Volume 22 Number 5, Part I May]990
Clinical development of mupirocin
Mupirocin-a novel topical antibiotic. The Royal Society of Medicine, International Congress and SymposiumSeries No. 80, 1984;13-22. 13. Baird D, Coia J. Mupirocin-resistant Staphylococcus aureus, Lancet 1987;2:387-8. 14. Rahman M, Noble WC, Cookson B. Mupirocin-resistant Staphylococcus aureus, Lancet 1987;2:387. IS. Kavi J, Andrews 1M, Wise R. Mupirocin-resistant Staphylococcus aureus, Lancet ]987;2:1472.
16. Smith MD, Sanghrijka M, Lock S. Mupirocin-resistant Staphylococcus aureus, Lancet 1987;2:1472-3. ]7. Overall summary: comparative and non-comparative studies of Bactroban ointment and its vehicle in patients with primary and secondary infections of the skin. Beecham Laboratories, 1984, NDA No. 50-591.
Mupirocin: A new topical antibiotic James J. Leyden, MD Philadelphia, Pennsylvania One hundred fifty-three strains of Staphylococcus aureus recovered from infected eczema frequently demonstrated resistance tomultiple antibiotics. Penicillin andampicillin resistance was extremely frequent (88%),methicillin resistance was found in nearly 14% of strains, and erythromycin and tetracycline resistance was present in 16%. S. aureus strains were uniformly sensitive to vancomycin, mupirocin, and cephalosporins, Experimental infections inhuman volunteers showed topical therapy with 2% mupirocin was moreeffective than oral erythromycin in suppression of both S. aureus and Streptococcus pyogenes. (J AM ACAD DERMATOL
1990;22:879-83.)
Mupirocin, formerly called pseudomonicacid, is the major component of a family of structurally related antibiotics produced by submerged fermentation of Pseudomonas fluorescens. l The microbiology, pharmacology, safety, and results of controlled clinical trials comparing mupirocin with its vehicle and with oral antibiotic therapy have been previously reported and are detailed in other papers presented at this symposiumThe novel mode of action by which this antibiotic inhibits bacterial growth by way of inhibition of isoleucyl transfer-RNA synthetase.' which results in inhibition of protein synthesis," and its effectagainst strains of Staphylococcus aureus that are resistant to multiple antibiotics' suggests that this antibiotic may be of use in the treatment of primary and secondary infections caused by antibiotic-resistant strains of S. aureus. The opportunity for the emergence of strains of S. aureus that are less sensitive and resistant to antibiotics exists in patients whoreFrom Duhring Laboratories, Department of Dermatology, University of Pennsylvania Schoolof Medicine. Reprint requests: James J. Leyden, MD, Duhring Laboratories, Department of Dermatology, University of Pennsylvania School of Medicine, 36th & Hamilton Walk, Philadelphia, PA 19104. 16/0/19725
ceive long-term or frequent courses of antibiotic therapy, particularly patients with chronic inflammatory conditions such as atopic dermatitis. Little informationis availableon the sensitivitypatterns of S. aureus recovered. from patients with chronic eczema. Aly et a1. 6 showed that S. aureus strains found in the lesions of atopic dermatitis are frequently resistant to penicillin and not infrequently resistant to erythromycin. In this study we have determined the antibiotic sensitivity pattern of 153 strains of S. aureus recovered from patients with infected eczematous conditions. Clinical trials comparing topical 2% mupirocin with oral antibiotics previously reported as well as thosereported. in this symposiumhave shown equivalent therapeutic response.U? In this report we describeour findings in experimental infectionstreated with 2% mupirocin and oral erythromycin, MATERIAL AND METHODS Antibiotic sensitivity
One hundred fifty-three unselected. strains of S.
aureus recovered from patients with chronic inflammatory disorders (primarily atopic dermatitis) were studied. Cultures were obtained from patients who
879
Journal of the American Academy of Derma lology
880 Leyden
Table 1. Disk content, zone of inhibition, and minimal inhibitory concentration of antibiotics Zone of inhibition (mm) Antimicrobial agent
Disk content (JLg)
Penicillin Ampicillin Methicillin Oxacillin Cephalothin Cefoxitin Gentamicin Neomycin Erythromycin Clindamycin Tetracycline Minocycline Chloramphenicol Vancomycin
10 10 5 I
30 30 IO 30 15 2
30 30 30 30
Resistant
28 28 9 10 14 14 12 12
13 14 14 14 12 9
J
Susceptible
I :
>29 >29 >14 >13 >18 >18 >15 >17 >18 >17 >19 >19 >18 >12
Equivalent MIC (JLg/ml)
0.1 0.25 3 I 8
8 4 2 1 4 4 12.5 5
Antibiotic sensitivity was determined by zones of inhibition on Mueller-Hinton II agar. American-type culture center S. aureus strain No. 2593 with defined sensitivity levels served as a reference control. MIC, Minimal inhibitory concentration.
