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Erythromycin 2% gel in comparison with clindamycin phosphate 1 % solution in acne vulgaris
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Erythromycin 2% gel in comparison with clindamycin phosphate 1% solution in acne vulgaris James J. Leyden, M . D . , * Alan R. Shalita, M.D.,** Gloria D. Saatjian, B.A.,*** and John Sefton, Ph.D.*** philadelphia. PA, Brooklyn, NY, and lrvine, CA One hundred two patients with mild to moderate facial acne vulgaris completed a 12-week, investigator-masked, randomized, parallel-group comparison of a gel formulation Of erythromycin (2%) with clindamycin phosphate 1% solution. Patients were evaluated at a baseline visit and after 4, .8, and 12 weeks of twice-daily treatment. Both medications significantly reduced the numbers of papules and open and closed comedones. No significant differences in lesion count reductions were detected between the treatment groups after 8 and 12 weeks Of treatment. By the end of 12 weeks, 48% of the patients in the erythromyein group and 47% in the clindamycin group ha d good or excellent responses to treatment. No patient was terminated from the study lbr side effects. Most patients, 65% in the erythromycin 2% gel group and 67% in the clindamycin phosphate I% solution group, had a favorable impression of the overall cosmetic characteristics of their study medication. (J AN ACAD DERMATOL 1987; 16:822-7.)
The dense population of Propionibacterium aches in the hyperkeratinized sebaceous follicle has been implicated as one of the factors in the development o f inflammatory acne vulgaris. ~'z These bacteria produce, among other enzymes, Iipases that liberate fatty acids from sebaceous triglycerides.3 The comedogenicity of free fatty acids has been demonstrated, 4'5 as has the chemotactic activity of the lipases and small molecular weight substances produced by P. acnes. 6 More recent evidence indicates that the activation o f complement by P. aches and the resultant rise in C5'
"
From the Department of Dermatology, Hospital of the University of Pennsy!vania, Philadelphia,* the Department of Dermatology, SUNY Downstate Medical Center, Brooklyn,** and Herbert Laboraiorics Clinical Research and Development, Irvine.*** Presented in part as a scientific exhibit at the 45th Annual Meeting of the American Academy of Dermatology, New Orleans, LA, December 1986. Accepted for publication Oct. 30, 1986. Reprint requests to: Dr. John Sefton, Herbert Laboratories Clinical Research and Development, 2525 Dupont Dr-, irvine, CA 92715.
822
Table I. Demographic variables
Erythromycin I Clindamvcin Clindamvc .
. . . Age (yr) n Mean M!nimum, maximum Sex (%) Male Female Race (%) White Black Oriental Other
.
. 52 18.4 14, 34
50 17.2 14, 28
48 52
54 46
77 6 6 12
80 8 4 8
derived neutrophil ehemotactic factors m a y be more directly responsible for the inflammation seen in acne. 7° Antibiotics are effective in the treatment o f inflammatory aene because their effect on P. aches reduces the potential for comedogenicity and in-
Volume 16
Number 4 April 1987
Erythromycin 2% gel #z comparison with clindamycin phosphate 1% solution
823
Table II. Mean lesion counts at week 0 and mean changes in lesion counts at weeks 4, 8, and 12 Clindamyein
Erythromycin
t
I
Mean ± SE
Mean ± SE
Papules Week Week Week Week
0 4 8 12
52 47 45 48
13.4 -5,9 -6.7 -8.2
± ± ±
0.9 0.8* 0.9* 0.9*
50 49 47 47
10.9 -5.2 -5.3 -6.3
± 0.6 _+ 0.5* ± 0,7* ___ 0.6*
0 4 8 12
52 47 45 48
5.6 1.8 0.5 -1.2
± __ ± +
0.6 0.9 1.2 1.0
50 49 47 47
5.1 -0.6 0.3 -0.8
"+" 0.'7 ± 0.5 ± 0.7 _. 0.8
52 47 45 48
15,7 -0.9 -3.7 -5.5
± ± ± ±
1.5 1,0 1.2" 1.2'
50 49 47 47
13,0 -0,5 -2.9 -4.8
± 1.5 ± 0,9 ± 1.0' ---+ 1.1'
52 47 45 48
14.7 - 1.3 -4.5 -6.5
± + _+ ±
1.3 0.8 1.1" 1.2'
50 49 47 47
12.7 - 2.3 -4.2 -5.6
± 1.2 +_ 0,8' _+_ 0.8* ± 0.8*
Pustules Week Week Week Week
Open comedones Week Week Week Week
0 4 8 12
Closed comedones Week Week Week Week
0 4[ 8 12
*A significant decrease from mean baseline value was detected (p < 0.05). 't'A significant between-group difference was detected (p = 0.049).
ttammation within the diseased follicle. ~°aj Additionally, antibiotics have been shown to directly suppress leukocyte chemotaxis, ~2 The systemic use o f antibiotics such as erythromycin, tetracycline, and minocycline for the treatment of inflammatory acne vulgaris has been widespread. In recent years, however, topical preparations of fintibiotics, particularly erythromycin and clindamycin phosphate, have been widely prescribed and have proved effective for the treatment of mild to moderate acne vulgaris.~3-~6 The clear advantage for the topical use of these antibiotics is the reduced potential for the side effects that are occasionally seen with their systemic counterparts. Even with topically applied clindamycin phosphate, there still may be a potential for systemic side effects. Recently, pseudomembranous colitis, thought to be related to the topical application of clindamycin phosphate, has been reported. ~7 In this study, we evaluated a new 2% eryth-
romycin gel formulation and comPared it, in terms Of efficacy, safety, and cosmetic acceptability, With clindamycin phosphate 1% solution.
