Assessing effectiveness in acne clinical trials: steps towards a core outcome measure set.

BACKGROUND: Acne ranks second to dermatitis in terms of global burden of skin disease. As such, it is essential that data on treatment efficacy are generated in a way that maximizes the opportunity for comparison among treatments. Interest in developing core outcome sets for use in clinical trials to standardize data collection in skin disease is surging. OBJECTIVES: The goal of this review is to provide an update on the efforts underway, challenges encountered and future directions in the development of an acne core outcome measure set for use in clinical trials. METHODS: The activities of the Acne Core Outcomes Research Network (ACORN) are presented in the context of currently acceptable methodologies for core outcome set development. CONCLUSIONS: Emphasis is placed on following a rigorous methodology, involving patients and recognizing a role for emerging technologies.

AGREE II assessments of recent acne treatment guidelines: how well do they reveal trustworthiness as defined by the U.S. Institute of Medicine criteria?

BACKGROUND: Up-to-date, trustworthy guidelines are a widely relied upon means of promoting excellent patient care. OBJECTIVES: To determine the quality of recently published acne treatment guidelines by utilizing the Appraisal of Guidelines for Research and Evaluation (AGREE) II Reporting Checklist, the U.S. Institute of Medicine's (IOM) criteria of trustworthiness, the red flags of Lenzer et al. and CheckUp. METHODS: Systematic searches were conducted in bibliographic databases, guideline depositories and using Google to identify acne treatment guidelines published since 2013. Six assessors independently scored each guideline using the AGREE II Reporting Checklist. Guidelines were concomitantly assessed for trustworthiness using the IOM criteria and for the red flags of Lenzer et al., indicative of potential bias. Updates were screened using CheckUp. RESULTS: Eight guidelines were identified, two of which were updates. Lowest scoring AGREE II domains across all guidelines were applicability (six poor, one fair, one average) and rigour (four poor, one fair, three average). Two of the three highest-scoring guidelines were developed using AGREE II. No guideline fully met each IOM criterion and all raised at least one red flag indicative of potential bias. One updated guideline did not address seven of 16 items on CheckUp and the other did not address four. Patient involvement in guideline development was minimal. CONCLUSIONS: Use of the AGREE II instrument during guideline development did not have as great an effect on guideline quality as might be expected. There is considerable room for improvement in acne treatment guidelines in order to satisfy the IOM trustworthiness criteria and avoid bias.

The management of acne vulgaris in primary care: a cohort study of consulting and prescribing patterns using the Clinical Practice Research Datalink.

BACKGROUND: Effective management of acne vulgaris in primary care involves support (usually provided over a number of consultations) and prescription of effective treatments. However, consulting and prescribing patterns for acne in primary care are not well described. OBJECTIVES: To describe the rate of primary-care consultations and follow-up consultations; prescribing patterns, including overall use of acne-related medications (ARMs); and initial and follow-up prescription for acne vulgaris in the U.K. METHODS: U.K. primary-care acne consultations and prescriptions for ARMs were identified in the Clinical Practice Research Datalink. Annual consultation rates (between 2004 and 2013) by age and sex, new consultations and consultations in the subsequent year were calculated, along with prescribing trends - during a new consultation and over the subsequent 90 days and year - using the number of registered patients as the denominator. RESULTS: Two-thirds (66·1%) of patients who had a new acne consultation had no further acne consultations in the subsequent year. Overall 26·7%, 24·9%, and 23·6% and 2·8% of patients were prescribed no ARM, an oral antibiotic, a topical antibiotic or an oral plus topical antibiotic, respectively, during a new acne consultation. In total 60·1% and 38·6% of patients prescribed an ARM received no further ARM prescriptions in the following 90 days and 1 year, respectively, despite most prescriptions being for 2 months or less. Prescribing rates for lymecycline and topical combined clindamycin and benzoyl peroxide increased substantially between 2004 and 2013. There were no important changes in consultation rates between 2004 and 2013. CONCLUSIONS: These data suggest that patients with acne are receiving a suboptimal initial choice of ARMs, longitudinal care and prescribing.

Tert-butyl benzoquinone: mechanism of biofilm eradication and potential for use as a topical antibiofilm agent.