were participants in a multicenter clinical trial comparing 2% mupirocin to its vehicle in the treatment of infected eczema. The centers included patients in Philadelphia, Cincinnati, and Denver. Swabs of purulent exudate were transported to Duhring Laboratories of the University of Pennsylvania and subcultured by first streaking on blood agar and mannitol salt agars. Organisms were then subcultivated onto blood agar, hemolysis and colonial morphologic findings were recorded, and coagulase testing and Gram stain were performed to confirm S. aureus identification. Antibiotic sensitivity was determined by the Bauer-Kirby technique. Fresh cultures were streaked onto Mueller-Hinton II agar (Baltimore Biological Laboratories, Baltimore, Md.) for testing to erythromycin, c1indamycin, tetracycline, minocycline, gentamicin, neomycin, chloramphenicol, and vancomycin; cultures were streaked onto MuelierHinton agar with 4% NaCI for penicillin, ampicillin, oxacillin, methicillin, cephalothin, and cefoxitin. The procedures we used are described in the third edition of "Performance Standards for Antimicrobial Disk Susceptibility Tests" of the American N ational Standards Institute. The details of the disk content of antibiotics, zones of inhibition for resistant and sensitive determination, and the correlation with minimum inhibitory concentration determinations in broth are found in Table L Controls con-
sisted of American-type culture center S. aureus strain No. 25923, which has known sensitivity patterns to the antibiotics used in this study. Minimum inhibitory concentration of S. aureus to mupirocin were determined in fresh l8-hour trypticase soy broth cultures, which were streaked onto Mueller-Hinton plates into which mupirocin had been incorporated in half-step dilutions to give concentrations of 100,50,25,12.5,6.25,3.125,1.56, 0.78,0.39, and 0.19 ,ug/ml. Experimental infections Twenty healthy subjects who gave informed consent participated in a crossover study. Superficial infections with S. aureus and Streptococcus pyogenes can be safely produced in human volunteers. Infections with S. aureus are produced by first inducing intraepidermal blisters by applying 50% ammonium hydroxide according to the method of Frosch and Kligman. 13 Twenty-four hours after removal of the blister roof, sites were inoculated with a fresh overnight suspension of S. aureus (10 5 organisms/rnl). The strain of S. aureus is one that has been maintained in our laboratory for many years, is susceptible to multiple antibiotics, and produces localized infections that are self-limited.l" After inoculation of the blister site, an occlusive dressing was applied for 24 hours. In the case of S. pyogenes, superficial scarification wounds were in-
Volume 22
Number 5, Part I May]990
Mupirocin: A new topical antibiotic 881
Table II. Antibiotic sensitivity of S. aureus in infected eczema
Table III. Comparison of rnupirocin and oral erythromycin in experimental infection in humans S . aureus"
Intermediate Antibiotic
Penicillin Ampicillin Methicillin Oxacillin Cephalothin Cefoxitin Gentamicin Neomycin Erythromycin Clindamycin Tetracycline Minocycline Chloramphenicol Vancomycin Mupirocin
S. pyogenes
(%)
11.2 11.2
88.8 88.8
84.3
13.7
86.3 100
13.7
100 97.3 94.7 83.0 94.2 74 .5 95.4 94.7
100 100
2
o o
1.3 1.9 16.4
o a
2.27 ± 1.06 4.97 ± 1.07 6.05 ± 0.40 5.80 ± 0.49
0.84 3.40 5.07 4.59
± ± ± ±
1.11 1.43 0.57 0.59
"Logarithm base 10 per cm 24 hours after treatment.
1.3 0.6
5.8 15.6 3.9 4.4
Mupirocin Vehicle Untreated control Erythromycin
9.8 9.8 0.6
Mupirocin minimal inhibitory concentration 0.34 !lg/ml-D.13 (range , 0.0625 to 0.5 pg /ml) .
oculated with a fresh overnight suspension of S. pyogenes (105/ml) according to the method of Leyden et al. I5Occlusive dressingswere then appliedfor 24 hours. Each subject had S. aureus infections induced on one forearm and S. pyogenes infections on the other forearm, and subjects were randomly assigned to one of two groups. One group received topical treatment three times daily with 2% mupirocin, its vehicle,or an untreated control site, whereas the other group was treated with 1 gm of oral erythromycin per day. Treatment was for 5 days, and quantitativecultures wereobtainedwith0.1%Tween 80 after 24 hours and 5 days of treatment. Cultures from antibiotic-treated siteswereobtained nosooner than 16 hours after the last treatment to minimize the opportunity for carryover of the test agent into the culture fluid. Carryover was also monitored by drop plating an aliquot of the culture fluid onto a lawn plate of a strain of Staphylococcus epidermidis that was sensitive to mupirocin. After a 2-week washout period, subjects were crossed over into the other treatment schedule.