MATERIALS AND METHoDs Male or female patients from two investigational centers were enrolled into this study. To be included, patients had to be at least 14 years of age and had to have a minimum of ten but no more than sixty facial papules and pustules, and no more than six facial nodular cystic lesions. Any of the following conditions disqualified patients from participation: (1) regular use of 0ral or topical antibiotics or other effective antiacne medication (e.g., benzoyl peroxide or tretinoin) within 30 days of study entry; (2) Use of any topical antiacne agent within 14 days of study entry; (3) treatment with estrogens for 12 weeks or less immediately preceding study entry; or (4) previous treatment with isotretinoin. The use of ~mtibiotics or other antiacne agents during the study was not allowed.
824
Journal of the American Academy of Dermatology
Leyden et al
Ot
• _Erythromycin 2 Z Gel
03
~
-2-
\
.o_ - 4 - f,O
.c
o Clin_d(Lmycin_Phosphate 1Z Solution
", - , ' ~ ,
o C.)
_
\\
-6-
cD ¢-
-8
(.) r--10
-12 0
4-
8
12
Weeks of TreatmenL Fig. 1. Effect of treatment on total inflammatory lesion counts. (Error bars represent
standard error of the mean.)
Informed consent was obtained from the patients and, if under the legal age, from a parent or legal guardian. Fifty-five patients were randomly assigned to treatment with erythromycin 2% gel and fifty-four to treatment with clindamycin phosphate 1% solution.* Because this was an investigator-masked study, the medication was d!spensed by a third party, and patients were instructed not to inform the investigator of the identity of their assigned medication or the nature of its container. Patients were supplied with a nonrnedicated soapt and were instructed to apply a thin film of the assigned medication to their faces twice daily, in the morning and evening, after washing. Facial lesions (papules, pustules, nodules, and open and closed Comedones) were counted at the baseline visit and after 4, 8, and 12 weeks of treatment. At the three follow-up visits, each patient's response to treatment, compared with the baseline condition, was assessed as follows: complete clearing (no sign or symptom of disease); excellent response (75%-99% improvement); good response (50%-74% improvement); fair response (25%-49% improvement); poor response (l%-24% improvement); or condition unchanged or worsened. Treatment success rate, defined as the percentage of patients with a good to excellent response to treatment or complete clearing of the disease, was determined for each of the three follow-up visits. *CIeocin T. The Upjohn Company, Kalamazoo, MI, ]Purpose. Ortho Pharmaceutical Corporation, Raritan, NJ.
At all visits, signs and symptoms such as dryness, erythema, oiliness, peeling, burning, and itching were evaluated as none, mild, moderate, or severe. At the follow-up visits, a judgment was made as to the relationship of these signs or symptoms to the study, treatment. At the final visit, patients rated the cosmetic characteristics of their assigned medication. Statistical tests were two-sided and were performed at the 0.05 level of significance. With the exception of nodule counts, which were not analyzed because of small numbers, lesion count data were analyzed with nonparametric methods. For comparisons within each treatment group, the signed-rank test was used. For comparisons between the treatment groups at baseline and at weeks 4, 8, and 12, a nonparametric analysis of covariance method was used that involved matching data from the two treatment groups. 's Treatment success rates were compared between the treatment groups with Fisher's exact test. RESULTS The data for seven patients were excluded from the analyses for treatment-unrelated protocol violations. None of the patients were terminated from the study for reasons related to the study treatments. The data for 102 patients, fifty-two male and fifty female, aged 14 to 34 years, Were included in the analyses. Analysis of the demographic variables listed in Table I indicated no significant differences between the treatment groups a t baseline.
Volume 16 Number 4 April 1987
Erythromycin 2% gel in comparison with clindamycin phosphate 1% solution
° ~J
~ ~ - ~ - ~ 2 ~ ~-
0 0 c 0
825
• Erythromyc]n 2% Gel ,, -"x~?linda.m._yein PhosE)hate 1% Solution
q c(3 (c (3
-15
....
0
I
i
4
8
....
i 12
Weeks of Treatment
Fig. 2. Effect of treatment on total noninflammatory lesion counts. (Error bars represent standard error of the mean.)