OBJECTIVES: Tert-butyl benzoquinone (TBBQ) is the oxidation product of tert-butyl hydroquinone (TBHQ), an antimicrobial food additive with >40 years of safe use. TBBQ displays potent activity against Staphylococcus aureus biofilms in vitro. Here, we report on studies to further explore the action of TBBQ on staphylococcal biofilms, and provide a preliminary preclinical assessment of its potential for use as a topical treatment for staphylococcal infections involving a biofilm component. METHODS: The antibacterial properties of TBBQ were assessed against staphylococci growing in planktonic culture and as biofilms in the Calgary Biofilm Device. Established assays were employed to measure the effects of TBBQ on biofilm structure and bacterial membranes, and to assess resistance potential. A living-skin equivalent was used to evaluate the effects of TBBQ on human skin. RESULTS: TBBQ eradicated biofilms of S. aureus and other staphylococcal species at concentrations ≤64 mg/L. In contrast to other redox-active agents exhibiting activity against biofilms, TBBQ did not cause substantial destructuring of the biofilm matrix; instead, the antibiofilm activity of the compound was attributed to its ability to kill slow- and non-growing cells via membrane perturbation. TBBQ acted synergistically with gentamicin, did not damage a living-skin equivalent following topical application and exhibited low resistance potential. CONCLUSIONS: The ability of TBBQ to eradicate biofilms appears to result from its ability to kill bacteria regardless of growth state. Preliminary evaluation suggests that TBBQ represents a promising candidate for development as a topical antibiofilm agent.

Redox-active compounds with a history of human use: antistaphylococcal action and potential for repurposing as topical antibiofilm agents.

OBJECTIVES: To investigate the antistaphylococcal/antibiofilm activity and mode of action (MOA) of a panel of redox-active (RA) compounds with a history of human use and to provide a preliminary preclinical assessment of their potential for topical treatment of staphylococcal infections, including those involving a biofilm component. METHODS: Antistaphylococcal activity was evaluated by broth microdilution and by time-kill studies with growing and slow- or non-growing cells. The antibiofilm activity of RA compounds, alone and in combination with established antibacterial agents, was assessed using the Calgary Biofilm Device. Established assays were used to examine the membrane-perturbing effects of RA compounds, to measure penetration into biofilms and physical disruption of biofilms and to assess resistance potential. A living skin equivalent model was used to assess the effects of RA compounds on human skin. RESULTS: All 15 RA compounds tested displayed antistaphylococcal activity against planktonic cultures (MIC 0.25-128 mg/L) and 7 eradicated staphylococcal biofilms (minimum biofilm eradication concentration 4-256 mg/L). The MOA of all compounds involved perturbation of the bacterial membrane, whilst selected compounds with antibiofilm activity caused destructuring of the biofilm matrix. The two most promising agents [celastrol and nordihydroguaiaretic acid (NDGA)] in respect of antibacterial potency and selective toxicity against bacterial membranes acted synergistically with gentamicin against biofilms, did not damage artificial skin following topical application and exhibited low resistance potential. CONCLUSIONS: In contrast to established antibacterial drugs, some RA compounds are capable of eradicating staphylococcal biofilms. Of these, celastrol and NDGA represent particularly attractive candidates for development as topical antistaphylococcal biofilm treatments.

Interleukin-10 secretion from CD14+ peripheral blood mononuclear cells is downregulated in patients with acne vulgaris.

BACKGROUND: Acne is a common chronic inflammatory dermatosis of the pilosebaceous unit. It is characterized by seborrhoea, comedone formation and an inflammatory response consistent with defective cellular immunity to Propionibacterium acnes. OBJECTIVES: The objective of this study was to investigate the immune reactivity of patients with acne compared with healthy controls by examining the response of peripheral blood mononuclear cells (PBMCs) to stimulation with P. acnes. Particular focus was placed upon measuring the production of interleukin (IL)-10, which has an established immunoregulatory role. PATIENTS AND METHODS: Venous blood was collected from 47 patients with acne and 40 age- and sex-matched healthy controls with no prior history of acne. PBMCs were cultured and their cytokine response to P. acnes investigated. RESULTS: Proinflammatory IL-8 and tumour necrosis factor (TNF)-alpha secretion from PBMCs was higher in patients with acne when stimulated with P. acnes. In contrast, a statistically significant reduction in PBMC secretion of anti-inflammatory IL-10 in patients with acne was identified. The impaired production of IL-10 by PBMCs from patients with acne was confined to CD14+ cells presumed to be monocytes. The ability of CD14 cells from patients with acne to phagocytose P. acnes bacteria was also observed to be defective but the addition of exogenous IL-10 to PBMC cultures restored phagocytic activity. CONCLUSIONS: These data suggest that patients with acne have a proinflammatory cytokine milieu and crucially are unable to contain early inflammatory changes due to a specific defect in immunosurveillance, namely low monocyte IL-10 production. Our observations raise the possibility that acne therapeutics might profitably target IL-10 both as a regulator of proinflammatory cytokines and in augmenting the CD14+ cell phagocytic response.

