Topical antibiotics for acne

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the efficacy and safety of topical antibiotics for the treatment of acne vulgaris.

Background

Please see Appendix 1 for an explanation of the terms we have used.

Description of the condition

Acne is a multifactorial inflammatory skin disease affecting 70% to 90% of individuals from the age of 12 to 24 years (Ghodsi 2009). Although acne is classically a self‐limiting disease of adolescence, evidence suggests it is occurring at earlier stages of puberty and is also lasting longer (Goulden 1999a; Goulden 1999b; Williams 2006). It is currently considered a chronic disease (Zouboulis 2014). Persistent acne beyond teenage years is more common in women than men and may be associated with hormonal imbalances (Goulden 1999a; Goulden 1999b; Williams 2006).

Acne is centred around the pilosebaceous unit (the hair follicle and shaft and sebaceous gland) (Zouboulis 2004). Therefore, acne is predominantly located in areas rich in sebaceous follicles, such as the face, back, and chest (Katsambas 2008). It is a polymorphic (variably expressed) disease that can present with open and closed comedones (blackheads and whiteheads), inflammatory lesions (papules, pustules, and nodules), and subsequent atrophic (indentations) or hypertrophic (raised) scars (Jordan 2000; Layton 1994; Layton 2001).

Clinical forms of acne, classified by the predominant type of lesions, include comedonal acne, papulopustular acne, and nodular or conglobate acne. For research purposes, lesions may be further categorised into inflamed (papules, pustules, nodules) and non‐inflamed (comedones), and the number of lesions per patient is counted and documented (Gollnick 2003). Many clinical trials also capture global assessments including patient perspectives (Nast 2012).

Several interrelated factors contribute to the development of an inflammatory response in acne; these include increased sebum production, disturbances in keratinisation of the follicular epithelium, and hypercolonisation of the bacterium Propionibacterium acnes (P. acnes) as well as immunological reactions (Kurokawa 2009; Zouboulis 2005). The onset of acne is precipitated by the increase in secretion of androgens (dehydroepiandrosterone, dehydroepiandrosterone sulphate) at the start of puberty and the subsequent activation of sebaceous glands (Thiboutot 2004; Zouboulis 2004). Androgens stimulate the enlargement of the sebaceous glands and increase sebum production; they also stimulate excessive build‐up of keratin within the intrafollicular duct, which results in the accumulation of sebum. These mechanisms lead to the plugging of the hair follicles and formation of comedones (Cunliffe 2004; Zouboulis 2005). P. acnes, an otherwise common and harmless commensal bacterium, becomes trapped inside the plugged hair follicles, thrives on the excess sebum, overgrows, and induces an intense inflammatory response by production of numerous proinflammatory cytokines. This contributes to the formation of inflammatory skin lesions (papules, pustules, and nodules) (Beylot 2014; Gollnick 2003; Thiboutot 2009). Recent evidence suggests that P. acnes grows in a biofilm, a sessile bacterial community encased in an extracellular matrix structure, which regulates bacterial growth and metabolism, alters host metabolism, and confers resistance to antimicrobial treatments and host inflammatory cells (Vlassova 2011).

Description of the intervention

The choice of treatment for acne is determined by the underlying pathophysiology and the clinical presentation (Gollnick 2003). Ideally, treatment should improve all of the major underlying pathogenic factors, for example, relating to the formation of comedones, seborrhoea, P.acnes overgrowth, and the inflammatory response (Katsambas 2008; Katsambas 2010).

The most commonly used topical antibiotics for acne treatment are erythromycin, which is a macrolide antibiotic, and clindamycin, which is a lincosamide derivative. These are available as solutions, lotions, gels, and saturated pads (Johnson 2000). Both clindamycin and erythromycin are effective in treating inflammatory acne, but have limited efficacy against non‐inflammatory lesions (Simonart 2005; Williams 2012). Major side‐effects are rare with topical antibiotics, although there have been a few reported cases of pseudomembranous colitis associated with one formulation of topical clindamycin (Drucker 2012). Topical antibiotic use is generally well tolerated apart from mild localised skin irritation, such as redness and desquamation, which is attributed to the drug vehicle rather than the antibiotic itself (Worret 2006).

