suggests that topical antibiotics decrease the risk of infection in both animal and human wounds (11). Watcher and Whelland reported that mupirocin has no effect on re-epithelialization, but significantly decreases the rate of wound contraction (12). Another study found that mupirocin ointment accelerated healing by as much as 8% (13). Several reports note that topical antibiotics, including mupirocin, are not toxic to human fibroblasts or keratinocytes (14 –16). Boyce et al. (17) reported that mupirocin had no toxicity

P. M. Williford

to cultured human skin grafts and was uniformly effective against S. aureus, including methicillin-resistant S. aureus.

CLINICAL PHARMACOLOGY OF MUPIROCIN Mupirocin (pseudomonic acid A; C26H4409) is a metabolite produced by submerged fermentation of Pseudomonas fluorescens (18,19). Its chemical structure and mechanism of action are unique among antibiotics in clinical use; therefore, cross resistance (and shared allergy) between mupirocin and other antibiotics is not a concern. Toxicity arising from inhibition of isoleucyl-t-RNA synthetase by mupirocin does not occur in humans because it has a low affinity for the mammalian enzyme (18). Mupirocin inhibits bacterial protein synthesis by binding to the enzyme, isoleucyl-t-RNA synthetase, which prevents the incorporation of isoleucine into proteins (20). Systemic absorption is minimal with topical administration of mupirocin; however, with intravenous administration, mupirocin is rapidly converted predominantly to monic acid, an inactive metabolite that is readily excreted in the urine (20). In one study of mupirocin ointment, not more than 0.24% of the dose was absorbed in the 24 h after topical administration (20). Multiple dosing of mupirocin calcium cream shows marginal percutaneous absorption in adults and children (21). Although one study showed that percutaneous absorption is more common in children than in adults, pediatric absorption levels as determined by urinary monic acid concentrations are within the observed range in the adult population (21). Radioactivity has been detected in the stratum corneum 72 h after administration of 14C-labeled mupirocin, suggesting that mupirocin resides in the skin for some time (22). Previously available only as a free acid in a polyethylene glycol base, the new formation of mupirocin as a calcium salt in a cream base is nongreasy and therefore generally better tolerated. The new formulation also eliminates the potential for allergic contact hypersensitivity that was occasionally caused by the polyethylene glycol base (23). Accumulation of polyethylene glycol in patients with poor renal function or hemodynamic instability also can result in nephrotoxicity and metabolic abnormalities (24,25). Mupirocin is bacteriostatic at low concentrations, but it is bactericidal at the higher local concentrations achieved with topical administration (26). The bactericidal activity of mupirocin is enhanced in an acid environment such as the skin (26). Mupirocin has a narrow spectrum of activity encompassing most clinically pertinent gram-positive organisms, specifically staphylococci

Muciprocin Cream in the ED

and streptococci. In an in vitro study of 1,000 S. aureus isolates, 100% of methicillin-sensitive and 95.9% of methicillin-resistant isolates were susceptible to mupirocin (27). Mupirocin demonstrates significant activity against Haemophilus influenza, Neisseria gonorrhoeae and meningitidis, Branhamella catarrhalis, and Pasteurella multocida, but activity against other gram-negative organisms is suspect (26,28). Interestingly, its in vitro activity against Candida albicans is comparable to that of many frequently used antifungals (28). Mupirocin is inactive against group D streptococci and anaerobes (26,28). Normal skin flora such as micrococcus, corynebacterium, and propionibacterium are unaffected, thereby maintaining the body’s natural inhibition of pathogens through competition from commensals (26,28). Resistance to mupirocin among ordinarily sensitive pathogens, which is an infrequent occurrence, is generally low level (MIC , 100 mg/mL) (29). The clinical significance of low-level resistance is unclear because concentrations of mupirocin applied to wounds reach 20,000 mg/mL, and treatment failures have been only rarely reported. Nevertheless, high-level resistance (MIC . 1024 mg/mL) has been reported in some strains of S. aureus and coagulase-negative staphylococci. The apparent cause of high-level resistance is plasmid coding for a modified form of isoleucyl tRNA synthetase (29).

CLINICAL EFFICACY AND SAFETY OF MUPIROCIN Treatment of Secondary Infected Traumatic Lesions and Dermatoses Because S. aureus and streptococci produce the majority of secondary skin infections, mupirocin calcium cream is a reasonable treatment choice compared to oral antibiotics for secondary infections affecting relatively small areas (#10 cm in length or 100 cm2 in area). Controlled studies comparing mupirocin with oral antibiotics are summarized in Table 1 (30 –37). In two randomized, double-blind trials, mupirocin calcium cream (n 5 357) applied to SITLs (e.g., lacerations, sutured wounds, abrasions) three times daily over 10 days was equally effective to oral cephalexin (n 5 349) over the same time period (30). At the end of therapy, the pathogen eradication rates were 96.9% for mupirocin patients and 98.9% for cephalexin patients. Similar results in another randomized, double-blind trial showed that mupirocin calcium cream (n 5 195) and oral cephalexin (n 5 178) were both 100% effective at pathogen eradication, and their clinical success rates were comparable (96.2% for mupirocin and 86.5% for cephalexin) (31).

