Clinical and laboratory observations Comparison of mupirocin and erythromycin in the treatment of impetigo LT Jeffrey W. Britton, MC, USNR,CAPT J. Eduardo Fajardo, MC, USN,a n d LCDR Brian Krafte-Jacobs, MC, USNR From the Department of Pediatrics, Naval Hospital, Portsmouth, Virginia
For the past two decades the accepted treatment of impetigo has been systemic antibiotic therapy, l The recently approved topical antibiotic mupirocin has excellent in vitro activity against Streptococcus pyogenes and Staphylococcus aureus, including multiply resistant strains. Originally called pseudomonic acid A, mupirocin is obtained from submerged fermentation of Pseudomonas fluorescens; it acts by inhibition of bacterial protein synthesis by inactivation of isoleucyl transfer R N A synthetase. Rapidly inactivated and rapidly excreted when given systemically, mupirocin has been shown to be safe in animal and human trials.2, 3 Double-blind studies prove mupirocin to be more effective than its polyethylene glycol vehicle for treatment of impetigo.4, 5 Several nonblind or poorly controlled clinical trials have suggested that mupirocin's efficacy is comparable to that of orally administered antibiotics commonly used to treat impetigo, namely, erythromycin, 6-1~ ampicillin, 11 and dicloxacillin.12 We intended to validate these findings in a double-blind, placebo-controlled study. We further hypothesized that erythromycin would cause more adverse side effects and result in poorer compliance, making mupirocin the preferred medication.
Sponsored and supported by the United States Navy Bureau of Medicine and Surgery Clinical Investigation Program, case No. 88-08-2461-00. The views expressed here are those of the authors and do not reflect the official policy or position of the United States Navy, the Department of Defense, or the United States Government. Submitted for publication March 5, 1990; accepted May 3, 1990. Reprint requests: Brian R. Krafte-Jacobs, MD, Department of Pediatrics, Naval Hospital, Portsmouth, VA 23708-5000. 9/26/22160
METHODS This study was conducted in the outpatient division of the Naval Hospital Dcpartment of Pcdiatrics, Portsmouth, Va., from October 1988 through October 1989. The study was approved by the rcsearch and human use committees of the Naval Hospital. Patients. Children aged 12 years and younger with thc clinical diagnosis of impetigo wcrc asked to participate in the study. We classified each patient by age, gender, and number of lesions, and sampled a representative lesion for bacteriologic culture. We categorized thc impetigo by total surface area as mild (36 cm2). Informed written consent was obtaincd from the parent and guardian. We excluded patients who had taken systemic antibiotics in the prcceeding 7 days, those with a history of erythromycin allergy, and thosc taking theophylline or carbamazcpine (because of the interferencc of crythromycin with the metabolism of these drugs). Using a random numbers table, the hospital pharmacy randomly assigned each patient to one of two groups: orally administered erythromycin plus topically applied placebo (erythromycin group) or orally administered placebo plus topically applied mupirocin (mupirocin group). The child's group assignment was not known to parents or investigators. Medications. Parents were instructed to givc the oral medication four times a day and to apply the topical medication three timcs a day, recording cach dose on a medication administration sheet as a measure of compliance. Erythromycin was given as erythromycin ethyl succinate, 200 rag/5 ml, in a total daily dose of 40 mg/kg. Fifteen grams of 2% mupirocin was supplied in its polyethylene glycol base. The Naval Hospital Pharmacy Department compounded the oral and topical placebos.
