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Mupirocin treatment of exudative venous ulcers
Journal of the American Academy of Dermatology Volume 29, Number 3
dramine without a specific provocation test; other ingredients of these proprietary remedies may also cause a fixed drug eruption. I I, 12 REFERENCES I. BrowneSQ. Fixed eruption in deeply pigmented subjects: clinical observations on 350 patients. Br Med J 1964; 2:1041-4. 2. Savin JA. Current causes of fixed drug eruptions. Br J Dermatol 1970;83:546-9. 3. Sehgal VN. Causes of fixed drug eruptions. Dermatologica 1974;148: 120-3. 4. Pasricha JS. Drugs causing fixed eruptions. Br J Dermatol 1979;100:183-5. 5. Shukla SR. Drugs causing fixed drug eruptions. Derrnatologica 1981;163:160-3.
Brief communications 497 6. Korkij W, Soltani K. Fixed drug eruption: a brief review. Arch Dermatol 1984;120:520-4. 7. Kauppinen K, Stubb S. Fixed eruptions: causative drugs and challenge tests. Br J Dermatol 1985;112:575-8. 8. Kanwar AJ, Bharija SC, Singh M, et al. Ninety-eight fixed drug eruptions with provocation tests. Dermatologica 1988;177:274-9. 9. Stubb S, A1anko K, Reitamo S. Fixed drug eruptions: 77 cases from 198[ to 1985. Br J Dermatol 1989;120:583. 10. Hogan DJ, Rooney ME. Fixed drug eruption due to dimenhydrinate. J AM ACAD DERMATOL 1989;20:503-4. 11. Stritzler C, Kopf A W. Fixed drug eruption caused by 8-chlorotheophylline in Dramamine with clinical and histologic studies. J Invest Dermatol 1960;34:319-30. 12. Stubb S, Reitamo S. Fixed drug eruption due to dextromethorphan. Arch Derrnatol 1990;126:970-1.
Mupirocin treatment of exudative venous ulcers Jeffrey B. Pardes, MD, Polly A. Carson, William H. Eaglstein, MD, and Vincent Falanga, MD Miami, Florida In vitro studies have proved the efficacy of topical mupirocin, especially against staphylococci, streptococci, and strains of the staphylococci resistant to systemic antibiotics. I Impetigo and secondarily infected dermatoses are benefited by treatment with mupirocin.? We report the results of a double-blind randomized study to evaluate the antibacterial effect of mupirocin 2% ointment on exudative venous ulcers.
METHODS Enrollment waslimited to patients with a venous ulcer with an abundant seropurulent drainage. No patients with cellulitis or in need of hospitalization wereincluded. The use of other topicalor systemicantibiotics or steroids was not permitted for 48 hours before, or during, the study. Patients were randomly selected to receive either mupirocin 2% ointment or its vehicle; all study participants and personnel were blindedas to the identityof the study drug. The baselineevaluation, consisting of a clinical assessFrom the Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine. Supported bySmithKline Beecham Pharmaceuticals, Philadelphia, Pa. Correspondence; Vincent Falanga, MD, University ofMiami School of Medicine, P.O. Box 016250, Miami, FL 33101. No reprints available. J AM ACAD DERMATOL 1993;29:497-8. Copyright © 1993 bythe American Academy of Dermatology, Inc. 0190-9622/93 $\.00 + .10 16/54/46113
ment and aerobic bacterial culture, constituted the initial visit that occurred within 48 hours of study drug application. Subjects were instructed to apply the study drug to the ulcer three times daily for 1 week. Before drug application subjects rinsed the ulcer with normal saline and gently patted it with gauze. The second and third visits occurred 3 and 7 days after initiation of the study, respectively. The final visit occurred 1 week after study completion and discontinuation of study drug. At each visit bacterial cultures were obtained. Only on study completion were the culture results reviewed.
