549

Review of Mupirocin OintmentIn the Treatment of ImpetigoJames J. Leyden, M.D.

From the Department of Dermatology,University of Pennsylvania, Philadelphia.

Address correspondence to: James J.Leyden, M.D., Professor of Dermatology,University of Pennsylvania Hospital,Department of Dermatology, 36th andSpruce, Philadelphia, PA 19104(215) 662-2740

Supported by an educational grant fromSmithKline Beecham.

Introduction

Superficial skin infections arecommon in pediatric prac-

tice and frequently are

treated with antibiotics. Tradition-

ally, however, topical antibiotics

have been regarded as ineffectivemonotherapy for primary skin in-fections such as impetigo.

Topical antibiotics may be of

particular value in the manage-ment of skin infections in children.

Oral antibiotics present a numberof familiar problems in children:noncompliance, interruption of

feedings due to drug-absorptionproblems, and gastrointestinal sideeffects.

Thus, topical antibiotics thus

are an attractive option in the treat-ment of skin infections that are not

widespread. Among their advan-tages are ease of administration,lower potential for adverse reac-tions, lower risk of noncompli-ance, delivery of high drugconcentrations to the site of infec-

tion, decreased risk of bacterial re-sistance or cross-resistance, and, in

some cases, cost savings as well.A recently introduced topical

agent, mupirocin ointment, pro-vides effective topical therapy forimpetigo. Mupirocin possesses

many of the properties desired ina topical antibiotic (e.g., a chemi-cal structure and mechanism ofaction unrelated to those of other

antibiotics to minimize the devel-

opment of resistance); it is also

not used systemically, it is active

against common gram-positiveskin pathogens, at the acid pH ofthe skin, and it is safe.

Bacteriology of Impetigo

Impetigo is the most commonskin infection in children. In tradi-tional classification, impetigo con-tagiosa was characterized by thick,crusted lesions and was primarilyof streptococcal origin. Bullous im-petigo, characterized by thin-

walled bullae, was thought to becaused most often by Staphylococcusaureus. 14

However, recent experience hasshown that S. aureus is now themost frequent cause of both vari-eties of impetigo. In numerous re-ports covering many geographicareas, 77% to 98% of cases wereattributed to staphylococci. Fewerthan 3% of cases were solely strep-tococcal in origin.5-8 Some of thesechanges may reflect methodolo-gies used in culturing lesions; e.g.,failure to use selective media mayresult in failure to detect group A

streptococci. Likewise, lesions

originally infected with group Astreptococci may be secondarilycolonized by large numbers of S.aureus, making recovery of Strepto-coccus pyogenes more difficult if se-lective media are not used.

Antibiotic resistance by S. aureusis an increasingly frequent find-ing.’ In one study of pediatric im-petigo, 95% of staphylococcalpathogens were resistant to peni-cillin ; 10% were resistant t to

erythromycin.’ In a study of com-munity-acquired, skin-isolated S.

aureus, researchers found erythro-mycin resistance in 51.5% of

strains from furunculosis lesions

and 26.2% of strains from impetigolesions.&dquo; In most studies, erythro-mycin resistance rates range be-tween 5% and 15%. 11-13 However,the clear trend is toward risingrates of resistance. 14-16

Factors in ChoosingType of Therapy

The choice between topical andoral antibiotic therapy depends ona number of factors, but the site ofinfection and the extent of involve-

ment are primary. Topical therapyis appropriate for superficial, local-ized infections.

Infections of deeper skin struc-tures, such as furunculosis, erysipe-las, or cellulitis, require systemictherapy, because topical agentslack the ability to penetrate to theinfection site. Systemic therapy isparticularly important when fever,lymphadenopathy, or concomitant

550

streptococcal pharyngitis is pres-ent. In superficial but widespreadinfections, administering a topicalagent to large areas of the skin maybe impractical. Some authors feelthat infections near the mouth also

may require systemic therapy, sincetopical therapy may be less effec-tive because patients often lick offthe agent. 17

Other factors in the choice of

therapy are the risk of inducingdrug resistance as well as side ef-fects such as allergic contact der-matitis or photosensitization.