A dramatic increase in bacterial resistance has developed over the past few decades (especially when topical antibiotics have been used as monotherapy) (Kinney 2010), which is leading to a potential decline in their efficacy as acne treatments (Patel 2010; Simonart 2005). Therefore, topical antibiotics are used in combination with agents that reduce or prevent bacterial resistance, i.e. benzoyl peroxide (BPO) (Nast 2012; Strauss 2007). Topical antibiotics are also combined with topical retinoids in order to reduce the length of exposure to antibiotics and hence the risk of resistance by achieving a maximised and accelerated treatment response (Nast 2012; Strauss 2007).

How the intervention might work

Topical antibiotics reduce the population of P. acnes within the follicles and are thought to possess an anti‐inflammatory and mild comedolytic effect; their bacteriostatic activity is based on interaction with ribosomal subunits and the inhibition of protein synthesis (Del Rosso 2008; Leyden 2007). They also inhibit the synthesis of lipase, the enzyme used by P. acnes for hydrolysing serum triglycerides to proinflammatory free fatty acids and glycerol, which is a substrate important for bacterial growth (Webster 1981). The anti‐inflammatory property of antibiotics is related to the inhibition of complement pathways and subsequently the impairment of neutrophil chemotaxis (Tan 2005). Increasing bacterial resistance has led to recommendations against the use of topical antibiotics as monotherapy, but they still play an important role when combined with other topical agents in mild to moderate acne (Nast 2012).

Benzoyl peroxide, the most frequently used agent for combination therapy with topical antibiotics, is a bactericidal agent that kills P. acnes and has mild anti‐inflammatory and comedolytic activities (Patel 2010; Strauss 2007). Due to its lipophilic properties, it accumulates inside the pilosebaceous unit, producing benzoic acid and reactive oxygen species, which oxidise bacterial proteins. This leads to the inhibition of protein and nucleotide synthesis, metabolic pathways, and mitochondrial activity of P. acnes (Dutil 2010).

Why it is important to do this review

Acne is the eighth most globally prevalent skin condition and the second most debilitating skin disease (Hay 2014). It is a chronic and common condition with recurrences and relapses during puberty and adolescence. It may persist into adulthood and may result in significant emotional disturbance as well as physical scarring (Williams 2012). The degree of scarring relates to the duration of acne, and it is therefore important to ensure that effective treatment is commenced in a timely fashion.

Many topical acne preparations that contain antibiotics as mono‐ or combination therapy are available. However, there is a lack of comparative data on the most appropriate choice, taking efficacy, compliance, tolerability, and overall patient satisfaction into consideration (Ozolins 2005). The issue of increasing antibiotic resistance highlights the need for the optimal use of both topical and systemic antibiotics in practice (Nast 2012). Furthermore, there is no standardised validated grading system for assessing acne, and this hinders comparisons between clinical trials (Nast 2012).

Many Cochrane Reviews have addressed different aspects of acne vulgaris, including interventions for acne scars (Abdel Hay 2016), complementary therapies for acne (Cao 2015), minocycline use (Garner 2012), and use of combined oral contraceptive pills in acne (Arowojolu 2012). Our aim with this review is to provide evidence that may help inform recommendations for the use, retention, or withdrawal of topical antibiotics for acne in clinical practice.

Objectives

To assess the efficacy and safety of topical antibiotics for the treatment of acne vulgaris.

Methods

Criteria for considering studies for this review

Types of studies

We will include only randomised controlled trials (RCTs) that use topical antibiotics as monotherapy or in combination with other treatment options (e.g. benzoyl peroxide, topical retinoids), and compare them with placebo and other topical or systemic drugs for the treatment of acne vulgaris.

Types of participants

We will include clinically diagnosed participants of all ages and both sexes with the following:

• acne vulgaris on the face or trunk, or both, regardless of acne severity and previous treatments;

• comedonal acne, papulopustular acne, nodulocystic acne, or acne conglobata; or

• inflammatory or non‐inflammatory acne.