RESULTS Antibiotic sensitivity of S. aureus in infected eczema The results are summarized in Table II. Penicillin and ampicillin resistance was high (89%). Resis-
Table IV. Comparison of mupirocin and oral erythromycin in experimental infection in humans
Mupirocin Vehicle Untreated control Erythromycin
S . aureus*
S.pyogenes
0.32 ± 0.66 2.47 ± 2.23 4.25 ± 2.01 3.92 ± 1.88
No growth No growth No growth No growth
"Logarithm base 10 per em 5 days after treatment.
tance to oxacillin/methicillin occurred in 14%, whereas erythromycin resistance was found in 16% and tetracycline resistance in I 5%. No strains were resistant to first- and second-generation cephalosporins, vancomycin, and mupirocin. S. aureus sensitivity to mupirocin ranged from 0.0625 to 0.5 p.g/ ml, with a mean of 0.34 J1-g/ml. Experimental infections The results are summarized in Tables III and IV. Topical treatment with mupirocin resulted in approximately a 4-10garithm reduction of S. aureus compared with untreated sites, whereas vehicletreated sites showed a l-Iogarithrn reduction 24 hours after three applications. The reduction in both S. aureus with mupirocin and its vehicle was statistically significant when compared with untreated control sites (Student t test, p < 0.00 I). S. aureus persisted after 5 days at untreated sites and sites treated with the vehicle, whereas mupirocin-treated sites showed very [ow numbers of S. aureus (p < 0.001). All S. pyogenes-infected sites showed no growth 5 days after treatment. Because control sites also showed no growth, comparison between treatments could not be done. However, differences in the recovery of S. pyogenes were seen at the 24-hour culture time. Mupirocin-treated sites showed a 4-
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Journal of the A merica n Academy of Dermalology
Leyden
logarithm reduction compared with untreated sites (p < 0.001, Student t test). Treatment for 24 hours with oral erythromycin resulted in a logarithm base 10 mean of 5.8 for S. aureus and 4.6 for S. pyogenes; both were significantly higher than the mean values of2.27 and 0.84 for S. aureus and S. pyogenes sites treated with topical mupirocin. After 5 days of treatment with oral erythromycin, there was a mean of 3.92 S. aureus organisms, significantly higher than the 0.32 for sites treated with mupirocin (p < 0.001, Student t test). DISCUSSION
In this study we found that strains of S. aureus recovered from infected eczema arc frequently resistant to antibiotics that may be used in the management of these patients. Resistance to penicillin and ampicillin was extremely high (89Cro) and would seem high enough to preclude their use. The finding that 14% of strains are resistant to methicillin is of particular importance. The emergence of resistance to penicillinase-resistant antibiotics, commonly referred to as methicillin-resistant S. aureus, has become a major problem in hospitalized patients. The findings of methicillin resistance in nonhospitalized patients and the possibility of dissemination of these strains throughout so-called "open" communities are potential public health hazards." Furthermore, the implications for choosing an antibiotic for the treatment of infected eczema are significant. Erythromycin resistance was found in 16% of strains. In view of the frequent use of erythromycin in dermato logic patients, this level of resistance should be considered when an antibiotic is selected for treating a patient with infected eczema. Likewise, tetracycline resistance was found in 15% of strains. S. aureus resistance to minocyc1ine was significantly less frequent and has been attributed to a greater penetration of bacterial cell walls by minocyc1ine. No resistance was found to vancom ycin, the current drug of choice for methicillin-resistant S. aureus infections. Likewise, no resistance was seen to a firstgeneration (cephalothin) or a second-generation cephalosporin (cefoxitin). The use of a cephalosporin to treat an infection caused by a methicillinresistant S. aureus is risky. Numerous examples exist of clinical failure when cephalosporins have been used to treat an infection caused by methicillin-resistant S. aureus.il- 18 None of our strains were resistant to mupirocin, and all had minimum inhibitory concentration levels that indicate exquisite sensitivity. However, low-levelresistance to rnupiro-
cin has been seen in patients receiving long-term treatment and is not surprising. The strains of S. aureus that are less sensitiveto mupirocin after several years of long-term use in patients with epidermolysis bullosa reported by Dr. Carter in this symposium highlight a basic principle of antibiotic therapy, specifically, long-term use of an antibiotic exerts an ecologic pressure that can select or induce resistance. When feasible, intermittent use of antibiotic is desirable. The exquisite sensitivity to mupirocin in a strain of S. aureus recovered from infected eczema suggests that brief courses of therapy may be sufficient to eradicate this organism and thus minimize the risk for selection of less sensitive strains. Our study that compared oral erythromycin with topical