Randomized, double-blind, controlled trial on the efficacy of 12.5% pomelo peel ointment versus 2% mupirocin ointment in the management of localized impetigo contagiosa
SPMC J Health Care Serv. 2019;5(2):1 ARK: https://n2t.net/ark:/76951/jhcs9b96wn
1Department of Dermatology, Southern Philippines Medical Center, JP Laurel Ave, Davao City, Philippines
2Davao Medical School Foundation, Inc., Medical School Drive, Poblacion District, Davao City, Philippines
3Brokenshire Memorial Hospital, Brokenshire Heights, Madapo, Davao City, Philippines
4Community Health & Development Cooperative Hospital, Anda Riverside, Davao City, Philippines
Correspondence Anna Liza Chiu, lyzaflip@yahoo.com
Article editors Joanne Kate Milana-Martinez
Received 13 February 2018
Accepted 2 October 2019
Cite as Chiu AL, Visitacion L. Randomized, double-blind, controlled trial on the efficacy of 12.5% pomelo peel ointment versus 2% mupirocin ointment in the management of localized impetigo contagiosa. SPMC J Health Care Serv. 2019;5(2):1. https://n2t.net/ark:/76951/jhcs9b96wn
Introduction
Mupirocin is one of the most effective topical antibiotics used in the management of localized impetigo contagiosa, an infectious dermatologic condition commonly affecting children and caused by Staphylococcus aureus or Streptococcus pyogenes.1 2 3 4 Until recently, mupirocin, retapamulin, and fusidic acid have been the mainstays in the management of localized impetigo contagiosa.3 4 Several studies have demonstrated the usefulness of hydrogen peroxide cream--an antiseptic and bacteriostatic agent--in the management of localized impetigo contagiosa in patients who are neither systemically unwell nor at high risk of developing complications.5 6 Hydrogen peroxide has been considered to be just as effective as topical antibiotics in reducing the spread of infection in localized impetigo, without the risk of contributing to the antimicrobial resistance of causative organisms.4 6
Localized impetigo contagiosa usually heals spontaneously within 2-3 weeks, but topical antibiotics are commonly given to patients to reduce the spread of infection to other body parts or to other people. Topical antibiotics also relieve discomfort, improve cosmetic appearance by preventing scarring, and prevent the occurrence of complications such as acute poststreptococcal glomerulonephritis.3 4
Mupirocin is relatively expensive.7 There is also the problem of microorganisms developing resistance to mupirocin.8 Thus, there is a need to develop alternative products, such as plant extracts and other active compounds, that will produce cheaper medications, and help vary the current armamentarium for bacterial skin infections. Additionally, the use of natural products as antimicrobials may afford fewer adverse effects and better patient tolerance.
Although in vitro studies have demonstrated the antimicrobial properties of citrus plant extracts,9 10 11 in vivo studies in humans about their antimicrobial properties are lacking. The closest study among humans involved the use of gel formulations of orange (Citrus sinensis) peel essential oils in the treatment of patients with acne.12
Pomelo (Citrus maxima or Citrus grandis), the world’s largest citrus fruit, has been investigated for its antimicrobial and anti-inflammatory effects. 13 In vivo studies of C. grandis extracts and phytochemicals demonstrated the anti-inflammatory activities of the pomelo peel through the inhibition of xylene- and carrageenan-induced edema in mice.14 Pomelo peel extract contains vitamin C and flavonoids—naringenin and hesperidin—which are responsible for wound healing in experimentally-induced wounds in diabetic rats.15
We did this study to compare clinical success between those who were given 12.5% pomelo peel ointment (PPO) and those given 2% mupirocin ointment (MO) as treatment for localized impetigo contagiosa.
Methodology
Study design and setting
We did a double-blind randomized controlled trial from September 2012 to November 2012 among patients clinically diagnosed with impetigo contagiosa at the Dermatology Outpatient Clinic in Southern Philippines Medical Center (SPMC), and barangay health centers in Agdao, Sasa, and Buhangin, Davao City. The specialty clinic at SPMC receives about 7,500 patient visits yearly, while each of the barangay health centers has an average of 175 dermatologic visits yearly.