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As an alternative to systemic antibiotics, mupirocin calcium cream has demonstrated efficacy in the treatment of secondarily infected dermatoses. Rist et al compared mupirocin calcium cream (n 5 82) to oral cephalexin (n 5 77) in the treatment of secondarily infected eczema over a 10-day period (33). While both agents were comparably effective in achieving clinical success (89% for mupirocin and 82% for cephalexin), mupirocin was significantly more effective ( p 5 0.004) at pathogen eradication. The groundwork for efficacy of mupirocin calcium cream in treating secondary infections was first established in placebo-controlled trials of mupirocin ointment. Ward et al evaluated a series of 11 double-blind, randomized clinical trials comparing mupirocin ointment with its vehicle (free acid in a polyethelene glycol base) as a placebo for the treatment of secondarily infected dermatoses including eczema, burns, wounds, bites, and ulcers (20). With the exception of a single study, bacterial eradication was greater with mupirocin, which was associated with an overall eradication rate of 90% (range: 73% to 100%), compared to 53% with its vehicle (range: 19% to 89%). For S. aureus, the overall eradication rate was 94% with mupirocin and 40% with its placebo vehicle. In terms of clinical efficacy, the overall response rate was 94% with mupirocin (range: 81% to 100%) and 71% with its vehicle (range: 38% to 93%). The success rates for infected eczema were 97% and 44%, respectively (20). Breneman evaluated the efficacy of mupirocin ointment vs. its vehicle for secondarily infected dermatoses in a double-blind, vehicle-controlled study with 92 evaluable patients (38). Patients suffered from atopic dermatitis, eczema, seborrheic dermatitis, neurodermatitis, and contact dermatitis. Mupirocin treatment produced significantly greater eradication of S. aureus (85% versus 6%, respectively, p , 0.01) and total pathogens (69% versus 14%, respectively, p , 0.01. When all pathogens were considered, there was marked or moderate improvement in global infections in 79% of mupirocin-treated patients and 65% of vehicle-treated patients. When only S. aureus- or S. pyogenes-associated infections were considered, marked or moderate improvement was observed in 85% of mupirocin-treated patients compared with 53% of vehicle-treated patients ( p 5 0.007). In addition to infection improvement, there was also a significantly greater improvement in dermatoses treated with mupirocin (53% versus 22%, respectively, p 5 0.01). The extent of beneficial clinical effect from the placebo treatment (the vehicle) highlights the difficulty of differentiating significant skin infections from trivial ones, or from colonization.

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Table 1. Clinical Trials Comparing Mupirocin with Oral Antibiotics for Primary and Secondary Skin Infections* (30 –37) Primary and Secondary Dermatoses

Reference Kraus et al. (30)

Henkel et al. (31)

Bass et al. (32) Rist et al. (33) Gratton (34)

Welsh and Saenz (35) Dux et al. (36)

Villiger et al. (37)

Secondarily infected open wound (e.g., laceration, sutured wound, abrasion) Secondarily infected open wound (e.g., laceration, sutured wound, abrasion) Impetigo Secondarily infected eczema Impetigo; boils; folliculitis; furuncles, infected lacerations, ulcers, eczema, herpes or scabies Impetigo; folliculitis; infected eczema, burns, ulcers; paronychia; others Impetigo; folliculitis; carbuncles; infected lacerations, ulcers, eczema; paronychia; sebaceous cyst; others Impetigo; furuncles; infected lacerations, eczema, ulcers or burns

Number

Regimen

Clinical Cure or Improvement (%)

357 Mupirocin 349 Cephalexin

Applied TID for 10 d PO QID for 10 d

233/245 (95.1) 222/233 (95.3)

195 Mupirocin 178 Cephalexin

Applied TID for 10 d PO QID for 10 d

125/130 (96.2) 110/114 (96.5)

7 Mupirocin 9 Bacitracin 10 Cephalexin 82 Mupirocin 77 Cephalexin 30 Mupirocin 28 Erythromycin

Applied TID for 10 d Applied TID for 10 d 50 mg/kg/d TID for 10 d Applied TID for 10 d 250 mg PO QID for 10 d Applied TID for 7 d 250 mg PO QID for 7 d

7/7 (100) 3/9 (33) 10/10 (100) 39/44 (89) 31/38 (82) 29/30 (97) 23/28 (82)