827
828
Clinical and laboratory observations
T a b l e I. Comparison of treatment groups Mupirocin group (n = 24)
Mean age (yr) Age range
3.8 2 mo to 11 yr Male/Female ratio 15:9 Mean No. of lesions 6.4 Patients with mild lesions 10 Patients with moderate lesions 11 Patients with severe lesions 3
The Journal of Pediatrics November 1990
T a b l e II. Culture results Erythromycin group (n = 30)
4.0 6 mo to 11 yr 12:18 5.4 9 20 1
Bacteriologic studies. Bacteriologic cultures were obtained from representative lesions by means of a Culturette collection and transport system (Marion Laboratories, Inc., Kansas City, Mo.). Swabs were sent to the hospital laboratory, where the microbiology department treated them as "wound cultures," plating them on blood, chocolate, and MacConkey agars and in thioglycolate broth. Cultures were then read by bacteriology technicians. Follow-up and questionnaire. Patients were seen in followup two or three times during a 2-week period, with attention paid to clinical course, side effects, and medication compliance. At the end of the treatment course, patients were asked to complete a questionnaire regarding ease of administration, preference for topical versus oral medication, and side effects. The medication administration record was collected at this time. Compliance was defined as the administration of at least 80% of the prescribed doses of a medication. Evaluation of efficacy. We defined treatment success as either complete resolution or clinical improvement to the point that further antibiotic therapy was deemed unnecessary (i.e., no new lesions and no lesions with continued exudate or inflammation). All cases not fitting this description were considered treatment failures and went on to receive a course of oral erythromycin or dicloxacillin therapy. Statistical analysis. Data were analyzed by means of the chi-square and Fisher Exact tests as appropriate. RESULTS Fifty-four children, aged 2 months to 11 years, participated in the study. Twenty-four received mupirocin and 30 received erythromycin. The groups were comparable in baseline characteristics except that more girls received erythromycin and more boys received mupirocin (Table I). Of the four patients with severe impetigo, three were randomly assigned to the mupirocin group. Culture results were available for 48 of the 54 patients
Organism S. S. S. S.
aureus alone aureus plus other organism aureus plus S. pyogenes pyogenes alone
Other species No growth TOTAL
No. of patients
26 6 7
2 5 2 48
(Table II). S. aureus grew in pure culture of specimens from 26 patients and in mixed culture of specimens from 13 patients (39 total S. aureus, 81%). S. pyogenes grew in seven of those mixed cultures and in pure culture of specimens from only two patients (nine total S. pyogenes, 19%). Forty-eight patients completed the study, 22 of the mupirocin group and 26 of the erythromycin group. Of the remaining six patients, three were lost to follow-up, two were dropped when misdiagnosis was suspected and antifungal therapy begun, and one was removed from the study after the development of S. pyogenes pharyngitis, leading to treatment with intramuscular penicillin. Ninety-one percent (20/22) of the mupirocin subjects and 92% (24/26) of those receiving erythromycin were successfully treated. Both of the mupirocin treatment failures occurred in patients with severe impetigo. The two patients with erythromycin failure had moderate impetigo and onset of new lesions at the end of the 10-day treatment period. Eleven patients reported adverse side effects. All such effects were minor, and none prevented completion of the study. Gastrointestinal and other complaints were equally distributed between the two groups. Of the 48 patients, 41 (85%) were compliant with the three-times-daily topical regimen. Only 31 of these patients (65%) complied with the four-times-daily oral regimen. (p = 0.02). Both mupirocin treatment failures were in patients who complied with the topical regimen; one of these patients was noncompliant with the oral placebo regimen. The two patients in whom erythromycin therapy failed were noncompliant with the oral medicine regimen but received 100% of the topical placebo doses. Forty-seven patients responded to the questionnaire. When patients were stratified by age group, no age-specific preference for oral versus topical medicine was observed. Although there was no statistically significant difference in overall preference for topical versus oral medication (24 topical vs 23 oral), all four parents of children with severe impetigo preferred oral therapy, whereas 64% (9/14) of
Volume 117 Number 5