mupirocin in the treatment of standardized, localized infections showed that mupirocin was more effectivethan oral erythromycin in suppressing S. aureus 24 hours and 5 days after the initiation of treatment. At both time points, the vehicle for mupirocin was equivalent to erythromycin. These results are due to the antibacterial properties of the polyethylene glycols in the vehicle of mupirocin. In the case of S. pyogenes, topical mupirocin was superior to oral erythromycin after 24 hours of therapy. By day 5, the host response was sufficient that S. pyogenes was no longer recovered from control sites, and no comparison between treatments was possible at that time point. These studies substantiate the results of other clinical studies indicating that treatment of impetigo with 2% mupirocin results in improvement equivalent to that seen with oral antibiotics.l'? REFERENCES I . Cha in EB, Mellows G. Structure of pseudomonic acid, an antibiotic from Pseudomonas fiuorescens . J Chem Soc Chern Commun 1974:847-8. 2. Leyden JJ . M upirocin: a new topical antibiotic. Semin DermatoJ 1987;1:48-54. 3. Hughes J, Mellows G. Inhibition of isoleucyl-transfer ribonucleic acid synthetase in Escherichia coli by pseudomonic acid. Biochem J 1978;176:305-18. 4. Hughes J, MellowsG. On the mode of action of pscudornonic acid: inhibition of protein synthesis in Staphylococcus aureus. J Antibiot (Tokyo) 1978;31:330-5. 5. While AR, Beale AS, Boon RJ, et al. Antibacterial activity of mupirocin. In: Dobson RL, Leyden JJ, Nobel WC, eds. Bactroban. Amsterdam: Excerpta Medica, 1985. 6. Aly R, Maibach HI, Shinefeld HR. Microbial flora of atopic dermatitis. Arch Derrnatol 1977;113:780-2. 7. Welsh 0, Saenz C. Topical mupirocin compared with oral a mpicillin in the treatment of primary and secondary skin infections. Curr Ther Res 1987;42:114-20. 8. Villiger JW, et al. A comparison of the new topical antibiotic mupirocin ('Bactroban ') with oral antibiotics in the
Volume 22 Number 5, Part 1 May 1990
treatment of skin infections in general practice. Curr Med Res Opin 1986;10:339-45. 9. Dux PH, Fields L, Pollock D. 2% topical mupirocin versus systemic erythromycin and cloxacillin in primary and secondary skin infections. Curr Ther Res 1986;40:933-40, 10. Arredondo JL. Efficacy and toleranceof topicalmupirocin compared with oral dicloxacillin in the treatment of primary skin infections. Curr Ther Res 1987;41:121-7. 11. Guertin-Larochelle S. Efficacy and tolerance of topical Bactroban (2% mupirocin) vs, systemic cloxacillin in the treatment of primary and secondary skin infections. Today's Therapeutic Trends 1986;4:1-14. 12. Maddin S, et at. Bactroban: efficacy and tolerance of a novel, new topical antibiotic vs conventional systemic and topical treatment of primary and secondaryskin infections. Contemp Dermatol 1987;(.June-July):32-9. 13. Frosch P, Kligman AM. Rapid blister formation in human skin with ammonium hydroxide. Br J Dermatol 1977; 96:461-73.
Mupirocin: A new topical antibiotic 14. Leyden JJ, Bartell N. Comparison of topical antibiotic ointments, a wound protectant and antiseptics for the treatment of human blister wounds contaminated with Staphylococcus aureus. Fam Pract J 1987;6:601-4. 15. Leyden JJ, Stewart R, Kligman AM. Experimental infections in human volunteers with group A streptococci. J Invest DermatoI1980;75:196-201. 16. Barrett FF, McGehee RF, Findland M. Methicillin-resistant Staphylococcus aureus at Boston City Hospital: bacteriologic and epidemiologicobservations. N Engl J Med 1968;279:441-8. 17. Myers JP, Linnemann CC. Bacteremia due to methicillinresistant Staphylococcus aureus. J Infect Dis 1982;145: 532-6. 18. Richmond AS, Simberkoff MS, Schaefler S, Rabal n. Resistance of Staphylococcus aureus to semisynthetic penicillin and cephalothin. J Infect Dis 1977;135:108-12.
A bacteriologically controlled, randomized study comparing the efficacy of 2% mupirocin ointment (Bactroban) with oral erythromycin in the treatment of patients with impetigo Samuel McLinn, MD Scottsdale, Arizona Sixty patientsparticipatedin a bacteriologically controlled, randomized, parallelgroup comparisonof 2% mupirocin ointment(Bactroban) and oral erythromycin ethylsuccinatefor the treatment of impetigo. The trial included clinical and bacteriologic evaluations and safety assessments. The Investigator's Global Evaluation, which compared the overall efficacy and safety of the trial drugs,demonstrated a morefavorable performancefor the mupirocin regimen. This difference was statistically and clinically significant. There were no significant differences between the trial regimens for any of the other efficacy variables examined. The bacteriologic success rate was 100% for both treatment groups.There was a clinically significant difference in adverse experience ratesbetween treatment groups, with four (13%)of the erythromycin-treated patientsreporting sixadverse experiences versus none of the mupirocin-treated patients. The results of the trial indicatethat 2% mupirocin ointment is as safe and effective as oralerythromycin cthylsuccinate in the treatment of patients with impetigo. (J AM ACAD DERMATOl 1990;22:883-5.)