"E
Erythromycin 2% Gel I---1 Clindamycin Phosphate 1% Solution
60-
©
E 50-
40o o_ 30-
©
o
20-
10-
8 4
8 Weeks of Treatment
12
Fig. 3. Treatment success rates. (Error bars represent standard error of the mean.)
Table II presents the effect of 12 weeks of treatment with either erythromycin or clindamycin on the numbers of papules, pustules, and open and closed comedones. Because no patient had more than two nodules at any time during the study, analysis o f the nodule data was not performed. In both treatment groups, statistically significant
decreases in papules were noted at all follow-up visits (weeks 4, 8, and 12) and in open comedones at weeks 8 and 12. Closed comedones were significantly reduced at weeks 8 and 12 in the erythromycin group and at weeks 4, 8, and 12 in the clindamycin group; the difference between the two treatments with respect to closed comedones at
826
Journal of the American Academy of Dermatology
L e y d e n et al
1% solution had a favorable impression o f the overall cosmetic characteristics of their assigned medication.
Table HI. Number of reports of side effects for which the maximum severity was moderate or severe
Erythromyein =
Side effect Burning Itching Dryness Erythema Oiliness Peeling
Moderate]Severe .... 1 1 4 0 1 4
Clindamyein ,
1 0 2 0 0 1
Moderate] Severe 3 1 2 0 0 0
0 0 0 0 1 0
week 4 was statistically, but not clinically, significant. Figs. 1 and 2 show the mean reductions in total inflammatory lesions (papules, pustules, and nodules) and total noninflammatory lesions (open and closed comedones), respectively. Both treatments caused significant reductions in total inflammatory lesions; total noninflammatory lesions were significantly reduced by both treatments at weeks 8 and 12. Results of the global evaluations of the response to treatment are presented in Fig. 3. Treatment success rates were similar for the two treatment groups at all follow-up visits. By the end of 12 weeks of treatment, 48% of the patients in the erythromycin group and 47% in the clindamycin group had good or excellent responses to treatment; there were no instances of complete clearing in either treatment group. Signs and symptoms were regarded as side effects of treatment if they were reported as being treatment-related and if they represented an increase from baseline severity. Table III presents the frequencies of moderate or severe side effects. The most frequently reported side effects among patients treated with erythromycin were dryness and peeling, while burning was most frequently reported among clindamycin-treated patients. None o f the reported side effects resulted in the termination of any patient from the study. Results of a questionnaire on the cosmetic characteristics of the study medications revealed that 65% of the patients receiving erythromycin 2% gel and 67% of those receiving clindamycin phosphate
DISCUSSION
In contrast with systemic antibiotic treatment for acne vulgaris, topical treatment offers the advantages of direct local application of the drug to the affected areas of the skin, decreased total absorption of the drug, and a resultant decreased potential for systemic side effects. The results of this evaluation of a topical erythromycin gel support those of previously studied topical erythromycin formulations showing efficacy for the treatment of ache vulgaris.1316.19-23 In addition, we have shown this formulation to be as effective as clindamycin phosphate 1% solution in reducing the lesions of acne and in improving the overall acne condition. The choice of vehicle for the topical antibiotic treatment of acne vulgaris depends on several factors: the degree of skin sensitivity, the environment, the presence or absence of excessive oiliness, and cosmetic considerations. Often, seasonal fluctuations will make different vehicles more appropriate for different times of the year. In this study, the high alcohol content of the gel formulation was most likely responsible for the modest drying effect experienced by the erythromycin-treated patients. Thus, a gel formulation may be preferred by those acne patients for whom excessive oiliness is a problem, or in warmer climates where the problem of dry skin is not as prevalent. REFERENCES 1. Marples RR, McGinley KJ, Mills OH. Microbiologyof comedones in ache vulgaris. J Invest Dermatol 1973; 60:80-3. 2. Kirschbaum JO, Kligman AM. The pathogenic role of Corynebacteriurn acnes in acne vulgaris. Arch Dermatol 1963;88:832-3. 3. ShalitaAR. Genesis of free fatty acids. J InvestDermatol 1974;62:332-5. 4. Kligman AM, Katz AG. Pathogenesisof acne vulgm:is. I. Comedogenicproperties of human sebum in the external ear canal of the rabbit. Arch Dermatol 1968;98: 53-7. 5. KligmanAM, WheatleyVR, Mills OH. Comedogenicity of human sebum. Arch Dermatol 1970;102:267-75. 6. PuhvelSM, SakamotoM. The chemoattractantproperties
Volume 16 Number 4 April 1987
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8.
9.
10.
11.
12. 13.
14.