parents of children with mild impetigo preferred topical medication (p = 0.076). DISCUSSION The unique properties of mupirocin and its reported success in the treatment of superficial skin infections have prompted the reevaluation of the use of topical therapy for impetigo. Several issues must be considered in a comparison of antibiotic regimens. Among these issues are clinical efficacy, bacteriologic efficacy, frequency and severity of side effects, medication compliance, and patient preference. initial open trials by Dux et al.,6 Welsh and Saenz, ll and Gratton 8 compared mupirocin with ampicillin11 or erythromycin6, 8 in the treatment of all skin infections. All three studies had small numbers of study subjects and equivalent cure rates for impetigo. Arrendondo12compared mupirocin with dicloxacillin for the treatment of impetigo in a nonblind study and had 100% and 93.5% cure rates, respectively. McLinn 7 and Goldfarb et al. 1~ used open-label parallel group designs to show nearly 100% clinical cure rates for both mupirocin and erythromycin. Using a blind but not placebo-controlled approach, Mertz et a1.13reported equal impetigo cure rates for mupirocin (93%) and erythromyein (96%). With a double-blind, placebo-controlled approach, we confirmed the finding that mupirocin and erythromycin are equally effective in the treatment of impetigo. There is mounting evidence that the predominant organism in impetigo is changing,v' 13 Twenty years ago, S p y o genes was the organism most frequently recovered from these lesions; recent studies have shown a 53% to 98% incidence of S. aureus in pure or mixed culture of specimens from patients with impetigo, with a much smaller rate of S. pyogenes involvement.13 Our culture results support these later studies. Oral administration of erythormycin has been associated with gastrointestinal side effects. Our study, however, revealed minimal side effects overall, and there were no significant differences between the erythromycin and mupirocin groups. Patients are more compliant when given simple and less frequent dosing regimens. 14 Our results support this principle, demonstrating significantly better compliance with three-times-daily topical administration than with fourtimes-daily oral dosing. Both erythromycin treatment failures were in patients who were noncompliant with the oral medication regimen. Sixty-four percent of parents of children with mild impetigo preferred topical therapy. The parents of the four children with severe impetigo unani-
Clinical and laboratory observations
829
mously preferred oral medication. Both muplrocin treatment failures were in this latter subset. We conclude that mupirocin and erythromycin are equally effective in the treatment of impetigo, and that both medications produce very few side effects. Compliance is significantly better with topical application three times a day than with oral dosing four times a day. We also conclude that S. aureus remains the most common causative organism in impetigo. We thank the Naval Hospital Pharmacy Department, Portsmouth, for their assistance in the random assignment of patients and in the preparation and distribution of medications. REFERENCES
1. Baltimore RS. Treatment of impetigo:a review. Pediatr Infect Dis 1985;4:597-601. 2. Sutherland R, Boon RJ, Griffen KE, Masters PJ, SlocombeB, White AR. Antibacterial activity of mupiroein (pseudomonic acid), a new antibiotic for topical use. Antimicrob Agents Chemother 1985;27:495-8. 3. Leyden JJ. Mupirocin: a new topical antibiotic. Semin Dermatol 1987;6:48-54. 4. Orecchio RM, Mischler TW. A double-blind multiclinic comparative trial of mupirocin and its vehicle in the treatment of bacterial skin infections. Curr Ther Res 1986;39:82-6. 5. EellsLD, Mertz PM, Piovanetti Y, Pekoe GM, Eaglstein WH. Topical antibiotic treatment of impetigo with mupirocin. Arch Dermatol 1986;122:1273-6. 6. Dux PH, Fields L, Pollock D. Two percent topical mupirocin versus systemic erythromycin and cloxacillin in primary and secondary skin infections. Curr Ther Res 1986;40:933-40. 7. McLinn S. Topical mupirocin vs. systemic erythromycin treatment for pyoderma. Pediatr Infect Dis J 1988;7:785-90. 8. Gratton D. Topical mupirocinversus oral erythromycin in the treatment of primary and secondary skin infections. Int J Dermatol 1987;26:472-3. 9. Barton LL, Friedman AD, Sharkey AM, Schneller DJ, Swierkosz EM. Impetigo contagiosa. IIl Comparative efficacy of oral erythromycin and topical mupirocin. Pediatr Dermatol 1989;6:134-8. 10. Goldfarb J, Crenshaw D, O'Horo J, Lemon E, Blumer JL. Randomized clinical trial of topical mupirocin versus oral erythromycin for impetigo. Antimicrob Agents Chemother 1988;32:1780-3. 11. Welsh O, Saenz C. Topical mupirocin compared with oral ampicillin in the treatment of primary and secondary skin infections. Curr Ther Res 1987;41:114-20. 12. Arredondo, JL. Efficacy and tolerance of topical mupirocin compared with oral dicloxacillinin the treatment of primary skin infections. Curr Ther Res 1987;41:121-7. 13. Schachner L, Taplin D, Scott GB, Morrison M. A therapeutic update of superficial skin infections. Pediatr Clin North Am 1983;30:397-404. 14. Cockburn J, Gibberd RW, Reid AL, Sanson-Fisher RW. Determinants of noncompliancewith short-term antibiotic regimens. Br Med J [Clin Res] 1987;295:814-8.