Mupirocin: A NewTopical Antibiotic

Mupirocin, formerly called

pseudomonic acid A, is the major

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component of a family of structur-ally related antibiotics produced bysubmerged fermentation of Pseudo-rrconas fluorescens. The mupirocinmolecule comprises a short fatty-acid side chain connected to the restof the molecule (given the trivial

name &dquo;monic acid&dquo;) by a, #-unsatu-rated ester linkage. The structure ofmupirocin is novel and cannot beeasily classified in any known groupof antibiotics. The position of itsweak ultraviolet-light-absorbingchromophobe in the electromag-netic spectrum (222 nm) suggeststhat mupirocin is extremely unlikelyto cause photoreactions in the skin,since that wavelength is filtered outby the ozone layer. Mupirocin is un-stable outside the pH range of 4 to 9,forming inactive products.&dquo; Mupiro-cin ointment (Bactroban, Smith-Kline Beecham), is formulated as 2%mupirocin in a bland, water-miscible,polyethylene-glycol base.19

Mechanism of Action

At low concentrations, mupirocinis bacteriostatic against S aureus andEscherichia coli. At high concentra-tions, mupirocin is bactericidal. Stud-ies of its mode of action against theseorganisms have shown that its pri-mary effect is inhibition of proteinsynthesis.20,21

Only one other antibiotic, furan-omycin, has demonstrated inhibi-tion of bacterial isoleucyl-tRNAsynthetase. However, no clinical usehas been found for furanomycin;therefore, mupirocin may be re-

garded as unique in both its struc-ture and its mechanism of action.22This suggests that mupirocin willnot exhibit cross-resistance with

other antibiotics, and, in fact, cross-resistance has not been demon-strated. Mupirocin has a very lowaffinity for mammalian isoleucyl-tRNA synthetase and appears to

have very low toxicity in humans.

551

Spectrum of Activity

Mupirocin ointment is highlyactive against staphylococci andstreptococci, the major pathogensseen in primary and secondary skininfections (Table 1).~ An excep-tion to the antistreptococcal activ-ity of mupirocin is group D

streptococci.24 Mupirocin is bacte-riostatic at concentrations near the

minimum inhibitory concentra-

tion (MIC) for S. aureus (0.12 to 1mg/¡lL) and bactericidal at theconcentrations found when oint-ment is applied to the skin.

Although mupirocin is less ac-tive against gram-negative organ-isms, it has shown in vitro activityagainst Hemophilus influenzae, Neis-seria gonorrhoeae, Pasteurella multo-cida, Moraxella catarrhalis,24-26 andBordetella pertussis.27

Mupirocin is inactive againstnormal skin flora such as Micrococ-

cus, Corynebacterium, and Propioni-bacterium species. Thus, the skin’snatural defense against infectiondoes not appear to be affected bymupirocin.The antibacterial activity of mupi-

rocin is enhanced at acid pH, 21 whichis important since the pH of the skinis approximately 5.5. The activity ofmupirocin is not significantly af-fected by inoculum size, but be-cause mupirocin is approximately95% protein-bound, it is less activein the presence of serum.2$

Mupirocin Monotherapyfor Impetigo

Mupirocin ointment is ap-proved as monotherapy for impe-tigo. In cases of impetigo for whichtopical therapy may be appropri-ate, mupirocin ointment is as effec-tive as systemic agents, both

clinically and bacteriologically. Inone investigator-blinded study,mupirocin ointment applied three

times daily was found to be clini-cally equivalent to oral erythromy-cin (30-50 mg/kg per day) in 53patients with clinically diagnosedimpetigo and positive cultures of S.aureus, S. pyogenes, or both.29 Mupi-rocin achieved a clinical cure in

93% of patients; erythromycin, in96%. Mupirocin showed superioreradication of S. aureus (88% ver-sus 37%). Half of the S. aureus

isolates were resistant to erythro-mycin, and 89% were resistant topenicillin G and ampicillin; allwere sensitive to mupirocin. Mupi-rocin eradicated more than 90% ofthe antibiotic-resistant strains. The

equivalent therapeutic response oforal erythromycin and topicalmupirocin demonstrates that thesecondary colonization by S. aureuswas far less important than infec-tion by group A streptococci in theoverall pathogenesis of lesions inthat population.

McLinn3° also found mupirocinto be as effective as erythromycinin the treatment of impetigo.Mupirocin therapy was superior toerythromycin in overall efficacyand side effects; the bacteriologicsuccess rate was 100% for both

drugs. While mupirocin caused noadverse effects in 29 patients, fourof the 30 patients treated with

erythromycin reported a total ofsix gastrointestinal side effects.The side effects were severe in

three patients and forced two pa-tients to terminate treatment.