We will exclude studies where participants had a diagnosis of hidradenitis suppurativa; acne mechanica; acne excoriée; occupational‐induced, drug‐induced, or cosmetic‐induced acne; infantile or neonatal acne; acne caused by underlying endocrinological (hormonally driven) conditions; acne fulminans; or rosacea.

Types of interventions

We will include studies assessing the efficacy of topical antibiotics of any treatment regimen, dose, duration, and mode of delivery, either used as monotherapy or in combination with other topical drugs. We will exclude studies that used systemic therapy in addition to topical antibiotics as in these studies, efficacy will be mostly due to the use of systemic therapy rather than the effect of the adjuvant topical treatment. However, in case we find any studies that include topical use only prior to inclusion of oral therapy, we will include these studies and assess the impact of topical treatment prior to use of additional oral treatment if possible.

Types of outcome measures

Timing of outcome assessment

We will assess our outcomes (except for the maintenance rate and Propionibacterium acnes (P. acnes) resistance) in short‐term (from two up to four weeks), medium‐term (from four up to eight weeks), and long‐term (more than eight weeks) follow‐up periods. Medium‐term follow‐up data are the primary end points for assessment of efficacy and tolerability. If studies present longitudinal analysis as a time‐course with each time point reported and there is adequate data, we may include these studies in longitudinal meta‐analyses.

We are also interested in short‐term data in order to assess early improvement or adverse events (AEs) as well as long‐term data in cases where topical antibiotics are prescribed in combination with other topical agents.

Primary outcomes

1. Proportion of participants expressing a self‐reported improvement in their acne.

2. Proportion of participants experiencing adverse events serious enough to lead to withdrawal from the study or in situations where AEs outweigh treatment benefits, such as pseudomembranous colitis, hypersensitivity reactions, allergic reactions, severe contact dermatitis, and similar reactions.

Secondary outcomes

1. Proportion of participants rated 'clear' or 'almost clear' on the Investigator Global Assessment (IGA) scale of acne severity.

2. Investigators' assessment of change in the lesion count.

3. Change in acne‐related quality of life score using validated scales, e.g. Skindex‐16, Skindex‐29, the Cardiff Acne Disability Index.

4. Maintenance rate at the end of treatment, defined as the percentage of participants able to maintain a 50% improvement in the total lesion count from baseline after 12 weeks of treatment withdrawal.

5. Evolution of resistance to P. acnes over time, assessed indirectly using an approach similar to that adopted by Simonart 2005 where decrease in lesion count has been compared across trials over time using linear regression.

6. Proportion of participants experiencing mild adverse effects that are documented but do not stop treatment or impact on its length and efficacy, e.g. local skin irritation.

Search methods for identification of studies

We aim to identify all randomised controlled trials (RCTs) regardless of language or publication status (published, unpublished, in press, or in progress).

Electronic searches

We will search the following databases for relevant trials:

• the Cochrane Skin Group Specialised Register;

• the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library;

• MEDLINE via Ovid (from 1946);

• Embase via Ovid (from 1974); and

• LILACS (Latin American and Caribbean Health Science Information database, from 1982).

We have devised a draft search strategy for RCTs for MEDLINE (Ovid), which is displayed in Appendix 2. This will be used as the basis for search strategies for the other databases listed.

Trials registers

We will search the following trials registers for any relevant registered trials using terms adapted from the MEDLINE strategy in Appendix 2.

• The ISRCTN registry (www.controlled‐trials.com).

• The US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov).

• The Australian New Zealand Clinical Trials Registry (www.anzctr.org.au).

• The World Health Organization International Clinical Trials Registry platform (www.who.int/trialsearch).

• The EU Clinical Trials Register (www.clinicaltrialsregister.eu).

Searching other resources

References from included studies

We will check the bibliographies of included studies for further references to relevant trials.

Unpublished trials

We will try to identify any unpublished trials by contacting researchers, organisations, and pharmaceutical companies in the dermatology field. We will attempt to contact the investigators of these trials to include their data, if applicable, in our review.

Adverse effects

We will not perform a separate search for adverse effects of the target intervention. However, we will examine data on adverse effects from the included studies that we identify.