MATERIAL AND METHODS
Sixty patients participated in a bacteriologically controlled, randomized, open-label, parallel group From Scottsdale Pediatrics. Reprint requests: Samuel McLinn, MD, Scottsdale Pediatrics, 733\ E. Osborn, Scottsdale, AZ 85251, 16/0/19726
comparison of 2% mupirocin ointment (Bactroban) and oral erythromycin ethylsuccinate for the treatment of impetigo. Persons eligible for the trial were of either sex and 6 months of age or older. Patients with staphylococcal or streptococcal pyoderma, localized bullous impetigo, or Bockhart's impetigo
883
Clinical development of mupirocin
Mupirocin-a novel topical antibiotic. The Royal Society of Medicine, International Congress and SymposiumSeries No. 80, 1984;13-22. 13. Baird D, Coia J. Mupirocin-resistant Staphylococcus aureus, Lancet 1987;2:387-8. 14. Rahman M, Noble WC, Cookson B. Mupirocin-resistant Staphylococcus aureus, Lancet 1987;2:387. IS. Kavi J, Andrews 1M, Wise R. Mupirocin-resistant Staphylococcus aureus, Lancet ]987;2:1472.
16. Smith MD, Sanghrijka M, Lock S. Mupirocin-resistant Staphylococcus aureus, Lancet 1987;2:1472-3. ]7. Overall summary: comparative and non-comparative studies of Bactroban ointment and its vehicle in patients with primary and secondary infections of the skin. Beecham Laboratories, 1984, NDA No. 50-591.
Mupirocin: A new topical antibiotic James J. Leyden, MD Philadelphia, Pennsylvania One hundred fifty-three strains of Staphylococcus aureus recovered from infected eczema frequently demonstrated resistance tomultiple antibiotics. Penicillin andampicillin resistance was extremely frequent (88%),methicillin resistance was found in nearly 14% of strains, and erythromycin and tetracycline resistance was present in 16%. S. aureus strains were uniformly sensitive to vancomycin, mupirocin, and cephalosporins, Experimental infections inhuman volunteers showed topical therapy with 2% mupirocin was moreeffective than oral erythromycin in suppression of both S. aureus and Streptococcus pyogenes. (J AM ACAD DERMATOL
1990;22:879-83.)
Mupirocin, formerly called pseudomonicacid, is the major component of a family of structurally related antibiotics produced by submerged fermentation of Pseudomonas fluorescens. l The microbiology, pharmacology, safety, and results of controlled clinical trials comparing mupirocin with its vehicle and with oral antibiotic therapy have been previously reported and are detailed in other papers presented at this symposiumThe novel mode of action by which this antibiotic inhibits bacterial growth by way of inhibition of isoleucyl transfer-RNA synthetase.' which results in inhibition of protein synthesis," and its effectagainst strains of Staphylococcus aureus that are resistant to multiple antibiotics' suggests that this antibiotic may be of use in the treatment of primary and secondary infections caused by antibiotic-resistant strains of S. aureus. The opportunity for the emergence of strains of S. aureus that are less sensitive and resistant to antibiotics exists in patients whoreFrom Duhring Laboratories, Department of Dermatology, University of Pennsylvania Schoolof Medicine. Reprint requests: James J. Leyden, MD, Duhring Laboratories, Department of Dermatology, University of Pennsylvania School of Medicine, 36th & Hamilton Walk, Philadelphia, PA 19104. 16/0/19725
ceive long-term or frequent courses of antibiotic therapy, particularly patients with chronic inflammatory conditions such as atopic dermatitis. Little informationis availableon the sensitivitypatterns of S. aureus recovered. from patients with chronic eczema. Aly et a1. 6 showed that S. aureus strains found in the lesions of atopic dermatitis are frequently resistant to penicillin and not infrequently resistant to erythromycin. In this study we have determined the antibiotic sensitivity pattern of 153 strains of S. aureus recovered from patients with infected eczematous conditions. Clinical trials comparing topical 2% mupirocin with oral antibiotics previously reported as well as thosereported. in this symposiumhave shown equivalent therapeutic response.U? In this report we describeour findings in experimental infectionstreated with 2% mupirocin and oral erythromycin, MATERIAL AND METHODS Antibiotic sensitivity
One hundred fifty-three unselected. strains of S.
aureus recovered from patients with chronic inflammatory disorders (primarily atopic dermatitis) were studied. Cultures were obtained from patients who
879
Journal of the American Academy of Derma lology
880 Leyden
Table 1. Disk content, zone of inhibition, and minimal inhibitory concentration of antibiotics Zone of inhibition (mm) Antimicrobial agent
Disk content (JLg)
Penicillin Ampicillin Methicillin Oxacillin Cephalothin Cefoxitin Gentamicin Neomycin Erythromycin Clindamycin Tetracycline Minocycline Chloramphenicol Vancomycin
10 10 5 I
30 30 IO 30 15 2
30 30 30 30
Resistant
28 28 9 10 14 14 12 12
13 14 14 14 12 9
J
Susceptible
I :
>29 >29 >14 >13 >18 >18 >15 >17 >18 >17 >19 >19 >18 >12
Equivalent MIC (JLg/ml)
0.1 0.25 3 I 8
8 4 2 1 4 4 12.5 5
Antibiotic sensitivity was determined by zones of inhibition on Mueller-Hinton II agar. American-type culture center S. aureus strain No. 2593 with defined sensitivity levels served as a reference control. MIC, Minimal inhibitory concentration.