E r y t h r o m y c i n 2 % g e l in c o m p a r i s o n with c l i n d a m y c i n p h o s p h a t e 1 % s o l u t i o n
of comedonal components. J Invest Dermatol 1978;71: 324-9. Webster GF, Leyden JJ, Tsai CC, et al. Polymorphonuclear leukocyte lysosomal release in response to Propionibacterium aches in vitro and its enhancement by sera from patients with inflammatory aene. J Invest Dermatol 1980;74:398-401. Webster GF, Leyden JJ, Norman ME, Nilsson UR. Complement activation in aene vulgaris: in vitro studies with Propionibacterium nones and Propionibacterium granulosum. Infect Immun 1978;22:523-9. Webster GF, Leyden JJ, Nilsson UR. Complement activation in acne vulgaris: consumption of complement by comedones. Infect Immun 1979;26:183-5. AdHoc Committee Report. Systemic antibiotics for treatment of acne vulgaris: efficacy and safety. Arch Dermatol 1975; 111:1630-6. Strauss JS, Pochi PE. Effect of orally administered antibacterial agents on titratable acidity of human sebum. J Invest Dermatol 1966;47:577-81. Esterly NB, Furey NL, Flanagan LE. The effect of antimicrobial agents on leukocyte ehemotaxis. J Invest Dermatol 1978;70:51-5. Bernstein JE, Shalita AR. Topically applidd erythromycin in inflammatory acne vulgaris. J AM ACADDERMATOL 1980;2:318-21. Jones EL, Crumley AF. Topical erythromycin vs blank
15.
16.
17. 18. 19. 20.
21.
22. 23.
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vehicle in a multiclinic ache study. Arch Dermatol 1981;117:551-3. Thomas DR, Raimer S, Smith EB. Comparison of topical erythromycin 1.5 percent solution versus topical ciindamycin phosphate 1.0 percent solution in the treatment of acne vulgaris. Cutis 1982;29:624-32. Lesher JL, Chalker DK, Smith JG Jr, et al. An evaluation of a 2% erytbromycin ointment in the topical therapy of ache vu/garis. J AM AC.ADDERMATOL 1985;12:526-31. Parry MF, Rha C. Pseudomembranous colitis caused by topical clindamycin phosphate. Arch Dermatol 1986; 122:583-4. Quade D. Nonparametric analysis of covariance by matching. Biometrics 1982;38:597-611. Fulton JE, Pablo G. Topical antibacterial therapy for acne. Arch Dermatol 1974;110:83-6. Mills OH, Kligman AM, Stewart R. The clinical effectiveness of topical erythromycin in ache vulgaris. Cutis 1975;15:93-6. Fulton JE, Bradley S. The choice of vitamin A acid, erythromycin or benzoyl peroxide for the topical treatment of acne. Cutis 1976;17:560-4. Dobson RL, Belknap BS. Topical erythromycin solution in acne. J AM ACAD D~.RMAa'Ot~1980;3:478-82. Shalita AR, Smith EB, Bauer E. Topical erythromyein vs clindamycin therapy for acne. Arch Dermatol 1984; 120:351-5.
ABSTRACTS
Polymyositis associated with AIDS retrovirus Dalakas MC, Pezeshkpour GH, Gravell M, Sever JL. JAMA 1986;256:2381-2 Polymyosltis was the initial manifestationof the human immunodeficiencyvirus infectionof two homosexualmen.Theydeveloped acquired immunodeficiencysyndrome(AIDS)-relatedcomplexa few weeks later, with typical AIDS 2 to 6 monthsafter onset of myopathy. J. Graham Smith, Jr., M.D.
Visceral and skin granuloma annulare, diabetes, and polyendocrine disease Thomas DJB, Rademaker M, Munro DD, Levison DA, Besser GM. Br Med J 1986;293:977-8 A 50-year-oldman with insulin-dependentdiabetes, autoimmune Addison's disease, myxedema, and severe ulcerative colitis, for which he had had a subtotal colectomy, developed granuloma annulare confinedto the anterior abdominalwall in 1981. In 1983, an episode of severe colicky pain occurred, with hyperglycemia. At laparotomy, adhesions and numerous white nodulesover the bowel, mesentery, and peritoneumwere found. The nodules were histologically identical with the skin lesions. A repeat laparotomy because of subacute small bowel obstruction showed widespread intra-ab-
dominal granuloma annulare. This appears to be the first reported case of visceral granulomaannulareto be reported. J. Graham Smith, Jr., M.D.
Oral hairy ieukoplakia in two women, a hemophiliac and a transfusion recipient Greenspan D, Hollander H, Freidman-Kien A, Freese UK, Greenspan JS. Lancet 1986;2:978-9 Reports of oral hairy leukoplakiahave previously been confined to homosexual men infected with human immunodefieiencyvirus (HIV). Three additionalpatientsare reported whose risk factors were: (1) a blood transfusion 4 years previously, (2) a hemophiliac, and (3) a 43-year-oldwomanwho was a partner of an HIV-infectedman. J. Graham Smith, Jr., M.D.
Erythema nodosum provoked by hepatitis B vaccine DiGiusto CA, Bernhard JD. Lancet 1986;2:1042 Fifteen days after the second injection of hepatitis B vaccine, a 24-year-old medical student developed erythema nodosum, which cleared over 13 weeks, She developed lesions again when a third dose was administered5 months after the second. J. Graham Smith, Jr., M.D.