Data collection and analysis

For standardisation of data collection and analysis, some parts of the methods section of this protocol use text that was originally published in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Selection of studies

After removal of duplicates, two independent authors, MG and CL, will screen the titles and abstracts identified in the initial search results to decide which trials are eligible for inclusion. If it is not clear from the title or abstract, or in case the study meets our inclusion criteria, we will retrieve the full text of the paper. The authors will independently read and analyse the full text of each study in order to confirm if it meets the predefined inclusion criteria. We will resolve any disagreement in study assessment by referring to a third author (EL). We will record the reasons for exclusion of the read full‐text papers in the 'Characteristics of excluded studies' tables.

Data extraction and management

Two authors, CL and EL, will independently extract the data using a standardised data extraction form, which we have modified for our review. Independent extraction will include blinding for each other's data extraction, but we will not blind the journal of publication or the authors of the studies. We will extract data according to Table 7.3.a 'Checklist of items to consider in data collection or data extraction' found in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and afterwards, the two authors will enter the data into the 'Characteristics of included studies' tables. They will resolve any differences in opinions through discussions with a third author (MG).

Assessment of risk of bias in included studies

Two authors, MG and CL, will independently assess the risk of bias of the eligible studies, using the following criteria suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). A third author will resolve disagreements. We will record the results in the 'Risk of bias' tables within the 'Characteristics of included studies' tables, according to the following categories of bias.

Selection bias

We will report in detail how the randomisation sequence was generated and which method was used for allocation concealment in order to assess whether it allowed the formation of comparable groups and whether intervention allocations could have been foreseen in advance of, or during, enrolment.

Performance bias

We will describe which measures were used to prevent study investigators and participants from knowledge of which intervention a participant received as well as provide any information relating to whether the intended blinding was effective.

Detection bias

We will describe which measures were undertaken to prevent outcome assessors from knowledge of which intervention a participant received as well as provide information relating to whether intended blinding was effective.

Attrition bias

We will report on the completeness of outcome data for each main outcome, i.e. how many participants were lost to follow up, whether reasons for losses were reported, and whether the intention‐to‐treat principle was followed.

Reporting bias

We will address how the review authors examined the possibility of selective outcome reporting and what was found.

Other bias

We will report on any other concerns that we may have about bias, which are not addressed in previous categories.

We will categorise and report the overall risk of bias of each of the included studies according to the following:

• low risk of bias (plausible bias unlikely to seriously alter the results) if we assess all bias criteria as low risk of bias;

• unclear risk of bias (plausible bias that raises some doubt about the results) if one or more criteria were unknown or we assess bias as unclear; or

• high risk of bias (plausible bias that seriously weakens confidence in the results) if we assess one or more criteria as high risk of bias.

Measures of treatment effect

We will make comparisons between topical antibiotics (applied as monotherapy or in combination with other topical treatments) and placebo or other treatment options for acne. We will also assess whether combination products are any more effective than topical antibiotics alone for treating acne vulgaris. Whenever possible, we will compare the dose, treatment regimen, duration, and mode of delivery of each topical antibiotic. Comparing the mode of delivery of the same topical antibiotic is important because of the different absorption characteristics and aesthetic properties of different vehicles.

We expect our primary outcome 'Proportion of participants expressing a self‐reported improvement in their acne' to have been mostly recorded using a Likert or Likert‐like scale (for example, participants may choose from the following categories to assess change of their acne after treatment: acne has 'worsened a lot', 'worsened a little', 'stayed the same', 'improved a little', or 'improved a lot'). We will log improvement with treatment as a dichotomous variable by recording any score on these scales implying change for the better as response to treatment, whereas we will note other options including no change and worsening with treatment as treatment failure.

We will assess our secondary outcome 'Investigators' assessment of change in the lesion count' as the absolute change from baseline in the number of inflamed lesions (papules or pustules, or both), non‐inflamed lesions (open or closed comedones, or both), and nodules and cysts (for nodulocystic acne only), with each category (inflamed, non‐inflamed, and nodules and cysts) counted separately. If lesion counts are not available, we will assess the absolute change from baseline in the total number of all lesion types.

Dichotomous data

For dichotomous outcomes, we will express the results as relative risks (RR) with their associated 95% confidence intervals (CIs) and I² statistics.