were participants in a multicenter clinical trial comparing 2% mupirocin to its vehicle in the treatment of infected eczema. The centers included patients in Philadelphia, Cincinnati, and Denver. Swabs of purulent exudate were transported to Duhring Laboratories of the University of Pennsylvania and subcultured by first streaking on blood agar and mannitol salt agars. Organisms were then subcultivated onto blood agar, hemolysis and colonial morphologic findings were recorded, and coagulase testing and Gram stain were performed to confirm S. aureus identification. Antibiotic sensitivity was determined by the Bauer-Kirby technique. Fresh cultures were streaked onto Mueller-Hinton II agar (Baltimore Biological Laboratories, Baltimore, Md.) for testing to erythromycin, c1indamycin, tetracycline, minocycline, gentamicin, neomycin, chloramphenicol, and vancomycin; cultures were streaked onto MuelierHinton agar with 4% NaCI for penicillin, ampicillin, oxacillin, methicillin, cephalothin, and cefoxitin. The procedures we used are described in the third edition of "Performance Standards for Antimicrobial Disk Susceptibility Tests" of the American N ational Standards Institute. The details of the disk content of antibiotics, zones of inhibition for resistant and sensitive determination, and the correlation with minimum inhibitory concentration determinations in broth are found in Table L Controls con-
sisted of American-type culture center S. aureus strain No. 25923, which has known sensitivity patterns to the antibiotics used in this study. Minimum inhibitory concentration of S. aureus to mupirocin were determined in fresh l8-hour trypticase soy broth cultures, which were streaked onto Mueller-Hinton plates into which mupirocin had been incorporated in half-step dilutions to give concentrations of 100,50,25,12.5,6.25,3.125,1.56, 0.78,0.39, and 0.19 ,ug/ml. Experimental infections Twenty healthy subjects who gave informed consent participated in a crossover study. Superficial infections with S. aureus and Streptococcus pyogenes can be safely produced in human volunteers. Infections with S. aureus are produced by first inducing intraepidermal blisters by applying 50% ammonium hydroxide according to the method of Frosch and Kligman. 13 Twenty-four hours after removal of the blister roof, sites were inoculated with a fresh overnight suspension of S. aureus (10 5 organisms/rnl). The strain of S. aureus is one that has been maintained in our laboratory for many years, is susceptible to multiple antibiotics, and produces localized infections that are self-limited.l" After inoculation of the blister site, an occlusive dressing was applied for 24 hours. In the case of S. pyogenes, superficial scarification wounds were in-
Volume 22
Number 5, Part I May]990
Mupirocin: A new topical antibiotic 881
Table II. Antibiotic sensitivity of S. aureus in infected eczema
Table III. Comparison of rnupirocin and oral erythromycin in experimental infection in humans S . aureus"
Intermediate Antibiotic
Penicillin Ampicillin Methicillin Oxacillin Cephalothin Cefoxitin Gentamicin Neomycin Erythromycin Clindamycin Tetracycline Minocycline Chloramphenicol Vancomycin Mupirocin
S. pyogenes
(%)
11.2 11.2
88.8 88.8
84.3
13.7
86.3 100
13.7
100 97.3 94.7 83.0 94.2 74 .5 95.4 94.7
100 100
2
o o
1.3 1.9 16.4
o a
2.27 ± 1.06 4.97 ± 1.07 6.05 ± 0.40 5.80 ± 0.49
0.84 3.40 5.07 4.59
± ± ± ±
1.11 1.43 0.57 0.59
"Logarithm base 10 per cm 24 hours after treatment.
1.3 0.6
5.8 15.6 3.9 4.4
Mupirocin Vehicle Untreated control Erythromycin
9.8 9.8 0.6
Mupirocin minimal inhibitory concentration 0.34 !lg/ml-D.13 (range , 0.0625 to 0.5 pg /ml) .
oculated with a fresh overnight suspension of S. pyogenes (105/ml) according to the method of Leyden et al. I5Occlusive dressingswere then appliedfor 24 hours. Each subject had S. aureus infections induced on one forearm and S. pyogenes infections on the other forearm, and subjects were randomly assigned to one of two groups. One group received topical treatment three times daily with 2% mupirocin, its vehicle,or an untreated control site, whereas the other group was treated with 1 gm of oral erythromycin per day. Treatment was for 5 days, and quantitativecultures wereobtainedwith0.1%Tween 80 after 24 hours and 5 days of treatment. Cultures from antibiotic-treated siteswereobtained nosooner than 16 hours after the last treatment to minimize the opportunity for carryover of the test agent into the culture fluid. Carryover was also monitored by drop plating an aliquot of the culture fluid onto a lawn plate of a strain of Staphylococcus epidermidis that was sensitive to mupirocin. After a 2-week washout period, subjects were crossed over into the other treatment schedule.