For the past two decades the accepted treatment of impetigo has been systemic antibiotic therapy, l The recently approved topical antibiotic mupirocin has excellent in vitro activity against Streptococcus pyogenes and Staphylococcus aureus, including multiply resistant strains. Originally called pseudomonic acid A, mupirocin is obtained from submerged fermentation of Pseudomonas fluorescens; it acts by inhibition of bacterial protein synthesis by inactivation of isoleucyl transfer R N A synthetase. Rapidly inactivated and rapidly excreted when given systemically, mupirocin has been shown to be safe in animal and human trials.2, 3 Double-blind studies prove mupirocin to be more effective than its polyethylene glycol vehicle for treatment of impetigo.4, 5 Several nonblind or poorly controlled clinical trials have suggested that mupirocin's efficacy is comparable to that of orally administered antibiotics commonly used to treat impetigo, namely, erythromycin, 6-1~ ampicillin, 11 and dicloxacillin.12 We intended to validate these findings in a double-blind, placebo-controlled study. We further hypothesized that erythromycin would cause more adverse side effects and result in poorer compliance, making mupirocin the preferred medication.
Sponsored and supported by the United States Navy Bureau of Medicine and Surgery Clinical Investigation Program, case No. 88-08-2461-00. The views expressed here are those of the authors and do not reflect the official policy or position of the United States Navy, the Department of Defense, or the United States Government. Submitted for publication March 5, 1990; accepted May 3, 1990. Reprint requests: Brian R. Krafte-Jacobs, MD, Department of Pediatrics, Naval Hospital, Portsmouth, VA 23708-5000. 9/26/22160
METHODS This study was conducted in the outpatient division of the Naval Hospital Dcpartment of Pcdiatrics, Portsmouth, Va., from October 1988 through October 1989. The study was approved by the rcsearch and human use committees of the Naval Hospital. Patients. Children aged 12 years and younger with thc clinical diagnosis of impetigo wcrc asked to participate in the study. We classified each patient by age, gender, and number of lesions, and sampled a representative lesion for bacteriologic culture. We categorized thc impetigo by total surface area as mild (36 cm2). Informed written consent was obtaincd from the parent and guardian. We excluded patients who had taken systemic antibiotics in the prcceeding 7 days, those with a history of erythromycin allergy, and thosc taking theophylline or carbamazcpine (because of the interferencc of crythromycin with the metabolism of these drugs). Using a random numbers table, the hospital pharmacy randomly assigned each patient to one of two groups: orally administered erythromycin plus topically applied placebo (erythromycin group) or orally administered placebo plus topically applied mupirocin (mupirocin group). The child's group assignment was not known to parents or investigators. Medications. Parents were instructed to givc the oral medication four times a day and to apply the topical medication three timcs a day, recording cach dose on a medication administration sheet as a measure of compliance. Erythromycin was given as erythromycin ethyl succinate, 200 rag/5 ml, in a total daily dose of 40 mg/kg. Fifteen grams of 2% mupirocin was supplied in its polyethylene glycol base. The Naval Hospital Pharmacy Department compounded the oral and topical placebos.