Continuous data

For continuous outcomes, we will calculate mean differences (MD) with 95% CIs, or we will use standardised mean differences (SMD) with 95% CIs for studies where continuous outcomes are measured with different but comparable outcomes across studies, e.g. quality of life.

Unit of analysis issues

If there are multiple intervention groups within a trial, we will combine groups to create pair‐wise comparisons, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 16) (Higgins 2011). We will analyse cross‐over trials using only the first‐phase data, which we will pool with data from parallel group studies. We will analyse internally controlled trials using adequate techniques for paired designs; we will not pool such trials with studies of other designs. We will reanalyse cluster randomised controlled trials that are not adequately corrected for clustering or inflate the standard deviation. Where it is not possible to inflate the standard deviation, we will present only the measure of treatment effect without the P value or 95% CI. We will analyse within‐participant studies consistently with the Cochrane Handbook for Systematic Reviews of Interventions Section 16.4.4 (Higgins 2011).

Dealing with missing data

For missing data, we will try to contact authors of included RCTs via emails to investigate if further data are available for analysis.

For dichotomous outcomes, we will conduct sensitivity analyses based on consideration of 'best‐case' and 'worse‐case' assumptions for those leaving the study early to understand how primary outcomes would change under each assumption. In best‐case assumptions, we will regard participants who dropped out of the intervention group as having improved after treatment (effective treatment), whereas we will regard those who dropped out of the control group as having ineffective results. In worst‐case assumptions, we will consider missing data in the intervention group as having an ineffective outcome and missing data in the control group as having an effective outcome (Gamble 2005).

For continuous outcomes, we will use the intention‐to‐treat analysis. In the absence of this, we will perform available case analysis.

Assessment of heterogeneity

For clinically similar studies, we will assess statistical heterogeneity using the I² statistic to determine if the studies can be pooled. If the I² statistic is less than 60%, we will pool across the studies; if it is greater than 80%, we will not pool studies as any treatment effect may be the subject of severe heterogeneity, and any finding may be likely to be unreliable. In cases where the I² statistic is between 60% and 80% and heterogeneity can be explained by clinical argument, we will pool the studies into a meta‐analysis (Higgins 2011; Van Zuuren 2014).

Assessment of reporting biases

If there are more than 10 studies pooled in a meta‐analysis for a particular outcome, we will assess any reporting bias using a funnel plot for publication bias (Egger 1997).

Data synthesis

We will provide a descriptive narrative for all outcomes for which data are available. For studies that are clinically and statistically homogenous, we will pool data using a Mantel‐Haenszel analysis with a random‐effects model for dichotomous data, and we will pool data using an inverse variance analysis with a random‐effects model for continuous data. We will determine statistical homogeneity as mentioned in the Assessment of heterogeneity section.

Where results are estimated for individual studies with low numbers of outcomes (< 10 in total) or where the total sample size is less than 30 participants and a risk ratio is used, we will report the proportion of outcomes in each treatment group together with a P value from a Fisher's exact test.

Subgroup analysis and investigation of heterogeneity

If we find substantial heterogeneity (I² statistic > 50%) between studies for the primary outcome, we will explore the possible causative factors for this heterogeneity, for example, differences in disease severity, dosage, and duration of treatment. Subgroups will include the categories just described and different case mix of the aggregated participants of the included studies. Subgroups will include studies consisting of different severity or types of acne, onset of acne, sex, and ages of participants (Higgins 2011).

Sensitivity analysis

We plan to perform sensitivity analyses, when necessary, only including those studies with a low risk of bias as well as studies reported with complete data. We will conduct sensitivity analyses of any included studies that we find were prospectively registered in trials registers in order to capture whether the trial publication actually reported the outcomes stated in the trial protocol.

'Summary of findings' tables

We plan to include at least one 'Summary of findings' table in our review and will assess the quality of the body of evidence using the five GRADE (Grading of Recommendations, Assessment, Development and Evaluation) considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias). We will summarise the primary outcomes (participant self‐assessment and adverse effects) for the most important comparisons: topical antibiotics versus placebo or other topical treatments. If we feel there are several major comparisons or that our findings need to be summarised for different populations, we will include further 'Summary of findings' tables.

