Complementary Therapies in Medicine 47 (2019) 102224 Contents lists available at ScienceDirect Complementary Therapies in Medicine journal homepage: www.elsevier.com/locate/ctim Essential oils as topical anti-infective agents: A systematic review and meta- T analysis Serawit Deynoa,b,c,*, Andrew G. Mtewab,d,i, Abiy Abebee, Ariya Hymetef, Eyasu Makonneng, Joel Bazirah, Paul E. Alelea a Department of Pharmacology, Mbarara University of Science and Technology, Mbarara, P.O.Box 1410, Uganda b Pharm-Biotechnology and Traditional Medicine (PHARMBIOTRAC) Center of Excellence, Mbarara University of Science and Technology, Mbarara, P.O.Box 1410, Uganda c Department of Pharmacology, School of Medicine, College of Medicine and Health Sciences, Hawassa University, P. O. Box 1560, Hawassa, Ethiopia d Chemistry Section, Department of Applied Sciences, Malawi Institute of Technology, Malawi University of Science & Technology, Limbe, Malawi e Traditional and Modern Drug Research Directorate, Ethiopian Public Health Research Institute, Ethiopia f Department of Pharmaceutical chemistry and Pharmacognosy, Addis Ababa University, Ethiopia g Center for Innovative Drug Development and Therapeutic Trials for Africa, College of Health Sciences, Ethiopia h Department of Microbiology, Mbarara University of Science and Technology, Mbarara, P.O.Box 1410, Uganda i Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, DD1 5 EH, Scotland, United Kingdom ARTICLE INFO ABSTRACT Keywords: Objective: This study summarized evidence on the efficacy and safety of essential oils (EOs) in the treatment of Tea tree oil topical infections. Clinical trial Design and setting: Systematic review of clinical trials conducted and reported in accordance with the Preferred Aromatherapy Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guideline. Electronic databases of the Alternative therapy Cochrane, PubMed, EMBASE, Web of Science, and Scopus were searched from inception to November 2018. Intervention: Essential oil of any type, standard treatment and placebo. Main outcome measures: Outcomes of the study include total acne count, acne severity index, reduction in total acne surface area, number of non-inflammatory acne lesions and inflammatory acne lesions, microbial cure rate, microbial decolonization rate, and new microbial emergence. Results: Non-significant but higher proportion of MRSA was cleared in EOs group (69% [95%CI: 34%,96%]) compared to routine care (45% [95%CI: 36%, 53%]). Essential oils significantly lowered level of new MRSA emergence (9% [95% CI: 5%, 14%], I2 = 86.59%) compared to routine care (53% [95%CI: 30%, 75%], I2 = 86.59%). Four of the five studies on acne treatment showed equal or superior efficacy of EOsandthe remaining one showed inferior efficacy to a control. In treatment of topical fungal infections, efficacy ofessential oils were non-inferior compared to a standard treatment but superior to a placebo. Conclusion: Essential oils could be considered as alternative treatment for acne, decolonization of MRSA, and topical fungal infections, yet the low quality and heterogeneity among the studies calls for further studies. 1. Introduction Asteraceae (Echinops kebericho), Umbelliferae (Carum nigrum), Zingi- beraceae (Zingiber officinale).3 Their use in dermatology, cosmetic pro- Essential oils (EOs) are one of the most common natural products ducts and popularity as self-care natural medicine products is recently used for various medical purposes since early human being.1,2 Common increasing.4 Combined with their popular use in dermatology, their EO-producing plant families include Lamiaceae (Ocimum citratus), easy availability, and the emergence of antimicrobial resistance, com- Poaceae (Cymbopogon citratus), Verbenaceae (Aloysia citriodora), mercial EOs are increasingly an option for therapy.5 Essential oils are Abbreviations: ASI, acne severity index; CFU, colony forming unit; EO, essential oil; ICU, intensive care unit; JBS, Johnson's baby soft wash; LFCO, lactobacillus- fermented Chamaecyparis obtusa; MRSA, Methicilin resistant Staphylococcus aureus; TLC, Total acne lesions count; TTO, Tea tree oil ⁎ Corresponding author at: P.O.BOX 1460 Mbarara, Uganda. E-mail addresses: [email protected] (S. Deyno), [email protected] (A.G. Mtewa), [email protected] (A. Abebe), [email protected] (A. Hymete), [email protected] (E. Makonnen), [email protected] (J. Bazira), [email protected] (P.E. Alele). https://doi.org/10.1016/j.ctim.2019.102224 Received 26 August 2019; Received in revised form 27 September 2019; Accepted 17 October 2019 Available online 24 October 2019 0965-2299/ © 2019 Elsevier Ltd. All rights reserved. S. Deyno, et al. Complementary Therapies