RESULTS The evaluable study group comprised 25 men and 32 women, with a mean ulcer duration of 2.3 years. Thirty patients received mupirocin 2% ointment and 27 received its vehicle. No demographic differences were found between the treatment groups. Multiple organisms were cultured in individual ulcers in 65% of subjects (Table 1). Pseudomonas aeruginosa was present in 14 (38%) of these 37 cases. P. aeruginosa was also the most commonly isolated organism (49%) at the initial visit and was poorly eliminated by both study drugs. Staphylococcus aureus was the second most commonly isolated organism (33%). Mupirocin eliminatedS. aureus and Staphylococcus epidermidis in 67% and 71 % of cases, whereas the vehicle was effective in 25% and 45%, respectively (Table II). Some patients had organisms present at the final
498
Journal of the American Academy of Dermatology September 1993
Brief communications
Table I. Organisms cultured at the initial visit No. of patients Organism
(N=57)
Multiple organisms Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus epidermidis Proteus spp. Escherichia coli a- Hemolytic streptococci Klebsiella species (3-Hemo1ytic streptococci Other No growth
37 (65%) 28 (49%) 20 (33%) 18(30%) 7 (12%) 7 (12%) 5 (8%) 5 (8%) 3 (5%) 7 (12%) 2 (3%)
Table II. Eradication by final visit of organisms present at baseline* Study drug
Organism
Mupirocin
Vehicle
P. aeruginosa S. aureus S. epidermidis Proteus spp. E. coli
4/14 (29%) 3/14(21%) 8/12 (67%) 2/8 (25%) 5/7 (71%) 5/11 (45%) 1/3 (33%) 2/4 (50%) 4/6 (67%) 0/1 (0%) a-Hemolytic streptococcus 1/2 (50%) 3/3 (100%) Klebsiella spp. 2/3 (67%) 1/2 (50%) (3-Hemolytic streptococcus 1/1 (100%) 2/2 (100%) Total 18/45 26/48
"Each fraction is the number of patientssuccessfully treated out of the total who had the organism at baseline.
visitthat were not present initially. Forty percent of all mupirocin-treated patientshad S. aureus isolated at the initial visit, whereas 13% had the same organism cultured at the final visit. Conversely, 27% of all vehicle-treatedpatientshad S. aureus isolatedat the initial visit, and 50% had the same organism cultured at the finalvisit. This difference between study drugs was statisticallysignificant (p < 0.02). DISCUSSION
Other studies havealsoshown that P. aeruginosa is commonlypresentin leg ulcers. Not surprisingly, mupirocin, with a minimum inhibitory concentration of 6400 ttg/ml against Pseudomonas species, wasunsuccessful in ourstudyagainstthisorganism. 3 As expected, mupirocin was more effective than its placebo in eradicating staphylococcal and streptococcal species, but the smallnumber of isolates did not result in statistically significant eradication rates. The clinical appearance of the ulcers during the limitedperiod ofobservation wasnot affected by either study drug. In a study of 42 patients, Mehtar and Fox4 found that mupirocin treatment of cutaneous ulcers containing staphylococcal or streptococcal initial isolates was beneficial and resulted in significant differences in clinicalresponse and bacteriologic eradication rates. Dahl and Bint,5 in a study of 13 patients with ulcers, reported that mupirocin was superiorto its vehicle in the eradicationof the same bacterial species. Our results agree with these reports. Chronicvenous ulcers should not be treated with mupirocin without bacteriologic evaluation because
resistant Pseudomonas organisms are frequently present. Exudative venous ulcers contain serum, whichisknown to inactivatemupirocin.fThere have been reports of mupirocin-resistant S. aureus, usually associated with long-term use.7, 8 At the final visit some of the ulcers contained S. aureus that had not been present at baseline. This occurred less frequently in patients treated with mupirocin than with its vehicle and representsa statistically significant finding (p < 0.02). REFERENCES 1. White AR, BealeAS, Boon RJ, et aJ.Antibacterialactivity of mupirocin. In: Dobson RL, Leyden JJ, Nobel WC, eds. Bactroban. Amsterdam: Excerpta Medica, 1985; 19-34. 2. Dobson RL. Antimicrobial therapyfor cutaneousinfections. JAM ACAD DERMATOL 1990;22(suppl):871-3. 3. Pappa KA. The clinical development of mupirocin. J AM ACAD DERMATOL 1990;22(suppl):873-9. 4. Mehtar S, Fox D. A double-blind comparative study with mupirocin versus placebo basein the treatment ofchronicleg ulcers. Br J Clin Pract 1988;42:324-8. 5. Dahl MGC, Bint AJ. Bacterialand clinical effects of Bactroban ointmentin infected ulcerated skin lesions. In: Dobson RL, Leyden JJ, et al, Nobel WC, eds. Bactroban: proceedings of an international symposium, Nassau, May 21-22, 1984. Curr Med Clin Pract Series 1985;16:91-5. 6. White AR, Beale AS, Boon RJ. Antibacterial activity of mupirocin, an antibiotic produced by Pseudomonas fiuorescens. In: Wilkinson T, Price JD, eds. Mupirocin: a novel topical antibiotic, International Congress and Symposium SeriesNo. 80. London: RoyalSocietyof Medicine, 1984:4355. 7. Moy JA, Caldwell-Brown D, Lin AN, et aJ. Mupirocin-resistant Staphylococcus aureus after long-termtreatment of patientswith epidermolysis bullosa. J AMACAD DERMATOL J990;22(Suppl):893-5. 8. Baird D, Coia J. Mupirocin-resistant Staphylococcus aureus [Letter]. Lancet 1987;1:388.