Appendices

Appendix 1. Glossary for unfamiliar terms used in the protocol

Term	Definition
Acne excoriée	Acne exacerbated by excessive or neurotic scratching or picking of the skin
Acne fulminans	A sudden onset of severe inflammatory and ulcerative acne, often with systemic symptoms like fever and polyarthritis
Acne mechanica	A form of acne triggered by heat, pressure, and repetitive rubbing of the skin. It commonly occurs in athletes and soldiers wearing special clothing or sports equipment
Acne vulgaris	The most common and chronic form of acne, usually starting at puberty and involving the face, chest, and shoulders; the condition is characterised by the formation of non‐inflammatory lesions like blackheads and whiteheads. There may also be inflammatory pimples, possibly resulting in scarring
Androgens	A group of steroid hormones (which include testosterone and androsterone) that are important for development and maintenance of the masculine characteristics of the body; among other functions, they stimulate growth and sebum production in the sebaceous glands
Bactericidal agent	A substance that kills bacteria
Bacterial resistance	The acquired capacity of particular strains of bacteria to tolerate and survive the effects of an antibiotic
Bacteriostatic	Having the ability to stop bacteria from growing or multiplying, without necessarily killing them
Benzoyl peroxide	An organic peroxide compound used as a topical agent for acne treatment mainly because of its ability to reduce the bacterial count of the Propionibacterium acnes (P. acnes) without inducing the bacterial resistance
Biofilm	A densely organised community of interadherent micro‐organisms embedded in a slime‐like extracellular polymeric substance, which is growing on either living surfaces like skin or mucosal membranes or non‐living surfaces like hospital walls and instruments
Chemotaxis	The movement of cells or organisms directed by chemicals in their environment
Clindamycin	A lincosamide antibiotic used in the treatment of various bacterial infections and the most commonly used topical antibiotic in the treatment of acne
Comedone	A widened hair follicle filled with skin debris, sebum, and bacteria, which may be open (blackhead) or closed (whitehead); it is clinically seen as a yellow or black bump or plug on the skin
Commensal	A close association of 2 organisms, usually of different species, in which 1 gains some benefit from the relationship without harming the other
Comedolytic	A characteristic of a product or medication to inhibit the formation of comedones by helping the skin to shed more effectively
Conglobata acne	A chronic form of acne that is the most severe form. It is characterised by extensive inflammatory lesions, such as deep abscesses, nodules, and draining sinus tracts, which heal while leaving atrophic and hypertrophic scars
Cyst	An epithelium‐lined closed sac that may contain a fluid or semi‐solid material
Cytokines	Soluble molecules produced and released by various cells that mediate specific intercellular communication or induce a certain behaviour in cells, like triggering an inflammatory response
Differentiation	The process of cellular maturation where a less specialised cell develops the specific morphology and function of a distinct cell type
Desquamation	Skin peeling
Erythema	Redness of the skin caused by vasodilatation of the small blood vessels in the lower layers of the skin, which is a sign of inflammation, injury, or infection
Erythromycin	A macrolide antibiotic used in systemic and topical treatment of various bacterial infections
Follicular epithelium	Epithelial cells lining the skin invagination from which the hair shaft develops and grows
Glycerol	Also called glycerin, a carbohydrate that can be formed from glucose in the form of sweet syrupy liquid. It can be derived from animal fats and oil and used as a skin emollient, solvent, plasticizer, sweetener, or antifreeze
Hypercolonisation	An abnormal increase in the quantity of micro‐organisms that are otherwise normally present on a body surface without causing symptoms or eliciting an immune response
Hydrolysing	Enabling a chemical reaction of decomposition of a substance in the presence of water
Intrafollicular	Situated inside the follicle
Keratinisation	Cornification ‐ the process of conversion of squamous epithelial cells into horny material made of keratin, in order to form an epidermal barrier, hair, or nails
Keratinocytes	Epidermal cells that produce keratin in their final stages of differentiation