Temporal changes in sebum excretion and propionibacterial colonization in preadolescent children with and without acne.

BACKGROUND: It is generally accepted that the onset of sebum secretion occurs before puberty in boys and girls as a result of increasing androgen output during the adrenarche. Propionibacteria are part of the commensal skin flora and, in adults, are found in highest numbers in sebum-rich areas of skin such as the face and upper trunk. Previous studies investigating the association between sebum output and propionibacterial population densities have been cross-sectional and have been carried out mainly in adults. OBJECTIVES: The purpose of this study was to examine the association between the onset of sebum secretion and expansion of the propionibacterial flora in a population of early adolescent children aged between 5.5 and 12 years, and to evaluate the temporal relation between the two factors longitudinally. In addition, the study aimed to evaluate the change with age in sebaceous gland activity and propionibacterial colonization on the skin and in the nares between children who developed acne and those who did not. METHODS: Biannual examinations of volunteers included age, pubertal (Tanner) stage, weight and height, lesion counting on the face, propionibacterial colonization on the skin surface and in the nares and sebum secretion. A longitudinal analysis based on all observations of each subject throughout the study was applied to examine the change of sebaceous gland activity and propionibacterial colonization with age and pubertal stage. A generalized estimating equation was used with a 0.05 level of significance. RESULTS: The commencement of sebum production was asynchronous, with only a small number of follicles initially starting to secrete sebum onto the skin surface. The number of secreting follicles and the area of sebum increased with age and pubertal stage (P < 0.0001, P < 0.05, respectively). Numbers of propionibacteria on the skin tended to increase after the age of 9 years, but not significantly so. In contrast, numbers of propionibacteria in the nares increased significantly with age (P < 0.0001) but not with pubertal maturation. Children who developed acne had higher sebum output and propionibacterial densities with increasing age than children who did not develop acne. This effect was significant for the increase of total sebum area with age in pubertal children (P = 0.0023), the increase in number of secreting follicles with age (P = 0.020) in prepubertal children, and the increase in propionibacteria densities in the nares with age (P = 0.0005) in pubertal children. Sebaceous gland activity and propionibacterial numbers on the skin surface remained unchanged with increasing age in children who did not develop acne. Propionibacterial population densities in the nares increased with age regardless of the development of acne. CONCLUSIONS: Onset of sebum secretion and consequently expansion of the propionibacterial skin flora occur earlier in children who develop acne than in children of the same age and pubertal status who do not develop acne. These observations suggest that postponing the onset of sebum production or the expansion of the propionibacterial skin flora until after puberty may represent ways of preventing the disease or minimizing its severity. Determinants of propionibacterial colonization on the skin and in the nares may be different.

Efficacy of oral isotretinoin in the control of skin and nasal colonization by antibiotic-resistant propionibacteria in patients with acne.

BACKGROUND: Skin colonization by antibiotic-resistant propionibacteria is commonplace among acne patients globally. Increasing attention is now being paid to how resistance rates might be reduced to preserve the future efficacy of antibiotics, especially erythromycin and clindamycin in acne therapy. OBJECTIVE: To assess the efficacy of oral isotretinoin in the control of antibiotic-resistant propionibacteria. METHODS: Acne patients (72 in the U.K., 62 in the U.S.A.) colonized with high numbers of antibiotic-resistant propionibacteria were sampled before, during and 12 weeks after oral isotretinoin therapy. Propionibacterial samples were collected from five acne-prone skin surface sites using a detergent scrub method and from the anterior nares using moistened swabs. Total and antibiotic-resistant propionibacteria were enumerated by viable counting on media with and without selective antibiotics. RESULTS: After 16 weeks of oral isotretinoin therapy, mean population densities of viable propionibacteria and variants resistant to erythromycin, clindamycin or tetracycline had fallen by more than 90% at all skin sites and in the nares. The sole exception was a smaller reduction in tetracycline-resistant strains on the lower back. In general, greater reductions were observed on skin than in the nares. By the end of the treatment period only three patients (all in Philadelphia) yielded no antibiotic-resistant strains from any site. Post-treatment, propionibacterial counts remained well below pretreatment levels but had begun to recover on the face and in the nares. The recovering propionibacterial population included both susceptible and resistant strains. Changes during and post-treatment at the two centres were similar but not identical. CONCLUSIONS: Oral isotretinoin effectively reduced skin and nasal colonization by antibiotic-resistant propionibacteria. However, viable populations of resistant isolates persisted post-treatment at multiple sites. Novel methods are required to eradicate antibiotic-resistant propionibacteria completely, especially from the nasal reservoir.

Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne.

OBJECTIVES: To determine the relative efficacy and cost-effectiveness of five of the most commonly used antimicrobial preparations for treating mild to moderate facial acne in the community; the propensity of each regimen to give rise to local and systemic adverse events; whether pre-existing bacterial resistance to the prescribed antibiotic resulted in reduced efficacy; and whether some antimicrobial regimens were less likely to give rise to resistant propionibacterial strains. DESIGN: This was a parallel group randomised assessor-blind controlled clinical trial. It was a pragmatic design with intention-to-treat analysis. All treatments were given for 18 weeks, after a 4-week treatment free period. Outcomes were measured at 0, 6, 12 and 18 weeks. SETTING: Primary care practices and colleges in and around Nottingham and Leeds, and one practice in Stockton-on-Tees, England. PARTICIPANTS: Participants were 649 people aged 12--39 years, all with mild to moderate inflammatory acne of the face. INTERVENTIONS: Study participants were randomised into one of five groups: 500 mg oral oxytetracycline (non-proprietary) twice daily (b.d.) + topical vehicle control b.d.; 100 mg oral Minocin MR (minocycline) once daily (o.d.) + topical vehicle control b.d.; topical Benzamycin (3% erythromycin + 5% benzoyl peroxide) b.d. + oral placebo o.d.; topical Stiemycin (2% erythromycin) o.d. + topical Panoxyl Aquagel (5% benzoyl peroxide) o.d. + oral placebo o.d., and topical Panoxyl Aquagel (5% benzoyl peroxide) b.d. + oral placebo o.d. (the active comparator group). MAIN OUTCOME MEASURES: The two primary outcome measures were: (1) the proportion of patients with at least moderate self-assessed improvement as recorded on a six-point Likert scale, and (2) change in inflamed lesion count (red spots). RESULTS: The best response rates were seen with two of the topical regimens (erythromycin plus benzoyl peroxide administered separately o.d. or in a combined proprietary formulation b.d.), compared with benzoyl peroxide alone, oxytetracycline (500 mg b.d.) and minocycline (100 mg o.d.), although differences were small. The percentage of participants with at least moderate improvement was 53.8% for minocycline (the least effective) and 66.1% for the combined erythromycin/benzoyl peroxide formulation (the most effective); the adjusted odds ratio for these two treatments was 1.74 [95% confidence interval (CI) 1.04 to 2.90]. Similar efficacy rankings were obtained using lesion counts, acne severity scores and global rating by assessor. Benzoyl peroxide was the most cost-effective and minocycline the least cost-effective regimen (ratio of means 12.3; difference in means -0.051 units/GBP, 95% CI -0.063 to -0.039). The efficacy of oxytetracycline was similar to that of minocycline, but at approximately one-seventh of the cost. For all regimens, the largest reductions in acne severity were recorded in the first 6 weeks. Reductions in disability scores using the Dermatology Quality of Life Scales were largest for both topical erythromycin-containing regimens and minocycline. The two topical erythromycin-containing regimens produced the largest reductions in the prevalence and population density of cutaneous propionibacteria, including antibiotic-resistant variants, and these were equally effective in participants with and without erythromycin-resistant propionibacteria. The clinical efficacy of both tetracyclines was compromised in participants colonised by tetracycline-resistant propionibacteria. None of the regimens promoted an overall increase in the prevalence of antibiotic-resistant strains. Systemic adverse events were more common with the two oral antibiotics. Local irritation was more common with the topical treatments, particularly benzoyl peroxide. Residual acne was present in most participants (95%) at the end of the study. CONCLUSIONS: The response of mild to moderate inflammatory acne to antimicrobial treatment in the community is not optimal. Only around half to two-thirds of trial participants reported at least a moderate improvement over an 18-week study period; extending treatment beyond 12 weeks increased overall benefit slightly. Around one-quarter dropped out when using such treatments, and 55% sought further treatment after 18 weeks. Topical antimicrobial therapies performed at least as well as oral antibiotics in terms of clinical efficacy. Benzoyl peroxide was the most cost-effective and minocycline the least cost-effective therapy for facial acne. The efficacy of all three topical regimens was not compromised by pre-existing propionibacterial resistance. Benzoyl peroxide was associated with a greater frequency and severity of local irritant reactions. It is suggested that the use of a combination of topical benzoyl peroxide and erythromycin gives less irritation and better quality of life. There was little difference between erythromycin plus benzoyl peroxide administered separately and the combined proprietary formulation in terms of efficacy or local irritation, except that the former was nearly three times more cost-effective. The data on cost-effectiveness, and outcomes in patients with resistant propionibacterial floras, did not support the first line use of minocycline for mild to moderate inflammatory acne of the face. Three priority areas for clinical research in acne are: defining end-points in acne trials (i.e. what is a satisfactory outcome?); developing and validating better patient-based measures for assessing treatment effects on facial and truncal acne; and exploring patient characteristics that may modify treatment effects (efficacy and tolerability).