dramine without a specific provocation test; other ingredients of these proprietary remedies may also cause a fixed drug eruption. I I, 12 REFERENCES I. BrowneSQ. Fixed eruption in deeply pigmented subjects: clinical observations on 350 patients. Br Med J 1964; 2:1041-4. 2. Savin JA. Current causes of fixed drug eruptions. Br J Dermatol 1970;83:546-9. 3. Sehgal VN. Causes of fixed drug eruptions. Dermatologica 1974;148: 120-3. 4. Pasricha JS. Drugs causing fixed eruptions. Br J Dermatol 1979;100:183-5. 5. Shukla SR. Drugs causing fixed drug eruptions. Derrnatologica 1981;163:160-3.
Brief communications 497 6. Korkij W, Soltani K. Fixed drug eruption: a brief review. Arch Dermatol 1984;120:520-4. 7. Kauppinen K, Stubb S. Fixed eruptions: causative drugs and challenge tests. Br J Dermatol 1985;112:575-8. 8. Kanwar AJ, Bharija SC, Singh M, et al. Ninety-eight fixed drug eruptions with provocation tests. Dermatologica 1988;177:274-9. 9. Stubb S, A1anko K, Reitamo S. Fixed drug eruptions: 77 cases from 198[ to 1985. Br J Dermatol 1989;120:583. 10. Hogan DJ, Rooney ME. Fixed drug eruption due to dimenhydrinate. J AM ACAD DERMATOL 1989;20:503-4. 11. Stritzler C, Kopf A W. Fixed drug eruption caused by 8-chlorotheophylline in Dramamine with clinical and histologic studies. J Invest Dermatol 1960;34:319-30. 12. Stubb S, Reitamo S. Fixed drug eruption due to dextromethorphan. Arch Derrnatol 1990;126:970-1.
Mupirocin treatment of exudative venous ulcers Jeffrey B. Pardes, MD, Polly A. Carson, William H. Eaglstein, MD, and Vincent Falanga, MD Miami, Florida In vitro studies have proved the efficacy of topical mupirocin, especially against staphylococci, streptococci, and strains of the staphylococci resistant to systemic antibiotics. I Impetigo and secondarily infected dermatoses are benefited by treatment with mupirocin.? We report the results of a double-blind randomized study to evaluate the antibacterial effect of mupirocin 2% ointment on exudative venous ulcers.
METHODS Enrollment waslimited to patients with a venous ulcer with an abundant seropurulent drainage. No patients with cellulitis or in need of hospitalization wereincluded. The use of other topicalor systemicantibiotics or steroids was not permitted for 48 hours before, or during, the study. Patients were randomly selected to receive either mupirocin 2% ointment or its vehicle; all study participants and personnel were blindedas to the identityof the study drug. The baselineevaluation, consisting of a clinical assessFrom the Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine. Supported bySmithKline Beecham Pharmaceuticals, Philadelphia, Pa. Correspondence; Vincent Falanga, MD, University ofMiami School of Medicine, P.O. Box 016250, Miami, FL 33101. No reprints available. J AM ACAD DERMATOL 1993;29:497-8. Copyright © 1993 bythe American Academy of Dermatology, Inc. 0190-9622/93 $\.00 + .10 16/54/46113
ment and aerobic bacterial culture, constituted the initial visit that occurred within 48 hours of study drug application. Subjects were instructed to apply the study drug to the ulcer three times daily for 1 week. Before drug application subjects rinsed the ulcer with normal saline and gently patted it with gauze. The second and third visits occurred 3 and 7 days after initiation of the study, respectively. The final visit occurred 1 week after study completion and discontinuation of study drug. At each visit bacterial cultures were obtained. Only on study completion were the culture results reviewed.