Goldfarb and colleagues3l com-pared mupirocin and erythromy-cin in 62 children with impetigo.The drugs were comparably effec-tive, but mupirocin therapy showeda more rapid clinical effect and pro-duced fewer side effects. Five chil-

dren in the erythromycin groupdeveloped mild diarrhea. No sideeffects of mupirocin were seen.

Barton and colleaguesl7 re-

ported similar results. They foundthe two drugs to be comparable in

efficacy, with some gastrointestinalside effects in the erythromycinportion of a prospective random-ized comparison with mupirocin.They concluded that mupirocinwas a well-tolerated alternative to

erythromycin.A recent double-blind, placebo-

controlled, randomized clinicaltrial has confirmed the efficacy ofmupirocin in the treatment of im-petigo. Britton and colleagues32compared mupirocin ointment

plus oral placebo against oral

erythromycin plus topical placeboin 54 children with impetigo.Mupirocin and placebo ointmentwere applied three times daily; oralerythromycin and placebo weregiven four times daily. The totaldaily dose of erythromycin was 40mg/kg. Six patients (four in themupirocin group and two in theerythromycin group) did not com-plete the study. Three were lost tofollow-up, two stopped therapywhen misdiagnosis was suspectedand fungal therapy was begun, andone was dropped after developingstreptococcal pharyngitis and re-ceiving intramuscular penicillintherapy.

Treatment was successful in

91 % (20/22) of the mupirocin pa-tients and in 92% (24/26) of theerythromycin patients (p = NS) .32The frequency of side effects wasminimal in both groups. All sideeffects of topical mupirocin wereminor, such as transient burning orstinging, and none led to cessationof therapy. The authors concludedthat the two medications were

equally effective in the treatmentof impetigo. However, compliancewas significantly better (85% vs

65%) with the topical regimensthan with the oral regimens (p =.02). Parents of children with mild

impetigo also professed a prefer-ence for topical therapy (64% vs36%; p = 0.76).

In all of these studies, entry cri-

552

teria excluded patients who, in thejudgment of the investigator, hadtoo many lesions to allow reliable

compliance with topical therapy.This, of course, involves clinical

judgment, as does the decision re-garding the presence of systemicsigns such as fever and lymphade-nopathy. If the latter signs are pres-ent, many physicians would usesystemic therapy in combinationwith a topical agent. No studies ex-ist to show that topical therapy is aseffective as systemic antibiotics forpatients with widespread, exten-

sive lesions or for those with signsof systemic disease. A nonclinicalbut nevertheless important consid-eration is the cost of therapy. Riceand colleagues33 investigated thisquestion in a group of 93 patientsbetween the ages of 3 months and

16 years (mean, 4.4 years). Theydetermined that the cost of treat-ment per case of impetigo wasslightly higher with mupirocinthan with erythromycin ($60.70versus $54.35). However, they sug-gested that the greater likelihoodof side effects with erythromycinmight offset the difference in cost.Other differences between the two

groups included the mean numberof school days missed (2.7 witherythromycin, 1.2 with mupirocin)and of parent workdays lost (0.5with erythromycin, 0.2 with mupi-rocin) .33 These differences were

not statistically significant, but fac-tors such as these might be impor-tant to parents should the trendsbe borne out in clinical practice.

Other researchers have com-

pared mupirocin therapy of impe-tigo and therapy with topicalneomycin, 34 topical chlortetracy-cline, 35 ampicillin,36 dicloxacillin,3’cloxacillin,38 and topical fusidic

acid. 39,40 Many of these studies in-cluded small numbers of patients orwere not double-blinded. In gen-eral, however, mupirocin was

clinically and bacteriologically

equivalent to the control agent andwas markedly superior to neomy-cin in these respects. As expected,mupirocin had fewer side effects

than systemic therapy. The sys-temic agents all caused a small but

significant frequency of gastroin-testinal side effects.

Summary

The introduction of mupirocinointment gives the pediatrician areliable topical alternative to oralantibiotic therapy for group A

streptococcal and staphylococcalimpetigo. It is as effective as oralantibiotics and is associated with

fewer adverse effects. In superficialskin infections that are not wide-

spread, mupirocin ointment offersseveral advantages. It is highly ac-tive against the most frequent skinpathogens, even those resistant toother antibiotics, and the topicalroute of administration allows de-

livery of high drug concentrationsto the site of infection.

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