27 Mupirocin 23 Ampicillin

Applied TID for 5–10 d 500 mg PO QID for 5–10 d

26/27 (96)† 18/23 (78)

78 Mupirocin 50 Erythromycin 20 Cloxacillin

Applied TID for 7 d 250 mg PO QID for 7 d 250 mg PO QID for 7 d

76/78 (97) 47/50 (94) 19/20 (95)

Applied TID for 4–10 d Usual PO dose for 4–10 d Usual PO dose for 4–10 d

100/101 (99)‡ 14/19 (74) 79/80 (99)

101 Mupirocin 19 Erythromycin 80 Flucloxacillin

* Randomized, parallel-group studies. † Statistically significant difference. ‡ Statistically significant difference for mupirocin vs erythromycin. Abbreviations: d 5 days; QID 5 four times daily; PO 5 oral; TID 5 three times daily.

Treatment of Impetigo Mupirocin is an alternative to systemic antibiotics for the treatment of impetigo because S. aureus alone or a mixed flora of S. aureus and S. pyogenes is often recovered from impetigo lesions (34,35). One small study comparing mupirocin cream (n 5 7) to topical bacitracin (n 5 9) and oral cephalexin (n 5 10) showed no treatment failures in the mupirocin and cephalexin groups, but six treatment failures in the bacitracin group ( p , 0.005) (36). The authors made two conclusions that need to be confirmed in larger studies: first, that bacitracin can no longer be recommended to treat impetigo; and second, that topical mupirocin and oral cephalexin are equally effective treatment choices. A number of studies have found mupirocin either more effective (34,36,37,41) or equivalent (42,43) to oral erythromycin in eradicating impetigo infection. Mupirocin was significantly more effective than oral ampicillin in a study comparing mupirocin with oral ampicillin in the treatment of primary and secondary skin infections

(35). In retrospect, this is to be expected, considering the limited staphylococci coverage of ampicillin. For treating impetigo cases that involve only a small number of lesions, it is recommended to use mupirocin cream and to reserve oral antibiotic use for more widespread cases (32). The superior performance of mupirocin may be due to a shift toward erythromycin and ampicillin-resistant S. aureus as the primary cause of impetigo (40). In a study in which 93% of impetigo lesion cultures yielded S. aureus, 28% of evaluable patients were infected with erythromycin-resistant isolates (44). The clinical failure rate for erythromycin-treated patients with erythromycin-resistant isolates was 47% compared with failure rates of 8% for patients infected with susceptible isolates and 2% for patients treated with mupirocin. A number of studies comparing mupirocin with oral antibiotics for impetigo also found it effective for the treatment of secondarily infected wounds, ulcers, burns, and eczema (35–37). These studies are summarized in Table 2 (32,46 –56).

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Table 2. Clinical Trials* Comparing Mupirocin Ointment with Its Polyethelene Glycol Vehicle for Secondary Skin Infections (32,46 –56) Reference Breneman, 1990 (32) Carney and Bickers, 1985 (46) D’Alessandri et al., 1985 (47) DeBoer, 1985 (48) Eaglstein, 1985 (49) Golitz and Beehler, 1985 (50) Leyden, 1985 (51) Orecchio and Mischler, 1986 (52) Pekoe and Dobson, 1985 (53) Rosenberg and Churchwell, 1985 (54) Whiting et al., 1985 (55) Zone and Weidner, 1985 (56)

Number 47 Mupirocin 43 Vehicle 22 Mupirocin 22 Vehicle 16 Mupirocin 15 Vehicle 26 Mupirocin 25 Vehicle 20 Mupirocin 17 Vehicle 24 Mupirocin 20 Vehicle 26 Mupirocin 26 Vehicle 76 Mupirocin 78 Vehicle 34 Mupirocin 34 Vehicle 25 Mupirocin 23 Vehicle 17 Mupirocin 19 Vehicle 26 Mupirocin 25 Vehicle

Application Regimen TID for 7–9 d TID for 7–8 d TID for 8 d TID for #10 d TID for #12 d TID for 8 d ND TID for #10 d TID for #12 d ND TID for 5–12 d ND

Clinical Cure or Improvement (%)

Bacteriologic Cure (%)

37/47 (79) 28/43 (65) 20/22 (91) 18/22 (82) 15/16 (94) 14/15 (93) 21/26 (81) 21/25 (84) 19/20 (95)† 12/17 (71) 22/24 (92) 16/20 (80) 26/26 (100)† 10/26 (38) 63/76 (83)† 37/78 (47) 32/34 (94) 31/34 (91) 24/25 (96) 19/23 (83) 17/17 (100) 16/19 (84) 25/26 (96) 22/25 (88)