827
828
Clinical and laboratory observations
T a b l e I. Comparison of treatment groups Mupirocin group (n = 24)
Mean age (yr) Age range
3.8 2 mo to 11 yr Male/Female ratio 15:9 Mean No. of lesions 6.4 Patients with mild lesions 10 Patients with moderate lesions 11 Patients with severe lesions 3
The Journal of Pediatrics November 1990
T a b l e II. Culture results Erythromycin group (n = 30)
4.0 6 mo to 11 yr 12:18 5.4 9 20 1
Bacteriologic studies. Bacteriologic cultures were obtained from representative lesions by means of a Culturette collection and transport system (Marion Laboratories, Inc., Kansas City, Mo.). Swabs were sent to the hospital laboratory, where the microbiology department treated them as "wound cultures," plating them on blood, chocolate, and MacConkey agars and in thioglycolate broth. Cultures were then read by bacteriology technicians. Follow-up and questionnaire. Patients were seen in followup two or three times during a 2-week period, with attention paid to clinical course, side effects, and medication compliance. At the end of the treatment course, patients were asked to complete a questionnaire regarding ease of administration, preference for topical versus oral medication, and side effects. The medication administration record was collected at this time. Compliance was defined as the administration of at least 80% of the prescribed doses of a medication. Evaluation of efficacy. We defined treatment success as either complete resolution or clinical improvement to the point that further antibiotic therapy was deemed unnecessary (i.e., no new lesions and no lesions with continued exudate or inflammation). All cases not fitting this description were considered treatment failures and went on to receive a course of oral erythromycin or dicloxacillin therapy. Statistical analysis. Data were analyzed by means of the chi-square and Fisher Exact tests as appropriate. RESULTS Fifty-four children, aged 2 months to 11 years, participated in the study. Twenty-four received mupirocin and 30 received erythromycin. The groups were comparable in baseline characteristics except that more girls received erythromycin and more boys received mupirocin (Table I). Of the four patients with severe impetigo, three were randomly assigned to the mupirocin group. Culture results were available for 48 of the 54 patients
Organism S. S. S. S.
aureus alone aureus plus other organism aureus plus S. pyogenes pyogenes alone
Other species No growth TOTAL
No. of patients
26 6 7
2 5 2 48
(Table II). S. aureus grew in pure culture of specimens from 26 patients and in mixed culture of specimens from 13 patients (39 total S. aureus, 81%). S. pyogenes grew in seven of those mixed cultures and in pure culture of specimens from only two patients (nine total S. pyogenes, 19%). Forty-eight patients completed the study, 22 of the mupirocin group and 26 of the erythromycin group. Of the remaining six patients, three were lost to follow-up, two were dropped when misdiagnosis was suspected and antifungal therapy begun, and one was removed from the study after the development of S. pyogenes pharyngitis, leading to treatment with intramuscular penicillin. Ninety-one percent (20/22) of the mupirocin subjects and 92% (24/26) of those receiving erythromycin were successfully treated. Both of the mupirocin treatment failures occurred in patients with severe impetigo. The two patients with erythromycin failure had moderate impetigo and onset of new lesions at the end of the 10-day treatment period. Eleven patients reported adverse side effects. All such effects were minor, and none prevented completion of the study. Gastrointestinal and other complaints were equally distributed between the two groups. Of the 48 patients, 41 (85%) were compliant with the three-times-daily topical regimen. Only 31 of these patients (65%) complied with the four-times-daily oral regimen. (p = 0.02). Both mupirocin treatment failures were in patients who complied with the topical regimen; one of these patients was noncompliant with the oral placebo regimen. The two patients in whom erythromycin therapy failed were noncompliant with the oral medicine regimen but received 100% of the topical placebo doses. Forty-seven patients responded to the questionnaire. When patients were stratified by age group, no age-specific preference for oral versus topical medicine was observed. Although there was no statistically significant difference in overall preference for topical versus oral medication (24 topical vs 23 oral), all four parents of children with severe impetigo preferred oral therapy, whereas 64% (9/14) of
Volume 117 Number 5