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Erythromycin 2% gel in comparison with clindamycin phosphate 1% solution in acne vulgaris James J. Leyden, M . D . , * Alan R. Shalita, M.D.,** Gloria D. Saatjian, B.A.,*** and John Sefton, Ph.D.*** philadelphia. PA, Brooklyn, NY, and lrvine, CA One hundred two patients with mild to moderate facial acne vulgaris completed a 12-week, investigator-masked, randomized, parallel-group comparison of a gel formulation Of erythromycin (2%) with clindamycin phosphate 1% solution. Patients were evaluated at a baseline visit and after 4, .8, and 12 weeks of twice-daily treatment. Both medications significantly reduced the numbers of papules and open and closed comedones. No significant differences in lesion count reductions were detected between the treatment groups after 8 and 12 weeks Of treatment. By the end of 12 weeks, 48% of the patients in the erythromyein group and 47% in the clindamycin group ha d good or excellent responses to treatment. No patient was terminated from the study lbr side effects. Most patients, 65% in the erythromycin 2% gel group and 67% in the clindamycin phosphate I% solution group, had a favorable impression of the overall cosmetic characteristics of their study medication. (J AN ACAD DERMATOL 1987; 16:822-7.)
The dense population of Propionibacterium aches in the hyperkeratinized sebaceous follicle has been implicated as one of the factors in the development o f inflammatory acne vulgaris. ~'z These bacteria produce, among other enzymes, Iipases that liberate fatty acids from sebaceous triglycerides.3 The comedogenicity of free fatty acids has been demonstrated, 4'5 as has the chemotactic activity of the lipases and small molecular weight substances produced by P. acnes. 6 More recent evidence indicates that the activation o f complement by P. aches and the resultant rise in C5'
"
From the Department of Dermatology, Hospital of the University of Pennsy!vania, Philadelphia,* the Department of Dermatology, SUNY Downstate Medical Center, Brooklyn,** and Herbert Laboraiorics Clinical Research and Development, Irvine.*** Presented in part as a scientific exhibit at the 45th Annual Meeting of the American Academy of Dermatology, New Orleans, LA, December 1986. Accepted for publication Oct. 30, 1986. Reprint requests to: Dr. John Sefton, Herbert Laboratories Clinical Research and Development, 2525 Dupont Dr-, irvine, CA 92715.
822
Table I. Demographic variables
Erythromycin I Clindamvcin Clindamvc .
. . . Age (yr) n Mean M!nimum, maximum Sex (%) Male Female Race (%) White Black Oriental Other
.
. 52 18.4 14, 34
50 17.2 14, 28
48 52
54 46
77 6 6 12
80 8 4 8
derived neutrophil ehemotactic factors m a y be more directly responsible for the inflammation seen in acne. 7° Antibiotics are effective in the treatment o f inflammatory aene because their effect on P. aches reduces the potential for comedogenicity and in-
Volume 16
Number 4 April 1987
Erythromycin 2% gel #z comparison with clindamycin phosphate 1% solution
823
Table II. Mean lesion counts at week 0 and mean changes in lesion counts at weeks 4, 8, and 12 Clindamyein
Erythromycin
t
I
Mean ± SE
Mean ± SE
Papules Week Week Week Week
0 4 8 12
52 47 45 48
13.4 -5,9 -6.7 -8.2
± ± ±
0.9 0.8* 0.9* 0.9*
50 49 47 47
10.9 -5.2 -5.3 -6.3
± 0.6 _+ 0.5* ± 0,7* ___ 0.6*
0 4 8 12
52 47 45 48
5.6 1.8 0.5 -1.2
± __ ± +
0.6 0.9 1.2 1.0
50 49 47 47
5.1 -0.6 0.3 -0.8
"+" 0.'7 ± 0.5 ± 0.7 _. 0.8
52 47 45 48
15,7 -0.9 -3.7 -5.5
± ± ± ±
1.5 1,0 1.2" 1.2'
50 49 47 47
13,0 -0,5 -2.9 -4.8
± 1.5 ± 0,9 ± 1.0' ---+ 1.1'
52 47 45 48
14.7 - 1.3 -4.5 -6.5
± + _+ ±
1.3 0.8 1.1" 1.2'
50 49 47 47
12.7 - 2.3 -4.2 -5.6
± 1.2 +_ 0,8' _+_ 0.8* ± 0.8*
Pustules Week Week Week Week
Open comedones Week Week Week Week
0 4 8 12
Closed comedones Week Week Week Week
0 4[ 8 12
*A significant decrease from mean baseline value was detected (p < 0.05). 't'A significant between-group difference was detected (p = 0.049).
ttammation within the diseased follicle. ~°aj Additionally, antibiotics have been shown to directly suppress leukocyte chemotaxis, ~2 The systemic use o f antibiotics such as erythromycin, tetracycline, and minocycline for the treatment of inflammatory acne vulgaris has been widespread. In recent years, however, topical preparations of fintibiotics, particularly erythromycin and clindamycin phosphate, have been widely prescribed and have proved effective for the treatment of mild to moderate acne vulgaris.~3-~6 The clear advantage for the topical use of these antibiotics is the reduced potential for the side effects that are occasionally seen with their systemic counterparts. Even with topically applied clindamycin phosphate, there still may be a potential for systemic side effects. Recently, pseudomembranous colitis, thought to be related to the topical application of clindamycin phosphate, has been reported. ~7 In this study, we evaluated a new 2% eryth-
romycin gel formulation and comPared it, in terms Of efficacy, safety, and cosmetic acceptability, With clindamycin phosphate 1% solution.