52/75 (69)† 10/69 (14) 22/30 (73) 12/31 (39) 18/18 (100) 16/18 (89) 23/29 (79)† 18/31 (58) 29/30 (97)† 11/24 (46) 27/29 (93)† 5/25 (20) 22/26 (85)† 5/26 (19) ND 45/53 (92)† 38/52 (73) 32/35 (91)† 27/41 (66) 19/20 (95)† 10/20 (50) 30/31 (97)† 18/33 (55)

* Randomized, double-blind, parallel-group studies. † Statistically significant difference. Abbreviations: d 5 days; ND 5 no data; TID 5 three times daily. Adapted, with permission, from Ward (45)

Mupirocin has shown a benefit in treating some lesions of a number of chronic dermatologic disorders that are exacerbated by S. aureus colonization. In atopic dermatitis, a decrease in S. aureus colonization with 2 weeks of mupirocin therapy was associated with a decrease in clinical severity (57). However, patients quickly became recolonized after mupirocin was discontinued. Mupirocin has been successfully used to decrease S. aureus colonization and enhance healing of epidermolysis bullosa (58), as well as to prepare wounds for epidermal autografts (59).

resistant S. aureus was eradicated from all wounds within 5 days (62). Subsequently, 20 wounds healed spontaneously, and 39 granulated enough for successful grafting. In this study, the average burn wound size was 8% of the body surface area (range: 2% to 20%). Based on these studies, mupirocin has demonstrated efficacy for the treatment of SITLs. Mupirocin has not been studied for the treatment of deeper soft tissue infections, such as cellulitis, lymphangitis, or fasciitis. The inability to reliably predict deep tissue concentrations of drug, and the rapid metabolism of systemically absorbed product to an inactive metabolite suggest that systemic antibiotic therapy is indicated in such cases.

Treatment of Burn Wounds

Intranasal Use

In an in vitro burn wound model that mimics penetration into eschar, 97.8% of S. aureus were killed within 24 h with mupirocin (60). Another in vitro study demonstrated diffusion of mupirocin through 1.5 mm of eschar within 2 h (61). When Rode et al used topical mupirocin to treat 59 burn wounds infected with methicillin-resistant S. aureus that had not responded to povidone– iodine, chlorhexidine, or silver sulfadiazine, methicillin-

Nasal carriage of S. aureus can be linked to the transient contamination of the carrier’s hand, which is the primary mode of transmission (and subsequent infection) from the carrier to a patient (63,64). In addition, patients with S. aureus nasal carriage are susceptible to autoinfection. The reliable bactericidal activity of mupirocin against gram-positive organisms routinely implicated in superficial skin infections has led to its use in clinical settings to

Treatment of Chronic Dermatologic Disorders

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modify or prevent disease. In 1996, paraffin-based mupirocin calcium was formulated for intranasal use that would not irritate the mucous membrane. Intranasal application of mupirocin calcium is used to eliminate S. aureus carriage among healthcare workers and hospitalized patients during outbreaks of methicillinresistant S. aureus (65,66). A single course of therapy (a twice-daily application for 5 days) has been found to reduce S. aureus nasal carriage in healthcare workers for up to a year (67). Intranasal administration of mupirocin has also been used to prevent S. aureus infections in hemodialysis patients, (68) a patient group at high risk for colonization and serious staphylococcal infections (69). The results from a large, controlled clinical trial conducted at the University of Iowa Hospital and Clinics investigating the efficacy of intranasal mupirocin use as surgical prophylaxis are expected to be reported by the end of this year.

ADVERSE EVENT PROFILE Mupirocin calcium is exceptionally well tolerated. In clinical trials of 339 patients, the most commonly reported adverse events were headache (1.7%), rash (1.1%), and nausea (1.1%). In another study of 82 patients, the most common adverse events were nausea

(4.9%), headache (3.6%), burning at application site (3.6%), and pruritis (2.4%). In comparison, systemic antibiotics used for superficial cutaneous infection are associated with a daunting array of rare but serious adverse effects, including pseudomembranous colitis, toxic epidermal necrolysis, hepatotoxicity, and serum sickness (70 –73). From the standpoint of potential toxicity, topical mupirocin’s safety profile is preferable.

CONCLUSIONS In choosing a topical antibiotic, a number of considerations should be entertained (74). The agent should demonstrate an appropriate spectrum of antibiotic effect while preserving normal flora, and it should be characterized by minimal systemic complications, minimal contact allergenicity, and infrequent emergence of resistant organisms. Based on current data, mupirocin cream fulfills these criteria well. It has significant bactericidal activity against the gram-positive organisms that most commonly cause secondary wound infections. It is not known to have systemic toxicity, and when absorbed, is metabolized rapidly to inactive products. Contact sensitivity occurs in fewer than 1% of patients, and 99% of S. aureus isolates remain susceptible to its antibacterial effect.

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