Participants
Patients 2 to 15 years old clinically diagnosed with localized impetigo contagiosa, with individual lesion diameter of not more than 2 cm, and with total skin surface involvement of less than 5% were recruited into the study. Excluded were patients who had known sensitivity to any ingredients to treatment drugs, infections of deeper skin structures, temperature of more than 37.5° C and cervical lymphadenopathies, as well as those who used systemic antibiotics or topical therapeutic agents 48 hours prior to entry into the study.
To determine the minimum sample size for this study, we assumed that patients prescribed with mupirocin ointment for impetigo contagiosa will have 96.67% clinical cure.16 Calculation was done in order for the study to detect a 30% difference in clinical cure rates between the two treatment groups as statistically significant. In a test for difference of two means carried out at 95% level of confidence, a total sample size of at least 46 will have 80% power of rejecting the null hypothesis if the alternative holds.
Interventions and randomization
Pomelo peel ointment 12.5%. The PPO was prepared using the USP29-NF24 as described in the US Pharmacopeia, 2006 Edition.17 Pomelo peel extract was prepared by mixing 125 grams of air-dried pomelo peel with 125 mL ethyl alcohol and storing the mixture in a tightly closed container for two weeks. Extraction was then done through rotary evaporation of the mixture. PPO was prepared by an industrial pharmacist by mixing 62.38 mL propylene glycol with water, 130.95 grams cetyl alcohol, 0.119 gram methyl paraben, 0.083 grams propyl paraben, 547.62 grams white petrolatum, 0.15 gram sodium laurate sulfate dissolved in water, and 93 grams pomelo peel ethanolic extract. The 12.5% concentration used to create the PPO was chosen based on the results of a study on the minimum inhibitory concentration (MIC) of Citrus paradisi (grapefruit), Citrus grandis (pomelo), and Citrofortunella microcarpa (calamansi).18
To initially test the allergenicity of the product, the ointment was tested on 10 healthy volunteers through patch testing. A thin layer, about 0.25 g, of the ointment was applied on a 1x1 cm2 skin area on the nape of each subject and allowed to stay for 72 hours with transparent occlusive dressing. Readings on the test area after 48 and 72 hours showed absence of pruritus, erythema, macules, papules or vesicles, or other skin lesions in all subjects.
Mupirocin. Commercial 2% MO was procured for use in this study.
Both ointments were similar in appearance and odor, and were packaged in identical 10-mL-capacity cosmetic jars.
Randomization
We randomly assigned patients to one of two treatment arms. Each of the patients in the first group received a 10-mL jar of 12.5% PPO, while each of those in the second group receive a 10-mL jar of 2% MO. Each patient also received a bar of hypoallergenic soap. A research assistant was in charge of dispensing the randomly assigned medications to patients. The allocation of treatment intervention was known only to the research assistant, and was unknown to the physicians, and the patients and/or their guardians.
The patients and/or their caregivers were instructed to wash the skin lesions twice a day for seven days using the hypoallergenic soap provided and to apply a small amount of the ointment on the skin lesions right after washing. They were also instructed to return for follow-up three and/or seven days after the start of ointment application.
Data collection
At baseline, we collected data on the patients’ age, sex, duration of illness, and comorbidities.
The main outcome measure for this study was clinical success rate within 7 days from the start of treatment. We considered clinical success in a patient when there was either ‘complete resolution of lesions’ or ‘dryness of the lesions without crusts, with intact skin, and with no to minimal local erythema’ at any time within 7 days from the start of intervention. We also checked for the presence of adverse effects of the ointments (pruritus, erythema, burning, and pain) during patient follow-up.
Patients from any intervention arm who did not achieve clinical success by day 7 were given oral cloxacillin at 50-100 mg/kg/day for 7 days.