MATERIALS AND METHoDs Male or female patients from two investigational centers were enrolled into this study. To be included, patients had to be at least 14 years of age and had to have a minimum of ten but no more than sixty facial papules and pustules, and no more than six facial nodular cystic lesions. Any of the following conditions disqualified patients from participation: (1) regular use of 0ral or topical antibiotics or other effective antiacne medication (e.g., benzoyl peroxide or tretinoin) within 30 days of study entry; (2) Use of any topical antiacne agent within 14 days of study entry; (3) treatment with estrogens for 12 weeks or less immediately preceding study entry; or (4) previous treatment with isotretinoin. The use of ~mtibiotics or other antiacne agents during the study was not allowed.
824
Journal of the American Academy of Dermatology
Leyden et al
Ot
• _Erythromycin 2 Z Gel
03
~
-2-
\
.o_ - 4 - f,O
.c
o Clin_d(Lmycin_Phosphate 1Z Solution
", - , ' ~ ,
o C.)
_
\\
-6-
cD ¢-
-8
(.) r--10
-12 0
4-
8
12
Weeks of TreatmenL Fig. 1. Effect of treatment on total inflammatory lesion counts. (Error bars represent
standard error of the mean.)
Informed consent was obtained from the patients and, if under the legal age, from a parent or legal guardian. Fifty-five patients were randomly assigned to treatment with erythromycin 2% gel and fifty-four to treatment with clindamycin phosphate 1% solution.* Because this was an investigator-masked study, the medication was d!spensed by a third party, and patients were instructed not to inform the investigator of the identity of their assigned medication or the nature of its container. Patients were supplied with a nonrnedicated soapt and were instructed to apply a thin film of the assigned medication to their faces twice daily, in the morning and evening, after washing. Facial lesions (papules, pustules, nodules, and open and closed Comedones) were counted at the baseline visit and after 4, 8, and 12 weeks of treatment. At the three follow-up visits, each patient's response to treatment, compared with the baseline condition, was assessed as follows: complete clearing (no sign or symptom of disease); excellent response (75%-99% improvement); good response (50%-74% improvement); fair response (25%-49% improvement); poor response (l%-24% improvement); or condition unchanged or worsened. Treatment success rate, defined as the percentage of patients with a good to excellent response to treatment or complete clearing of the disease, was determined for each of the three follow-up visits. *CIeocin T. The Upjohn Company, Kalamazoo, MI, ]Purpose. Ortho Pharmaceutical Corporation, Raritan, NJ.
At all visits, signs and symptoms such as dryness, erythema, oiliness, peeling, burning, and itching were evaluated as none, mild, moderate, or severe. At the follow-up visits, a judgment was made as to the relationship of these signs or symptoms to the study, treatment. At the final visit, patients rated the cosmetic characteristics of their assigned medication. Statistical tests were two-sided and were performed at the 0.05 level of significance. With the exception of nodule counts, which were not analyzed because of small numbers, lesion count data were analyzed with nonparametric methods. For comparisons within each treatment group, the signed-rank test was used. For comparisons between the treatment groups at baseline and at weeks 4, 8, and 12, a nonparametric analysis of covariance method was used that involved matching data from the two treatment groups. 's Treatment success rates were compared between the treatment groups with Fisher's exact test. RESULTS The data for seven patients were excluded from the analyses for treatment-unrelated protocol violations. None of the patients were terminated from the study for reasons related to the study treatments. The data for 102 patients, fifty-two male and fifty female, aged 14 to 34 years, Were included in the analyses. Analysis of the demographic variables listed in Table I indicated no significant differences between the treatment groups a t baseline.
Volume 16 Number 4 April 1987
Erythromycin 2% gel in comparison with clindamycin phosphate 1% solution
° ~J
~ ~ - ~ - ~ 2 ~ ~-
0 0 c 0
825
• Erythromyc]n 2% Gel ,, -"x~?linda.m._yein PhosE)hate 1% Solution
q c(3 (c (3
-15
....
0
I
i
4
8
....
i 12
Weeks of Treatment
Fig. 2. Effect of treatment on total noninflammatory lesion counts. (Error bars represent standard error of the mean.)