Leukocytes	White blood cells ‐ cells of the immune system important for defending the body against both infectious diseases and foreign materials
Lincosamides	A class of antibiotics that act on the bacterial ribosomes in order to prevent bacteria from multiplying by inhibiting their protein formation
Lipophilic	Having an affinity to combine with lipids and dissolve in them
Macrocomedones	Open comedones larger than 3 mm in diameter
Macrolides	A class of antibiotics with bacteriostatic characteristics achieved by inhibition of bacterial protein synthesis, which also have immunomodulatory properties
Microcomedones	Comedones that can be detected only by a microscope, not visible to the naked eye
Mitochondrial	Related to mitochondria, which are the cellular structures that convert energy derived from food into a form usable by cells
Monotherapy	Therapeutic administration of a single drug
Neutrophils	A type of white blood cell essential to the innate immune system because of its function of fighting off bacterial and fungal infections by ingesting micro‐organisms and releasing soluble antimicrobial proteins
Nodule	A solid, raised, or palpable tissue formation, usually 1 to 2 cm large in diameter, which may be found at all skin levels as well as in other tissues
Papule	A well‐circumscribed solid dome‐shaped skin elevation smaller than 1 cm in diameter
Pilosebaceous unit	The hair follicle with the accompanying sebaceous gland
Polymorphic	The ability to present in various forms
Proinflammatory	Having the capacity to promote inflammation
Pseudomembranous colitis	Infection of the large intestine due to overgrowth of Clostridium difficile bacteria, which is usually attributed to recent antibiotic use
Pustule	A small bump on the skin with a visible superficial collection of pus
Reactive oxygen species	Highly chemically reactive oxygen‐containing ions and free radicals that in increased levels induce damage of cell structures called oxidative stress
Retinoic acid receptor (RAR)	1 of the 2 types of retinoid receptors; it is a nuclear receptor activated by all‐trans retinoic acid and 9‐cis retinoic acid, which belongs to the superfamily of nuclear deoxyribonucleic acid (DNA) transcription factors, together with steroid, thyroid hormone, and vitamin D receptors
Retinoic X receptor (RXR)	1 of the 2 types of retinoid receptors, it is a nuclear receptor activated by 9‐cis retinoic acid as well as 9‐cis‐13,14‐dihydro‐retinoic acid, which belongs to the superfamily of nuclear DNA transcription factors, together with steroid, thyroid hormone, and vitamin D receptors
Retinoids	A class of chemical compound related chemically to vitamin A. They are used for topical and systemic treatment of acne and other dermatoses including photoaging because of the way they regulate epithelial cell growth
Ribosomal subunits	The ribosome is the cellular site of protein synthesis, and it consists of 2 major components ‐ the small subunit, which plays the decoding role in reading ribonucleic acid (RNA), and the large subunit, which has catalytic function in forming aminoacid chains
Sebaceous glands	Sebum‐producing glands attached to the hair follicles through which sebum is delivered to the skin surface. Sebaceous follicles contain especially large sebaceous glands that produce more sebum, and they are found in the skin of the typical acne‐prone areas ‐ the face, back, and chest
Sebum	An oily product of the sebaceous glands of the skin, which functions as a protective waterproof layer of the hair and skin. Excessive production of sebum is a predisposing factor for skin and scalp disorders, like acne and seborrhoeic dermatitis
Serum triglycerides	A type of fat present in the blood
Sessile	Inability to move
Scar	An area of fibrous tissue that replaces normal tissues after being destroyed by injury
Substrate	A compound that serves as a food source for an organism or provides support for its growth
Toll‐like receptors	A class of transmembranous proteins that play a central role of the innate immune system. Being expressed on dendritic cells and macrophages, they recognise microbes invading an organism, which is followed by immediate activation of immune cell responses
Topical therapy	A form of administering a medication by applying it to body surfaces
Vitamin A	A group of fat‐soluble vitamins (retinol, retinal, retinoic acid) and provitamins (beta‐carotene) that are important for proper cell growth and specialisation, prenatal and postnatal development of an organism, good vision, and a well‐functioning immune system