Statistical analysis
Primary analysis for this study was done using the intention-to-treat analysis (ITT) approach. The ITT analysis for the clinical success outcome included all patients randomized to either of the two interventions. Per-protocol analysis was done by excluding all patients who were lost to follow-up before they had the outcome. To assess the robustness of the results, we also did several sensitivity analyses by assuming the best and worst case scenarios for the outcome results of patients who did not have clinical success by day 3 and were lost to follow-up at day 7. Continuous data were summarized as means ± standard deviations and compared using t-test. Categorical data were summarized using frequencies and percentages and compared using chi-square test or Fisher’s exact test. A two-tailed p-value of <0.05 was considered significant. All statistical tests were done using Epi Info 7.2.2.6.
Results
A total of 46 patients with localized impetigo contagiosa were recruited into and included in the primary analysis of this study, 23 of whom were randomized to receive PPO, and the remaining 23 were randomized to receive MO. Figure 1 shows the flow of patients from recruitment, randomization, and follow-up.
|
|
Figure 1 Screening, randomization, follow-up, and analysis of patients in the study. |
The baseline characteristics of patients in both intervention groups are shown in Table 1. The two groups were comparable in terms of mean age, sex distribution, mean duration of illness, and comorbidities.
| Table 1 Baseline characteristics of patients | ||||
| Characteristics | 12.5% pomelo peel ointment
n=23 |
2% mupirocin ointment n=23 |
p-value | |
|---|---|---|---|---|
| Mean age ± SD, years | 4.35 ± 2.99 | 4.65 ± 2.19 | 0.6957 | |
| Sex, frequency (%) | 0.7646 | |||
| Male | 14 (60.87) | 13 (56.52) | ||
| Female | 9 (39.13) | 10 (43.48) | ||
| Duration of illness ± SD, days | 3.57 ± 2.04 | 2.87 ± 1.22 | 0.1674 | |
| Comorbidities, frequency (%) | ||||
| Cough | 1 (4.35) | 2 (8.70) | 1.0000* | |
| Colds | 1 (4.35) | 1 (4.35) | 1.000* | |
| Myalgia | 0 (0.00) | 1 (4.35) | 1.0000* | |
| * Using Fisher’s exact test. | ||||
Table 2 shows the proportion of patients who had clinical success within seven days from treatment. Both intention-to-treat and per protocol analyses showed that the clinical success within 7 days between the two treatment groups were comparable to each other.
| Table 2 Proportion of patients with treatment success | |||
| Outcome and analyses | 12.5% pomelo peel ointment | 2% mupirocin ointment | p-value |
|---|---|---|---|
| Clinical success within 7 days, frequency (%) | |||
| Intention-to-treat analysis | 15/23 (65.22) | 19/23 (82.61) | 0.1880 |
| Per-protocol analysis | 15/20 (75.00) | 19/21 (90.48) | 0.1880 |
No patient from any treatment group experienced pruritus, erythema, burning, or pain during the follow-up.
Sensitivity analyses
Sensitivity analyses using best and worst case scenarios for the outcome results of patients who did not have clinical success before they were lost to follow-up are shown in Table 3. The results for clinical success were inconsistent across the scenarios.
| Table 3 Sensitivity analyses | ||||
| Characteristics | 12.5% pomelo peel ointment | 2% mupirocin ointment | p-value | |
|---|---|---|---|---|
| Scenario 1* | 18 (78.26) | 21 (91.30) | 0.2182 | |
| Scenario 2† | 18 (78.26) | 19 (82.61) | 0.7101 | |
| Scenario 3‡ | 15 (65.22) | 21 (91.30) | 0.0320§ | |
| * Scenario 1 - All patients who did not have the outcome before they were lost to follow up were assumed to have the outcome.
† Scenario 2 - All patients in PPO group who did not have the outcome before they were lost to follow up were assumed to have the outcome. All patients in MO group who did not have the outcome before they were lost to follow up were assumed not to have the outcome. ‡ Scenario 3 - All patients in PPO group who did not have the outcome before they were lost to follow up were assumed to not have the outcome. All patients in MO group who did not have the outcome before they were lost to follow up were assumed to have the outcome. § Significant at p<0.05. |
||||
Discussion
Key results
In this study, we found out that 12.5% PPO and 2% MO had comparable results in terms of clinical success—i.e., complete resolution or dryness of the lesions of impetigo contagiosa—within 7 days from the start of intervention.