"E
Erythromycin 2% Gel I---1 Clindamycin Phosphate 1% Solution
60-
©
E 50-
40o o_ 30-
©
o
20-
10-
8 4
8 Weeks of Treatment
12
Fig. 3. Treatment success rates. (Error bars represent standard error of the mean.)
Table II presents the effect of 12 weeks of treatment with either erythromycin or clindamycin on the numbers of papules, pustules, and open and closed comedones. Because no patient had more than two nodules at any time during the study, analysis o f the nodule data was not performed. In both treatment groups, statistically significant
decreases in papules were noted at all follow-up visits (weeks 4, 8, and 12) and in open comedones at weeks 8 and 12. Closed comedones were significantly reduced at weeks 8 and 12 in the erythromycin group and at weeks 4, 8, and 12 in the clindamycin group; the difference between the two treatments with respect to closed comedones at
826
Journal of the American Academy of Dermatology
L e y d e n et al
1% solution had a favorable impression o f the overall cosmetic characteristics of their assigned medication.
Table HI. Number of reports of side effects for which the maximum severity was moderate or severe
Erythromyein =
Side effect Burning Itching Dryness Erythema Oiliness Peeling
Moderate]Severe .... 1 1 4 0 1 4
Clindamyein ,
1 0 2 0 0 1
Moderate] Severe 3 1 2 0 0 0
0 0 0 0 1 0
week 4 was statistically, but not clinically, significant. Figs. 1 and 2 show the mean reductions in total inflammatory lesions (papules, pustules, and nodules) and total noninflammatory lesions (open and closed comedones), respectively. Both treatments caused significant reductions in total inflammatory lesions; total noninflammatory lesions were significantly reduced by both treatments at weeks 8 and 12. Results of the global evaluations of the response to treatment are presented in Fig. 3. Treatment success rates were similar for the two treatment groups at all follow-up visits. By the end of 12 weeks of treatment, 48% of the patients in the erythromycin group and 47% in the clindamycin group had good or excellent responses to treatment; there were no instances of complete clearing in either treatment group. Signs and symptoms were regarded as side effects of treatment if they were reported as being treatment-related and if they represented an increase from baseline severity. Table III presents the frequencies of moderate or severe side effects. The most frequently reported side effects among patients treated with erythromycin were dryness and peeling, while burning was most frequently reported among clindamycin-treated patients. None o f the reported side effects resulted in the termination of any patient from the study. Results of a questionnaire on the cosmetic characteristics of the study medications revealed that 65% of the patients receiving erythromycin 2% gel and 67% of those receiving clindamycin phosphate
DISCUSSION
In contrast with systemic antibiotic treatment for acne vulgaris, topical treatment offers the advantages of direct local application of the drug to the affected areas of the skin, decreased total absorption of the drug, and a resultant decreased potential for systemic side effects. The results of this evaluation of a topical erythromycin gel support those of previously studied topical erythromycin formulations showing efficacy for the treatment of ache vulgaris.1316.19-23 In addition, we have shown this formulation to be as effective as clindamycin phosphate 1% solution in reducing the lesions of acne and in improving the overall acne condition. The choice of vehicle for the topical antibiotic treatment of acne vulgaris depends on several factors: the degree of skin sensitivity, the environment, the presence or absence of excessive oiliness, and cosmetic considerations. Often, seasonal fluctuations will make different vehicles more appropriate for different times of the year. In this study, the high alcohol content of the gel formulation was most likely responsible for the modest drying effect experienced by the erythromycin-treated patients. Thus, a gel formulation may be preferred by those acne patients for whom excessive oiliness is a problem, or in warmer climates where the problem of dry skin is not as prevalent. REFERENCES 1. Marples RR, McGinley KJ, Mills OH. Microbiologyof comedones in ache vulgaris. J Invest Dermatol 1973; 60:80-3. 2. Kirschbaum JO, Kligman AM. The pathogenic role of Corynebacteriurn acnes in acne vulgaris. Arch Dermatol 1963;88:832-3. 3. ShalitaAR. Genesis of free fatty acids. J InvestDermatol 1974;62:332-5. 4. Kligman AM, Katz AG. Pathogenesisof acne vulgm:is. I. Comedogenicproperties of human sebum in the external ear canal of the rabbit. Arch Dermatol 1968;98: 53-7. 5. KligmanAM, WheatleyVR, Mills OH. Comedogenicity of human sebum. Arch Dermatol 1970;102:267-75. 6. PuhvelSM, SakamotoM. The chemoattractantproperties
Volume 16 Number 4 April 1987
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8.
9.
10.
11.
12. 13.
14.