Short-term effects of topical fusidic acid or mupirocin on the prevalence of fusidic acid resistant (FusR) Staphylococcus aureus in atopic eczema.

BACKGROUND: Staphylococcus aureus has a role in the pathophysiology of atopic eczema. Topical fusidic acid is widely used in its treatment. There is concern that topical use of fusidic acid may be driving the selection and dissemination of fusidic acid-resistant (FusR) S. aureus. OBJECTIVES: To test the hypothesis that treatment of atopic eczema for 2 weeks with topical fusidic acid/steroid combination can increase carriage of FusRS. aureus. METHODS: Forty-six patients with atopic eczema were allocated randomly to one of two treatment groups. Group 1 (28 patients) were treated with topical 2% fusidic acid plus 0.1% betamethasone cream, and group 2 (18 patients) with topical 2% mupirocin and 0.1% betamethasone cream. The clinical response and nasal and skin colonization with S. aureus were recorded before treatment and after 1 and 2 weeks of therapy. RESULTS: Baseline samples from the site of worst eczema showed S. aureus (sensitive and resistant) in 76% of patients, and FusRS. aureus in 26%, with no significant difference between treatment groups. After 1 and 2 weeks, both groups showed similar significant clinical improvement. The overall median clinical improvement was paralleled by a reduction in prevalence and population density of S. aureus (sensitive and resistant) at the worst eczema site (P < 0.0001). However, for FusRS. aureus there was no significant change in the prevalence of carriage, or population density in either group compared to baseline. Over 50% of patients carried S. aureus in the nerves and over 20% carried FusRS. aureus. Neither regimen affected either the prevalence or population density of S. aureus or FusRS. aureus in the nerves. CONCLUSIONS: In this small study there is no evidence to support the hypothesis that short-term treatment of atopic eczema with fusidic acid/steroid combination increases fusidic acid resistant S. aureus during a 2-week period.

Antibiotic-resistant acne: lessons from Europe.

BACKGROUND: Propionibacterium acnes and P. granulosum are widely regarded as the aetiological agents of inflammatory acne. Their proliferation and metabolism are controlled using lengthy courses of oral and/or topical antibiotics. Despite numerous reports of skin colonization by antibiotic-resistant propionibacteria among acne patients, accurate prevalence data are available only for the U.K. OBJECTIVES: To determine the prevalence of skin colonization by antibiotic-resistant propionibacteria among acne patients and their contacts from six European centres. METHODS: Skin swabs were collected from 664 acne patients attending centres in the U.K., Spain, Italy, Greece, Sweden and Hungary. Phenotypes of antibiotic-resistant propionibacteria were determined by measuring the minimum inhibitory concentrations (MIC) of a panel of tetracycline and macrolide, lincosamide and streptogramin B (MLS) antibiotics. Resistance determinants were characterized by polymerase chain reaction (PCR) using primers specific for rRNA genes and erm(X), followed by nucleotide sequencing of the amplified DNA. RESULTS: Viable propionibacteria were recovered from 622 patients. A total of 515 representative antibiotic-resistant isolates and 71 susceptible isolates to act as control strains were characterized phenotypically. The prevalence of carriage of isolates resistant to at least one antibiotic was lowest in Hungary (51%) and highest in Spain (94%). Combined resistance to clindamycin and erythromycin was much more common (highest prevalence 91% in Spain) than resistance to the tetracyclines (highest prevalence 26.4% in the U.K.). No isolates resistant to tetracycline were detected in Italy, or in Hungary. Overall, there were strong correlations with prescribing patterns. Prevalence of resistant propionibacteria on the skin of untreated contacts of the patients varied from 41% in Hungary to 86% in Spain. Of the dermatologists, 25 of 39 were colonized with resistant propionibacteria, including all those who specialized in treating acne. None of 27 physicians working in other outpatient departments harboured resistant propionibacteria. CONCLUSIONS: The widespread use of topical formulations of erythromycin and clindamycin to treat acne has resulted in significant dissemination of cross-resistant strains of propionibacteria. Resistance rates to the orally administered tetracycline group of antibiotics were low, except in Sweden and the U.K. Resistant genotypes originally identified in the U.K. are distributed widely throughout Europe. Antibiotic-resistant propionibacteria should be considered transmissible between acne-prone individuals, and dermatologists should use stricter cross-infection control measures when assessing acne in the clinic.