Strengths and limitations
We were able to demonstrate that 12.5% PPO can be used as an alternative to 2% mupirocin ointment in the management of localized lesions of impetigo contagiosa. Further, we have also found out that the application of 12.5% PPO on the skin did not cause pruritus, erythema, burning, or pain among the patients in our study. We believe that this is the first study in literature that uses pomelo extract on humans to assess its effectiveness against impetigo contagiosa.
There were some limitations in this study. We did not perform formal studies to determine the physicochemical characteristics of the PPO we developed. These studies can generate useful information (i.e., pH, viscosity, stability, etc.) that can facilitate replication and mass production of the new formulation in the future.19 Also, the observation period in our study, within which we measured clinical success in the management of localized impetigo lesions, was rather short. While 7 days may be enough to determine local changes in lesions, the same duration may not reasonably be adequate for the observation of common and equally important sequelae of localized impetigo contagiosa such as recurrence of lesions, spread of lesions to other parts of the body, and transmission of infection to other people.2 4
Interpretation
A recent meta-analysis showed the effectiveness of mupirocin ointment in the cure of localized impetigo contagiosa.20 Mupirocin is bactericidal at high concentrations and bacteriostatic at lower concentrations.21 22 23 24 More recently, the UK National Institute for Health and Care Excellence issued a draft on the guidelines on antimicrobial prescribing strategy for impetigo, recommending the use of topical hydrogen peroxide 1% cream or another topical antiseptic as first-line agent in the management of localized impetigo contagiosa.5 Since localized impetigo contagiosa may spontaneously heal without treatment,3 4 hydrogen peroxide cream may be a more practical choice for the management of the condition. The use of antiseptics rather than antimicrobials in this case would help prevent the development of antimicrobial resistance of bacteria.25
Several in vitro studies have demonstrated the bacteriostatic and bactericidal effects of pomelo peel and other citrus peel extracts and essential oils.9 10 11 Beta sitosterol, oleic acid, and limonene—phytochemical components found in great quantities in pomelo peel extract—all exhibit antimicrobial activity.26 27 28 Hence, citrus fruit peel essential oils are commonly incorporated into some topical medications that are widely used for the management of skin infections. 29 Clearance of lesions among our patients was probably due to the antimicrobial property of the pomelo peel extract and its components.
Generalizability
The patients in our study represent those who are typically seen in outpatient clinics and subsequently diagnosed as having impetigo contagiosa. Our participants were mainly male and female children who consulted for the management of impetigo within the first few days of the appearance of lesions. As what is typical in this group, some of our patients had non-dermatologic symptoms—cough, colds, and/or myalgia—that accompany the skin lesions. The results of this study, specifically the role of PPO in the management of localized impetigo contagiosa, may therefore be applied to most patients diagnosed to have the infection.
Conclusion
In this randomized controlled trial among patients with localized impetigo contagiosa, proportions of patients with resolved of impetigo lesions within 7 days of intervention were comparable between the group that received 12.5% PPO and the group that received 2% MO.
Contributors
ALC and LV both had substantial contributions to the study design, and to the acquisition, analysis and interpretation of data. ALC and LV wrote the original draft and subsequent revisions, and both authors reviewed, edited, and approved the final version of the manuscript. ALC and LV both agreed to be accountable for all aspects of the work.
Ethics approval
This study was reviewed and approved by the Department of Health XI Cluster Ethics Review Committee (DOH XI CERC reference P12042701).
Reporting guideline used
CONSORT Checklist (https://bit.ly/2wdPaNv)
Article source
Submitted
Peer review
External
Funding
Supported by personal funds of the authors
Competing interests
None declared
Access and license
This is an Open Access article licensed under the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to share and adapt the work, provided that derivative works bear appropriate citation to this original work and are not used for commercial purposes. To view a copy of this license, visit https://creativecommons.org/licenses/by-nc/4.0/.
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Copyright © 2019 AL Chiu et al.
Published
December 26, 2019
Issue
Volume 5 Issue 2 (2019)
Section
Research
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