E r y t h r o m y c i n 2 % g e l in c o m p a r i s o n with c l i n d a m y c i n p h o s p h a t e 1 % s o l u t i o n
of comedonal components. J Invest Dermatol 1978;71: 324-9. Webster GF, Leyden JJ, Tsai CC, et al. Polymorphonuclear leukocyte lysosomal release in response to Propionibacterium aches in vitro and its enhancement by sera from patients with inflammatory aene. J Invest Dermatol 1980;74:398-401. Webster GF, Leyden JJ, Norman ME, Nilsson UR. Complement activation in aene vulgaris: in vitro studies with Propionibacterium nones and Propionibacterium granulosum. Infect Immun 1978;22:523-9. Webster GF, Leyden JJ, Nilsson UR. Complement activation in acne vulgaris: consumption of complement by comedones. Infect Immun 1979;26:183-5. AdHoc Committee Report. Systemic antibiotics for treatment of acne vulgaris: efficacy and safety. Arch Dermatol 1975; 111:1630-6. Strauss JS, Pochi PE. Effect of orally administered antibacterial agents on titratable acidity of human sebum. J Invest Dermatol 1966;47:577-81. Esterly NB, Furey NL, Flanagan LE. The effect of antimicrobial agents on leukocyte ehemotaxis. J Invest Dermatol 1978;70:51-5. Bernstein JE, Shalita AR. Topically applidd erythromycin in inflammatory acne vulgaris. J AM ACADDERMATOL 1980;2:318-21. Jones EL, Crumley AF. Topical erythromycin vs blank
15.
16.
17. 18. 19. 20.
21.
22. 23.
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vehicle in a multiclinic ache study. Arch Dermatol 1981;117:551-3. Thomas DR, Raimer S, Smith EB. Comparison of topical erythromycin 1.5 percent solution versus topical ciindamycin phosphate 1.0 percent solution in the treatment of acne vulgaris. Cutis 1982;29:624-32. Lesher JL, Chalker DK, Smith JG Jr, et al. An evaluation of a 2% erytbromycin ointment in the topical therapy of ache vu/garis. J AM AC.ADDERMATOL 1985;12:526-31. Parry MF, Rha C. Pseudomembranous colitis caused by topical clindamycin phosphate. Arch Dermatol 1986; 122:583-4. Quade D. Nonparametric analysis of covariance by matching. Biometrics 1982;38:597-611. Fulton JE, Pablo G. Topical antibacterial therapy for acne. Arch Dermatol 1974;110:83-6. Mills OH, Kligman AM, Stewart R. The clinical effectiveness of topical erythromycin in ache vulgaris. Cutis 1975;15:93-6. Fulton JE, Bradley S. The choice of vitamin A acid, erythromycin or benzoyl peroxide for the topical treatment of acne. Cutis 1976;17:560-4. Dobson RL, Belknap BS. Topical erythromycin solution in acne. J AM ACAD D~.RMAa'Ot~1980;3:478-82. Shalita AR, Smith EB, Bauer E. Topical erythromyein vs clindamycin therapy for acne. Arch Dermatol 1984; 120:351-5.
ABSTRACTS
Polymyositis associated with AIDS retrovirus Dalakas MC, Pezeshkpour GH, Gravell M, Sever JL. JAMA 1986;256:2381-2 Polymyosltis was the initial manifestationof the human immunodeficiencyvirus infectionof two homosexualmen.Theydeveloped acquired immunodeficiencysyndrome(AIDS)-relatedcomplexa few weeks later, with typical AIDS 2 to 6 monthsafter onset of myopathy. J. Graham Smith, Jr., M.D.
Visceral and skin granuloma annulare, diabetes, and polyendocrine disease Thomas DJB, Rademaker M, Munro DD, Levison DA, Besser GM. Br Med J 1986;293:977-8 A 50-year-oldman with insulin-dependentdiabetes, autoimmune Addison's disease, myxedema, and severe ulcerative colitis, for which he had had a subtotal colectomy, developed granuloma annulare confinedto the anterior abdominalwall in 1981. In 1983, an episode of severe colicky pain occurred, with hyperglycemia. At laparotomy, adhesions and numerous white nodulesover the bowel, mesentery, and peritoneumwere found. The nodules were histologically identical with the skin lesions. A repeat laparotomy because of subacute small bowel obstruction showed widespread intra-ab-
dominal granuloma annulare. This appears to be the first reported case of visceral granulomaannulareto be reported. J. Graham Smith, Jr., M.D.
Oral hairy ieukoplakia in two women, a hemophiliac and a transfusion recipient Greenspan D, Hollander H, Freidman-Kien A, Freese UK, Greenspan JS. Lancet 1986;2:978-9 Reports of oral hairy leukoplakiahave previously been confined to homosexual men infected with human immunodefieiencyvirus (HIV). Three additionalpatientsare reported whose risk factors were: (1) a blood transfusion 4 years previously, (2) a hemophiliac, and (3) a 43-year-oldwomanwho was a partner of an HIV-infectedman. J. Graham Smith, Jr., M.D.
Erythema nodosum provoked by hepatitis B vaccine DiGiusto CA, Bernhard JD. Lancet 1986;2:1042 Fifteen days after the second injection of hepatitis B vaccine, a 24-year-old medical student developed erythema nodosum, which cleared over 13 weeks, She developed lesions again when a third dose was administered5 months after the second. J. Graham Smith, Jr., M.D.