RESULTS The evaluable study group comprised 25 men and 32 women, with a mean ulcer duration of 2.3 years. Thirty patients received mupirocin 2% ointment and 27 received its vehicle. No demographic differences were found between the treatment groups. Multiple organisms were cultured in individual ulcers in 65% of subjects (Table 1). Pseudomonas aeruginosa was present in 14 (38%) of these 37 cases. P. aeruginosa was also the most commonly isolated organism (49%) at the initial visit and was poorly eliminated by both study drugs. Staphylococcus aureus was the second most commonly isolated organism (33%). Mupirocin eliminatedS. aureus and Staphylococcus epidermidis in 67% and 71 % of cases, whereas the vehicle was effective in 25% and 45%, respectively (Table II). Some patients had organisms present at the final
498
Journal of the American Academy of Dermatology September 1993
Brief communications
Table I. Organisms cultured at the initial visit No. of patients Organism
(N=57)
Multiple organisms Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus epidermidis Proteus spp. Escherichia coli a- Hemolytic streptococci Klebsiella species (3-Hemo1ytic streptococci Other No growth
37 (65%) 28 (49%) 20 (33%) 18(30%) 7 (12%) 7 (12%) 5 (8%) 5 (8%) 3 (5%) 7 (12%) 2 (3%)
Table II. Eradication by final visit of organisms present at baseline* Study drug
Organism
Mupirocin
Vehicle
P. aeruginosa S. aureus S. epidermidis Proteus spp. E. coli
4/14 (29%) 3/14(21%) 8/12 (67%) 2/8 (25%) 5/7 (71%) 5/11 (45%) 1/3 (33%) 2/4 (50%) 4/6 (67%) 0/1 (0%) a-Hemolytic streptococcus 1/2 (50%) 3/3 (100%) Klebsiella spp. 2/3 (67%) 1/2 (50%) (3-Hemolytic streptococcus 1/1 (100%) 2/2 (100%) Total 18/45 26/48
"Each fraction is the number of patientssuccessfully treated out of the total who had the organism at baseline.
visitthat were not present initially. Forty percent of all mupirocin-treated patientshad S. aureus isolated at the initial visit, whereas 13% had the same organism cultured at the final visit. Conversely, 27% of all vehicle-treatedpatientshad S. aureus isolatedat the initial visit, and 50% had the same organism cultured at the finalvisit. This difference between study drugs was statisticallysignificant (p < 0.02). DISCUSSION
Other studies havealsoshown that P. aeruginosa is commonlypresentin leg ulcers. Not surprisingly, mupirocin, with a minimum inhibitory concentration of 6400 ttg/ml against Pseudomonas species, wasunsuccessful in ourstudyagainstthisorganism. 3 As expected, mupirocin was more effective than its placebo in eradicating staphylococcal and streptococcal species, but the smallnumber of isolates did not result in statistically significant eradication rates. The clinical appearance of the ulcers during the limitedperiod ofobservation wasnot affected by either study drug. In a study of 42 patients, Mehtar and Fox4 found that mupirocin treatment of cutaneous ulcers containing staphylococcal or streptococcal initial isolates was beneficial and resulted in significant differences in clinicalresponse and bacteriologic eradication rates. Dahl and Bint,5 in a study of 13 patients with ulcers, reported that mupirocin was superiorto its vehicle in the eradicationof the same bacterial species. Our results agree with these reports. Chronicvenous ulcers should not be treated with mupirocin without bacteriologic evaluation because
resistant Pseudomonas organisms are frequently present. Exudative venous ulcers contain serum, whichisknown to inactivatemupirocin.fThere have been reports of mupirocin-resistant S. aureus, usually associated with long-term use.7, 8 At the final visit some of the ulcers contained S. aureus that had not been present at baseline. This occurred less frequently in patients treated with mupirocin than with its vehicle and representsa statistically significant finding (p < 0.02). REFERENCES 1. White AR, BealeAS, Boon RJ, et aJ.Antibacterialactivity of mupirocin. In: Dobson RL, Leyden JJ, Nobel WC, eds. Bactroban. Amsterdam: Excerpta Medica, 1985; 19-34. 2. Dobson RL. Antimicrobial therapyfor cutaneousinfections. JAM ACAD DERMATOL 1990;22(suppl):871-3. 3. Pappa KA. The clinical development of mupirocin. J AM ACAD DERMATOL 1990;22(suppl):873-9. 4. Mehtar S, Fox D. A double-blind comparative study with mupirocin versus placebo basein the treatment ofchronicleg ulcers. Br J Clin Pract 1988;42:324-8. 5. Dahl MGC, Bint AJ. Bacterialand clinical effects of Bactroban ointmentin infected ulcerated skin lesions. In: Dobson RL, Leyden JJ, et al, Nobel WC, eds. Bactroban: proceedings of an international symposium, Nassau, May 21-22, 1984. Curr Med Clin Pract Series 1985;16:91-5. 6. White AR, Beale AS, Boon RJ. Antibacterial activity of mupirocin, an antibiotic produced by Pseudomonas fiuorescens. In: Wilkinson T, Price JD, eds. Mupirocin: a novel topical antibiotic, International Congress and Symposium SeriesNo. 80. London: RoyalSocietyof Medicine, 1984:4355. 7. Moy JA, Caldwell-Brown D, Lin AN, et aJ. Mupirocin-resistant Staphylococcus aureus after long-termtreatment of patientswith epidermolysis bullosa. J AMACAD DERMATOL J990;22(Suppl):893-5. 8. Baird D, Coia J. Mupirocin-resistant Staphylococcus aureus [Letter]. Lancet 1987;1:388.