parents of children with mild impetigo preferred topical medication (p = 0.076). DISCUSSION The unique properties of mupirocin and its reported success in the treatment of superficial skin infections have prompted the reevaluation of the use of topical therapy for impetigo. Several issues must be considered in a comparison of antibiotic regimens. Among these issues are clinical efficacy, bacteriologic efficacy, frequency and severity of side effects, medication compliance, and patient preference. initial open trials by Dux et al.,6 Welsh and Saenz, ll and Gratton 8 compared mupirocin with ampicillin11 or erythromycin6, 8 in the treatment of all skin infections. All three studies had small numbers of study subjects and equivalent cure rates for impetigo. Arrendondo12compared mupirocin with dicloxacillin for the treatment of impetigo in a nonblind study and had 100% and 93.5% cure rates, respectively. McLinn 7 and Goldfarb et al. 1~ used open-label parallel group designs to show nearly 100% clinical cure rates for both mupirocin and erythromycin. Using a blind but not placebo-controlled approach, Mertz et a1.13reported equal impetigo cure rates for mupirocin (93%) and erythromyein (96%). With a double-blind, placebo-controlled approach, we confirmed the finding that mupirocin and erythromycin are equally effective in the treatment of impetigo. There is mounting evidence that the predominant organism in impetigo is changing,v' 13 Twenty years ago, S p y o genes was the organism most frequently recovered from these lesions; recent studies have shown a 53% to 98% incidence of S. aureus in pure or mixed culture of specimens from patients with impetigo, with a much smaller rate of S. pyogenes involvement.13 Our culture results support these later studies. Oral administration of erythormycin has been associated with gastrointestinal side effects. Our study, however, revealed minimal side effects overall, and there were no significant differences between the erythromycin and mupirocin groups. Patients are more compliant when given simple and less frequent dosing regimens. 14 Our results support this principle, demonstrating significantly better compliance with three-times-daily topical administration than with fourtimes-daily oral dosing. Both erythromycin treatment failures were in patients who were noncompliant with the oral medication regimen. Sixty-four percent of parents of children with mild impetigo preferred topical therapy. The parents of the four children with severe impetigo unani-
Clinical and laboratory observations
829
mously preferred oral medication. Both muplrocin treatment failures were in this latter subset. We conclude that mupirocin and erythromycin are equally effective in the treatment of impetigo, and that both medications produce very few side effects. Compliance is significantly better with topical application three times a day than with oral dosing four times a day. We also conclude that S. aureus remains the most common causative organism in impetigo. We thank the Naval Hospital Pharmacy Department, Portsmouth, for their assistance in the random assignment of patients and in the preparation and distribution of medications. REFERENCES
1. Baltimore RS. Treatment of impetigo:a review. Pediatr Infect Dis 1985;4:597-601. 2. Sutherland R, Boon RJ, Griffen KE, Masters PJ, SlocombeB, White AR. Antibacterial activity of mupiroein (pseudomonic acid), a new antibiotic for topical use. Antimicrob Agents Chemother 1985;27:495-8. 3. Leyden JJ. Mupirocin: a new topical antibiotic. Semin Dermatol 1987;6:48-54. 4. Orecchio RM, Mischler TW. A double-blind multiclinic comparative trial of mupirocin and its vehicle in the treatment of bacterial skin infections. Curr Ther Res 1986;39:82-6. 5. EellsLD, Mertz PM, Piovanetti Y, Pekoe GM, Eaglstein WH. Topical antibiotic treatment of impetigo with mupirocin. Arch Dermatol 1986;122:1273-6. 6. Dux PH, Fields L, Pollock D. Two percent topical mupirocin versus systemic erythromycin and cloxacillin in primary and secondary skin infections. Curr Ther Res 1986;40:933-40. 7. McLinn S. Topical mupirocin vs. systemic erythromycin treatment for pyoderma. Pediatr Infect Dis J 1988;7:785-90. 8. Gratton D. Topical mupirocinversus oral erythromycin in the treatment of primary and secondary skin infections. Int J Dermatol 1987;26:472-3. 9. Barton LL, Friedman AD, Sharkey AM, Schneller DJ, Swierkosz EM. Impetigo contagiosa. IIl Comparative efficacy of oral erythromycin and topical mupirocin. Pediatr Dermatol 1989;6:134-8. 10. Goldfarb J, Crenshaw D, O'Horo J, Lemon E, Blumer JL. Randomized clinical trial of topical mupirocin versus oral erythromycin for impetigo. Antimicrob Agents Chemother 1988;32:1780-3. 11. Welsh O, Saenz C. Topical mupirocin compared with oral ampicillin in the treatment of primary and secondary skin infections. Curr Ther Res 1987;41:114-20. 12. Arredondo, JL. Efficacy and tolerance of topical mupirocin compared with oral dicloxacillinin the treatment of primary skin infections. Curr Ther Res 1987;41:121-7. 13. Schachner L, Taplin D, Scott GB, Morrison M. A therapeutic update of superficial skin infections. Pediatr Clin North Am 1983;30:397-404. 14. Cockburn J, Gibberd RW, Reid AL, Sanson-Fisher RW. Determinants of noncompliancewith short-term antibiotic regimens. Br Med J [Clin Res] 1987;295:814-8.