Appendix 2. MEDLINE (Ovid) search strategy

1. exp Acne Vulgaris/ 2. acne$.ti,ab. 3. 1 or 2 4. Dapsone/ 5. Erythromycin/ 6. exp Anti‐Bacterial Agents/ 7. Tetracycline/ 8. (dapsone or erythromycin or tetracycline).ti,ab. 9. or/4‐8 10. (topical or topically or gel$1 or foam$1 or ointment$ or solution$1 or lotion$1 or saturated pad$).ti,ab. 11. Ointments/ or Gels/ 12. administration, topical/ or administration, cutaneous/ 13. (cutaneous or dermal or skin or transcutaneous or transdermal or percutaneous).ti,ab. 14. or/10‐13 15. 9 and 14 16. topical antibiotic$.ti,ab. 17. Clindamycin/ 18. Metronidazole/ 19. (nadifloxacin or clindamycin or metronidazole).ti,ab. 20. aminoglycosides/ or gentamicins/ 21. Neomycin/ 22. (aminoglycoside$ or neomycin or gentamycin$ or gentamicin$).ti,ab. 23. Macrolides/ 24. Sulfacetamide/ 25. sulfonamide antibiotic$.ti,ab. 26. meclocycline$.ti,ab. 27. Lincoside$.ti,ab. 28. Quinolones/ 29. Quinolone$.ti,ab. 30. Chloramphenicol/ 31. Chloramphenicol.ti,ab. 32. Fusidic Acid/ 33. Fusidic acid$.ti,ab. 34. Nitromidazole.ti,ab. 35. Mupirocin/ 36. mupirocin$.ti,ab. 37. bactroban.ti,ab. 38. pseudomonic acid$.ti,ab. 39. Pleuromutilin.ti,ab. 40. retapamulin.ti,ab. 41. Polypetide$.ti,ab. 42. Bacitracin/ 43. bacitracin.ti,ab. 44. Polymyxins/ 45. polymyxin$.ti,ab. 46. or/16‐45 47. 15 or 46 48. randomized controlled trial.pt. 49. controlled clinical trial.pt. 50. randomized.ab. 51. placebo.ab. 52. clinical trials as topic.sh. 53. randomly.ab. 54. trial.ti. 55. 48 or 49 or 50 or 51 or 52 or 53 or 54 56. exp animals/ not humans.sh. 57. 55 not 56 58. 3 and 47 and 57

[Lines 48‐57: Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐ and precision‐maximizing version (2008 revision)]

What's new

Date	Event	Description
23 January 2018	Amended	This protocol was withdrawn by the Managing Editor as the team could not commit the time necessary to complete the review.

Contributions of authors

MAG was the contact person with the editorial base and co‐ordinated the contributions from the co‐authors. ELM, MAG, and CL prepared the primary drafts of the protocol. AML provided clinical guidance and assistance in the preparation of relevant clinical aspects in the protocol. BC provided statistical guidance and assistance in the preparation of the methods section of the protocol. MTK was the consumer co‐author and checked the protocol for readability and clarity. He also ensured that the outcomes are relevant to consumers.

Disclaimer

This project was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the Cochrane Skin Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

Sources of support

Internal sources

• No sources of support supplied

External sources

• The National Institute for Health Research (NIHR), UK.

  The NIHR, UK, is the largest single funder of the Cochrane Skin Group.

Declarations of interest

Elvira Lazic Mosler: nothing to declare. Christina Leitner: nothing to declare. Mohamed A Gouda: nothing to declare. Ben Carter: nothing to declare. Alison M Layton: "I have received remuneration from several different pharmaceutical companies: a) in support of research projects (funding has been provided as unrestricted educational grants for basic science research from Galderma and GSK; funding went to the institution as research costs to support a study); b) via honorarium for lecturing at educational meetings (the content of the talks was unrestricted) from Galderma, MEDA, and GSK (Steifel) (personal remuneration for time spent on preparation and presentation); and c) via honorarium to support work done in an advisory capacity, e.g. as a member of a drug‐monitoring committee or on an advisory board, from Galderma and GSK (personal remuneration for time spent)." Mahmoud Tawfik KhalafAllah: nothing to declare.

Notes

This protocol was withdrawn by the Managing Editor as the team could not commit the time necessary to complete the review.

Withdrawn from publication for reasons stated in the review