RESULTS Antibiotic sensitivity of S. aureus in infected eczema The results are summarized in Table II. Penicillin and ampicillin resistance was high (89%). Resis-
Table IV. Comparison of mupirocin and oral erythromycin in experimental infection in humans
Mupirocin Vehicle Untreated control Erythromycin
S . aureus*
S.pyogenes
0.32 ± 0.66 2.47 ± 2.23 4.25 ± 2.01 3.92 ± 1.88
No growth No growth No growth No growth
"Logarithm base 10 per em 5 days after treatment.
tance to oxacillin/methicillin occurred in 14%, whereas erythromycin resistance was found in 16% and tetracycline resistance in I 5%. No strains were resistant to first- and second-generation cephalosporins, vancomycin, and mupirocin. S. aureus sensitivity to mupirocin ranged from 0.0625 to 0.5 p.g/ ml, with a mean of 0.34 J1-g/ml. Experimental infections The results are summarized in Tables III and IV. Topical treatment with mupirocin resulted in approximately a 4-10garithm reduction of S. aureus compared with untreated sites, whereas vehicletreated sites showed a l-Iogarithrn reduction 24 hours after three applications. The reduction in both S. aureus with mupirocin and its vehicle was statistically significant when compared with untreated control sites (Student t test, p < 0.00 I). S. aureus persisted after 5 days at untreated sites and sites treated with the vehicle, whereas mupirocin-treated sites showed very [ow numbers of S. aureus (p < 0.001). All S. pyogenes-infected sites showed no growth 5 days after treatment. Because control sites also showed no growth, comparison between treatments could not be done. However, differences in the recovery of S. pyogenes were seen at the 24-hour culture time. Mupirocin-treated sites showed a 4-
882
Journal of the A merica n Academy of Dermalology
Leyden
logarithm reduction compared with untreated sites (p < 0.001, Student t test). Treatment for 24 hours with oral erythromycin resulted in a logarithm base 10 mean of 5.8 for S. aureus and 4.6 for S. pyogenes; both were significantly higher than the mean values of2.27 and 0.84 for S. aureus and S. pyogenes sites treated with topical mupirocin. After 5 days of treatment with oral erythromycin, there was a mean of 3.92 S. aureus organisms, significantly higher than the 0.32 for sites treated with mupirocin (p < 0.001, Student t test). DISCUSSION
In this study we found that strains of S. aureus recovered from infected eczema arc frequently resistant to antibiotics that may be used in the management of these patients. Resistance to penicillin and ampicillin was extremely high (89Cro) and would seem high enough to preclude their use. The finding that 14% of strains are resistant to methicillin is of particular importance. The emergence of resistance to penicillinase-resistant antibiotics, commonly referred to as methicillin-resistant S. aureus, has become a major problem in hospitalized patients. The findings of methicillin resistance in nonhospitalized patients and the possibility of dissemination of these strains throughout so-called "open" communities are potential public health hazards." Furthermore, the implications for choosing an antibiotic for the treatment of infected eczema are significant. Erythromycin resistance was found in 16% of strains. In view of the frequent use of erythromycin in dermato logic patients, this level of resistance should be considered when an antibiotic is selected for treating a patient with infected eczema. Likewise, tetracycline resistance was found in 15% of strains. S. aureus resistance to minocyc1ine was significantly less frequent and has been attributed to a greater penetration of bacterial cell walls by minocyc1ine. No resistance was found to vancom ycin, the current drug of choice for methicillin-resistant S. aureus infections. Likewise, no resistance was seen to a firstgeneration (cephalothin) or a second-generation cephalosporin (cefoxitin). The use of a cephalosporin to treat an infection caused by a methicillinresistant S. aureus is risky. Numerous examples exist of clinical failure when cephalosporins have been used to treat an infection caused by methicillin-resistant S. aureus.il- 18 None of our strains were resistant to mupirocin, and all had minimum inhibitory concentration levels that indicate exquisite sensitivity. However, low-levelresistance to rnupiro-
cin has been seen in patients receiving long-term treatment and is not surprising. The strains of S. aureus that are less sensitiveto mupirocin after several years of long-term use in patients with epidermolysis bullosa reported by Dr. Carter in this symposium highlight a basic principle of antibiotic therapy, specifically, long-term use of an antibiotic exerts an ecologic pressure that can select or induce resistance. When feasible, intermittent use of antibiotic is desirable. The exquisite sensitivity to mupirocin in a strain of S. aureus recovered from infected eczema suggests that brief courses of therapy may be sufficient to eradicate this organism and thus minimize the risk for selection of less sensitive strains. Our study that compared oral erythromycin with topical mupirocin in the treatment of standardized, localized infections showed that mupirocin was more effectivethan oral erythromycin in suppressing S. aureus 24 hours and 5 days after the initiation of treatment. At both time points, the vehicle for mupirocin was equivalent to erythromycin. These results are due to the antibacterial properties of the polyethylene glycols in the vehicle of mupirocin. In the case of S. pyogenes, topical mupirocin was superior to oral erythromycin after 24 hours of therapy. By day 5, the host response was sufficient that S. pyogenes was no longer recovered from control sites, and no comparison between treatments was possible at that time point. These studies substantiate the results of other clinical studies indicating that treatment of impetigo with 2% mupirocin results in improvement equivalent to that seen with oral antibiotics.l'? REFERENCES I . Cha in EB, Mellows G. Structure of pseudomonic acid, an antibiotic from Pseudomonas fiuorescens . J Chem Soc Chern Commun 1974:847-8. 