Propionibacterium acnes resistance: a worldwide problem.

Antibiotic therapy directed against Propionibacterium acnes has been a mainstay of treatment for more than 40 years. Despite years of widespread use of systemic tetracyclines and erythromycin, change in P. acnes sensitivity to antibiotics was not seen until the early 1980s. The first clinically relevant changes in P. acnes antibiotic sensitivity were found in the USA shortly after the introduction of topical formulations of erythromycin and clindamycin. By the late 1980s, P. acnes strains with very high MIC levels for erythromycin and elevated MICs for tetracycline were increasingly found in the UK and the USA. Mutations in the genes encoding the 23S and 16S subunits of ribosomal RNA were first identified in the UK and also seen in a recent survey from clinics in Europe, Japan, Australia and the USA. In addition, strains were found in which these known mutations could not be identified, indicating that as yet unidentified resistance mechanisms have evolved. These findings indicate the need to develop strategies to minimize the use of antibiotics in acne therapy.

Minocycline for acne vulgaris: efficacy and safety.

BACKGROUND: Minocycline is a tetracycline antibiotic that is commonly used in the treatment of moderate to severe acne vulgaris. Although it is more convenient for patients to take than first-generation tetracyclines, as it only needs to be taken once or twice a day and can be taken with food, it is more expensive. Concerns have also been expressed over its safety following the deaths of two patients taking the drug. There is a lack of consensus among dermatologists over the relative risks and benefits of minocycline. As most acne prescribing is undertaken by general practitioners, it is important that guidelines issued to them are based on the best available evidence rather than personal judgements. OBJECTIVES: To collate and evaluate the evidence on the clinical efficacy of minocycline in the treatment of inflammatory acne vulgaris. Specific objectives were to compare the efficacy of minocycline with other drug treatments for acne and to collate information on the incidence of adverse drug reactions. SEARCH STRATEGY: Randomised controlled trials (RCTs) of minocycline for acne vulgaris were identified by searching the following electronic databases; MEDLINE, EMBASE, Biosis, Biological Abstracts, International Pharmaceutical Abstracts, Cochrane Skin Group's Trial Register, Theses Online, BIDS ISI Science Citation Index, National Research Register, Current Controlled Trials and Bids Index to Scientific and Technical Proceedings. Other strategies used were scanning the references of articles retrieved, hand-searching of major dermatology journals and personal communication with trialists and drug companies. SELECTION CRITERIA: To be eligible for the review, studies had to be RCTs comparing the efficacy of minocycline at any dose to active or placebo control, in subjects with inflammatory acne vulgaris. Diagnoses of papulo-pustular, polymorphic and nodular acne were also accepted. Trials were not excluded on the basis of language. DATA COLLECTION AND ANALYSIS: 27 randomised controlled trials met the inclusion criteria and were included in this review. The comparators used were placebo (2 studies), oxytetracycline (1), tetracycline (6), doxycycline (7), lymecycline (2), topical clindamycin (3), topical erythromycin/zinc (1), cyproterone acetate/ ethinyloestradiol (1), oral isotretinoin (2), topical fusidic acid (1) and there was one dose response study. Two studies are ongoing and it remains to be clarified whether one further study is a RCT. Major outcome measures used in the trials included lesion counts, acne grades/severity scores, doctors' and patients' global assessments, adverse drug reactions and drop out rates. The quality of each study was assessed independently by two assessors and an effect size calculated where possible. An additional three RCTs and three safety studies were identified by searches conducted in November 2002; these will be reviewed for a major update in early 2003 when it is anticipated that the results of the two ongoing studies will be available. MAIN RESULTS: The trials were generally small and of poor quality and in many cases the published reports were inadequate for our purpose. Pooling of the studies was not attempted due to the lack of common outcome measures and endpoints and the unavailability of some primary data. Although minocycline was shown to be an effective treatment for acne vulgaris, in only two studies was it found to be superior to other tetracyclines. Both of these were conducted under open conditions and had serious methodological problems. A third study showed it to be more effective than 2% fusidic acid, applied topically, against inflammatory lesions in mild to moderate acne. Differences in the way adverse drug reactions were identified could have accounted for the wide variation between studies in numbers of events reported. This meant that no overall evaluation could be made of incidence rates of adverse events associated with minocycline therapy. No RCT evidence was found to support the benefits of minocycline in acne resistant to other therapies and the dose response has only been evaluated up to eight weeks of therapy. REVIEWER'S CONCLUSIONS: Minocycline is likely to be an effective treatment for moderate acne vulgaris, but this review found no reliable RCT evidence to justify its continued use first-line, especially given the price differential and the concerns that still remain about its safety. Its efficacy relative to other acne therapies could not be reliably determined due to the poor methodological quality of the trials and lack of consistent choice of outcome measures. Similarly the relative risk of adverse drug reactions could not be ascertained reliably and no recommendations can be made concerning the appropriate dose that should be used. It is hoped that this review will highlight the inadequacy of acne trials in general and encourage improvements in methodological quality and standards of reporting.