in Medicine 47 (2019) 102224 considered a means of treatment for resistant and difficult-to-treat 2.4. Methodological quality assessment strains which synergize the antimicrobial activity of conventional an- timicrobial agents when combined with conventional antimicrobial Cochrane risk-of-bias tool was used to assess randomized controlled agents.6 This synergistic activity was attributed to the membrane dis- studies while the Newcastle-Ottawa quality assessment score (NOS) was ruption property of the EOs.7 Their antimicrobial efficacy study in used for non-randomized studies. The bias was graded as low, high or humans particularly have shown promising results as in mouth wash for unclear. oral mal-odour,8 reduced gingival inflammation and dental plaque9,10 and acute external otitis. 2.5. Outcome, intervention, data extraction and management Of the 98 EOs recommended for dermatological use, 88 are en- dorsed for treating skin infections of which 73 are used for bacterial Data on methods, participants, interventions, and outcomes were infections, 49 specifically for acne, 34 for fungal infections, and 16for retrieved. Outcomes of the study included total acne count, acne se- 5 viral infections as outlined by Orchard and Vuuren (2017). The review verity index, reduction in total acne surface area, number of non-in- described the details of commercial EOs use as potential antimicrobials flammatory acne lesions and inflammatory acne lesions, microbial cure to treat skin diseases and focuses on in vitro antimicrobial activities. To rate, microbial decolonization rate and new microbial emergence. date, several clinical studies have been conducted to evaluate the effi- Adverse events were considered secondary outcomes. Intervention of 10–13 14 cacy of these EOs. Except for dental infection, there is no sys- the study included essential oil of any type, standard treatment, and tematic review summarizing the clinical studies conducted on anti-in- placebo. For each dichotomous outcome the number of participants fective use of EOs. The studies are worth summarizing to direct future experiencing the event and the number of patients randomized in each studies and establish evidence-based medicine. The aim of the current treatment group were extracted. study was to synthesize the findings of clinical studies/trials on EOs that have been conducted to treat topical infections. 2.6. Statistical analyses Analyses were performed using STATA version 13.0 (Statacorp, LP, 2. Methods college station, TX). Odds ratios (OR) and 95% confidence intervals (CI) were pooled using the metan command. Heterogeneity was assessed 2.1. Study design 2 using I statistic and Chi square test. Random-effects model (REM) was employed using DerSimonian and Laird method.16 The subgroup ana- This systematic review of clinical trials was conducted using best lysis was done based on the type of intervention. available evidence and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) 3. Results guideline. PRISMA checklist was used to ensure inclusion of relevant information. The protocol was registered in the International 3.1. Characteristics of included studies Prospective Registry of Systematic review with registration number (PROSPERO = 2018 CRD42018106478).15 A total of 1060 articles were identified of which 883 articles re- mained after de-duplications. Titles and abstracts screening reduced the number of articles to 849. With further screening for inclusion and 2.2. Search strategy exclusion criteria, 33 remained for full-texts examination. Fifteen arti- cles were further excluded based on the predefined inclusion/exclusion Electronic databases of the Cochrane, PubMed, EMBASE, Web of criteria. The reasons for exclusion were: dental infection, review arti- Science, and Scopus were searched from inception to November 2018. cles, study protocols, in vitro study, Spanish language article, head lice The search syntax was developed based on guidance from the Cochrane infestation, and duplicate publication. Finally, eighteen articles were handbook in Table 1. Other sources including Google Scholar, the meta included among which were five studies on acne,17–21 five on methicilin register of controlled trials, bibliography of retrieved publications, and resistant S. aureus (MRSA) decolonization22–26 and eight on topical conference proceedings were also searched. fungal infections.13,27–33 A PRISMA flow diagram depicted number of studies retrieved, screened, excluded and included in the study (Fig. 1). 2.3. Selection of papers, inclusion and exclusion criteria 3.2. Risk of bias assessment of included studies Two reviewers (SD and AM) independently performed a literature search