2. Leyden JJ . M upirocin: a new topical antibiotic. Semin DermatoJ 1987;1:48-54. 3. Hughes J, Mellows G. Inhibition of isoleucyl-transfer ribonucleic acid synthetase in Escherichia coli by pseudomonic acid. Biochem J 1978;176:305-18. 4. Hughes J, MellowsG. On the mode of action of pscudornonic acid: inhibition of protein synthesis in Staphylococcus aureus. J Antibiot (Tokyo) 1978;31:330-5. 5. While AR, Beale AS, Boon RJ, et al. Antibacterial activity of mupirocin. In: Dobson RL, Leyden JJ, Nobel WC, eds. Bactroban. Amsterdam: Excerpta Medica, 1985. 6. Aly R, Maibach HI, Shinefeld HR. Microbial flora of atopic dermatitis. Arch Derrnatol 1977;113:780-2. 7. Welsh 0, Saenz C. Topical mupirocin compared with oral a mpicillin in the treatment of primary and secondary skin infections. Curr Ther Res 1987;42:114-20. 8. Villiger JW, et al. A comparison of the new topical antibiotic mupirocin ('Bactroban ') with oral antibiotics in the
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treatment of skin infections in general practice. Curr Med Res Opin 1986;10:339-45. 9. Dux PH, Fields L, Pollock D. 2% topical mupirocin versus systemic erythromycin and cloxacillin in primary and secondary skin infections. Curr Ther Res 1986;40:933-40, 10. Arredondo JL. Efficacy and toleranceof topicalmupirocin compared with oral dicloxacillin in the treatment of primary skin infections. Curr Ther Res 1987;41:121-7. 11. Guertin-Larochelle S. Efficacy and tolerance of topical Bactroban (2% mupirocin) vs, systemic cloxacillin in the treatment of primary and secondary skin infections. Today's Therapeutic Trends 1986;4:1-14. 12. Maddin S, et at. Bactroban: efficacy and tolerance of a novel, new topical antibiotic vs conventional systemic and topical treatment of primary and secondaryskin infections. Contemp Dermatol 1987;(.June-July):32-9. 13. Frosch P, Kligman AM. Rapid blister formation in human skin with ammonium hydroxide. Br J Dermatol 1977; 96:461-73.
Mupirocin: A new topical antibiotic 14. Leyden JJ, Bartell N. Comparison of topical antibiotic ointments, a wound protectant and antiseptics for the treatment of human blister wounds contaminated with Staphylococcus aureus. Fam Pract J 1987;6:601-4. 15. Leyden JJ, Stewart R, Kligman AM. Experimental infections in human volunteers with group A streptococci. J Invest DermatoI1980;75:196-201. 16. Barrett FF, McGehee RF, Findland M. Methicillin-resistant Staphylococcus aureus at Boston City Hospital: bacteriologic and epidemiologicobservations. N Engl J Med 1968;279:441-8. 17. Myers JP, Linnemann CC. Bacteremia due to methicillinresistant Staphylococcus aureus. J Infect Dis 1982;145: 532-6. 18. Richmond AS, Simberkoff MS, Schaefler S, Rabal n. Resistance of Staphylococcus aureus to semisynthetic penicillin and cephalothin. J Infect Dis 1977;135:108-12.
A bacteriologically controlled, randomized study comparing the efficacy of 2% mupirocin ointment (Bactroban) with oral erythromycin in the treatment of patients with impetigo Samuel McLinn, MD Scottsdale, Arizona Sixty patientsparticipatedin a bacteriologically controlled, randomized, parallelgroup comparisonof 2% mupirocin ointment(Bactroban) and oral erythromycin ethylsuccinatefor the treatment of impetigo. The trial included clinical and bacteriologic evaluations and safety assessments. The Investigator's Global Evaluation, which compared the overall efficacy and safety of the trial drugs,demonstrated a morefavorable performancefor the mupirocin regimen. This difference was statistically and clinically significant. There were no significant differences between the trial regimens for any of the other efficacy variables examined. The bacteriologic success rate was 100% for both treatment groups.There was a clinically significant difference in adverse experience ratesbetween treatment groups, with four (13%)of the erythromycin-treated patientsreporting sixadverse experiences versus none of the mupirocin-treated patients. The results of the trial indicatethat 2% mupirocin ointment is as safe and effective as oralerythromycin cthylsuccinate in the treatment of patients with impetigo. (J AM ACAD DERMATOl 1990;22:883-5.)
MATERIAL AND METHODS
Sixty patients participated in a bacteriologically controlled, randomized, open-label, parallel group From Scottsdale Pediatrics. Reprint requests: Samuel McLinn, MD, Scottsdale Pediatrics, 733\ E. Osborn, Scottsdale, AZ 85251, 16/0/19726
comparison of 2% mupirocin ointment (Bactroban) and oral erythromycin ethylsuccinate for the treatment of impetigo. Persons eligible for the trial were of either sex and 6 months of age or older. Patients with staphylococcal or streptococcal pyoderma, localized bullous impetigo, or Bockhart's impetigo
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