Prevalence of antibiotic-resistant propionibacteria on the skin of acne patients: 10-year surveillance data and snapshot distribution study.

BACKGROUND: Cutaneous propionibacteria are implicated in acne pathogenesis, although their exact role in the genesis of inflammation is still poorly understood. Agents, including antibiotics, that reduce the numbers of propionibacteria on skin are therapeutic. Resistance in the target organism is a well-recognized consequence of antibiotic therapy for acne but formal prevalence and distribution data are lacking. OBJECTIVES: To monitor the prevalence of skin colonization by antibiotic-resistant propionibacteria in acne patients attending the dermatology out-patient clinic at Leeds General Infirmary over a 10-year period beginning in 1991, and to examine the distribution of resistant strains on acne-prone skin and in the nares. METHODS: Propionibacterial samples were obtained from the skin surface of the worst affected site (usually the face) of 4274 acne patients using a moistened swab. The swab was used to inoculate agar plates with and without selective antibiotics. After anaerobic incubation at 37 degrees C for 7 days, the amount of growth in the presence of each antibiotic was scored on a scale from 0 to 5+. A small number of patients (72) were selected for more detailed quantitative sampling at six different sites to examine the distribution of resistant propionibacteria on acne-prone skin and in the anterior nares. RESULTS: The proportion of patients carrying strains resistant to one or more commonly used antiacne antibiotics rose steadily from 34.5% in 1991 to a peak of 64% in 1997. The prevalence dropped to 50.5% during 1999 and then rose again to 55.5% in 2000. Resistance to erythromycin was the most common and the majority of erythromycin-resistant strains were cross-resistant to clindamycin. Resistance to tetracyclines was less common in all years and with little increase over time. The more detailed quantitative study in 72 patients showed that population densities of resistant propionibacteria varied considerably between sites and between individuals. Almost invariably, patients were colonized with resistant strains at multiple sites, including the nares. CONCLUSIONS: Skin colonization with antibiotic-resistant propionibacteria is much more common now than a decade ago. Resistant propionibacteria are widely distributed on acne-prone skin and in the nares. This suggests that they will be very difficult to eradicate using existing therapeutic regimens, especially from the nasal reservoir.

Phenotypic and genotypic characterization of antibiotic-resistant Propionibacterium acnes isolated from acne patients attending dermatology clinics in Europe, the U.S.A., Japan and Australia.

BACKGROUND: Propionibacterium acnes is the target of antimicrobial treatments for acne vulgaris. Acquired resistance to erythromycin, clindamycin and tetracyclines has been reported in strains from diverse geographical loci, but the molecular basis of resistance, via mutations in genes encoding 23S and 16S rRNA, respectively, has so far only been elucidated for isolates from the U.K. OBJECTIVES: To determine whether similar or different resistance mechanisms occur in resistant P. acnes isolates from outside the U.K. METHODS: The phenotypes and genotypes of 73 antibiotic-resistant strains of P. acnes obtained from the skin of acne patients in the U.K., U.S.A., France, Germany, Australia and Japan were compared. Antibiotic susceptibilities were determined by minimum inhibitory concentration (MIC) measurements, and polymerase chain reaction and DNA sequencing were used to identify mutations in genes encoding rRNA. RESULTS: Most erythromycin-resistant isolates (MIC(90) > or = 512 microg mL(-1)) were cross-resistant to clindamycin but at a much lower level (MIC(90) > or = 64 microg mL(-1)). As in the U.K., resistance to erythromycin was associated with point mutations in 23S rRNA in 49 of 58 strains. An A-->G transition at Escherichia coli equivalent base 2058 was present in 24 strains. This gave a unique cross-resistance phenotype against a panel of macrolide, lincosamide and type B streptogramin antibiotics. Two further point mutations (at E. coli equivalent bases 2057 and 2059) were identified (in three and 22 isolates, respectively) and these were also associated with specific cross-resistance patterns originally identified in isolates from the U.K. However, nine of 10 erythromycin resistant-strains from Germany did not exhibit any of the three base mutations identified and, in six cases, cross-resistance patterns were atypical. Consistent with previous U.K. data, 34 of 38 tetracycline-resistant strains carried a base mutation at E. coli 16S rRNA equivalent base 1058. Tetracycline-resistant isolates displayed varying degrees of cross-resistance to doxycycline and minocycline, but isolates from the U.S.A. had higher MICs for minocycline (4--16 microg mL(-1)) than isolates from other countries and, in particular, Australia. All the P. acnes isolates resistant to one or more of the commonly used antiacne antibiotics were sensitive to penicillin, fusidic acid, chloramphenicol and the fluoroquinolone, nadifloxacin. All but one isolate (from the U.K.) were sensitive to trimethoprim. CONCLUSIONS: This study shows that 23S and 16S mutations identified in the U.K. conferring antibiotic resistance in P. acnes are distributed widely. However, resistant strains were isolated in which mutations could not be identified, suggesting that as yet uncharacterized resistance mechanisms have evolved. This is the first report of high-level resistance to minocycline and is of concern as these strains are predicted to be clinically resistant and are unlikely to remain confined to the U.S.A. Epidemiological studies are urgently required to monitor how resistant strains are selected, how they spread and to ascertain whether the prevalence of resistance correlates with antibiotic usage patterns in the different countries.

Antibiotic resistance patterns of aerobic coryneforms and furazolidone-resistant Gram-positive cocci from the skin surface of the human axilla and fourth toe cleft.

Samples of skin surface bacteria from 28 healthy subjects plated directly on to selective and non-selective media revealed that the proportion of aerobic coryneforms and furazolidone-resistant Gram-positive cocci (FURECs) resistant to erythromycin was significantly greater in the fourth toe cleft than in the axilla (P < 0.05). There were more erythromycin-resistant bacteria than tetracycline-resistant bacteria at both sites (P = 0.001 for the toe cleft; P < 0.01 for the axilla). In total, 160 distinct isolates were obtained, of which 42 were FURECs and 118 were aerobic coryneforms. Of these, 153 (96%) were resistant to erythromycin and 66 (41%) to tetracycline. All except seven of the tetracycline-resistant strains were also resistant to erythromycin. The resistant isolates belonged to a variety of species. CDC group ANF corynebacteria were most numerous and composed 31% of all isolates. The majority (76%) of FURECs were identified as Micrococcus luteus. MIC determinations on selected strains revealed that tetracycline-resistant FURECs were sensitive to doxycycline and minocycline, as were most tetracycline-resistant coryneforms. Nine coryneform isolates were cross-resistant to all three tetracyclines. Only a minority of erythromycin-resistant FURECs (21%) demonstrated a macrolide-lincosamide-streptogramin type B (MLS)-resistant phenotype with inducible or constitutive cross-resistance to clindamycin and the type B streptogramin, pristinamycin IA. Twenty-nine erythromycin-resistant FURECs had a novel phenotype distinct from MLS and macrolide-streptogramin type B resistance. In contrast, most coryneforms (79%) were MLS resistant. Among the remainder, two unusual erythromycin resistance phenotypes were apparent, both of which differed from the unusual phenotype in FURECs. This study has revealed that the non-staphylococcal aerobic flora of skin contains a considerable reservoir of tetracycline and erythromycin resistance determinants. The three unusual macrolide resistance phenotypes may be associated with novel resistance mechanisms.