Topical antibacterial therapy for acne vulgaris

Topical antibiotics and benzoyl peroxide, are the two main topical antibacterial treatments indicated for mild-to-moderate acne vulgaris. Topical antibiotics act both as antibacterial agents suppressing Propionibacterium acnes in the sebaceous follicle and as anti-inflammatory agents. Benzoyl peroxide is a powerful antimicrobial agent that rapidly destroys both bacterial organisms and yeasts. Topical clindamycin and erythromycin have been proven to be effective against inflammatory acne vulgaris in concentrations of 1-4% with or without the addition of zinc. However, none of the antibacterials tested was more effective than benzoyl peroxide, which also has the advantage of not being associated with antimicrobial resistance.Topical antibacterial therapy should be discontinued once improvement is observed. If no improvement is observed within 6-8 weeks, the agent should be discontinued and a therapeutic switch considered. The primary limitation of benzoyl peroxide for some acne vulgaris patients is cutaneous irritation or dryness.Antibacterial therapy can be used in combination with other agents. Combining topical antibiotics and topical retinoids may enhance the efficacy, since the retinoid will improve the penetration of the antibiotic. Combining a topical antibiotic with benzoyl peroxide may increase the bactericidal effect of the antibiotic and reduce the potential for bacterial resistance. Topical and oral antibacterials should not be used in combination for the treatment of acne vulgaris, since this association may increase the risk of bacterial resistance.     

Emerging drugs for acne

Acne vulgaris is a common skin disorder that affects most individuals at some point in their lives. It may result in significant morbidity, including cutaneous scarring and psychological impairment. Current treatments include topical retinoids, benzoyl peroxide, topical and systemic antibiotics, and systemic isotretinoin. There are growing concerns of rising antibiotic resistance, significant side effects of isotretinoin therapy, and lack of safe and effective treatment for pregnant females. Recent advances in the pathogenesis of acne have led to a greater understanding of the underlying inflammatory mechanisms and the role the Propionibacterium acnes and biofilms. This has led to the development of new therapeutic targets. This article reviews emerging treatments of acne, including topical picolinic acid, topical antibiotic dapsone, systemic zinc salts, oral antibiotic lymecycline, new formulations of and synergistic combinations of benzoyl peroxide, photodynamic therapy with topical photosensitizers and potential acne vaccines.     

Delayed type hypersensitivity to benzoyl peroxide

Benzoyl peroxide (BP) has been a standard and effective topical treatment for acne vulgaris for the past 35 years. Previous studies and case reports have documented benzoyl peroxide to be a strong irritant and a weak allergen, with many cases of tolerance induced with repeat use of this irritant. While less common, numerous cases of BP-induced allergic contact dermatitis (delayed type hypersensitivity reaction) have been reported in the literature. We report here an individual with an incipient edematous reaction to topical BP used for acne therapy. This under-recognized presentation is discussed in the context of published literature on BP-induced hypersensitivity and irritation.     

Low intrinsic drug activity and dominant vehicle (placebo) effect in the topical treatment of acne vulgaris

In drug treatment for acne, topical products alone or in combination with systemic products are commonly prescribed. It was recently pointed out by Chiou that oral tetracyclines, the most commonly prescribed systemic drugs, may not be as effective as commonly assumed because the effect of placebo can approach drug effects during the 4 - 12 weeks of daily administration. The present work evaluated the percent contribution of vehicle (placebo) toward the reported efficacy of reduction in total (inflammatory and non-inflammatory) lesion counts of 8 commonly prescribed topical preparations at the end of 10 - 12 weeks of daily administration. These preparations included 0.1% tretinoin, 0.1% adapalene, 5% dapsone, 1% clindamycin, a combination of benzoyl peroxide with adapalene or clindamycin, and a clindamycin-tretinoin combination. The mean reduction from drugs and vehicles were 42 ± 7.1%, and 23 ± 5.0%, respectively; the mean contribution of vehicle toward drug effect was 55 ± 15% (range 35 - 82%). For 5 benzoyl peroxide preparations evaluated (2 for 2.5%, and 3 for 5.0%), their respective means were 40 ± 9%, and 25 ± 15%, and vehicle-toward-drug contribution was 58 ± 31% (range 9 - 89%). The present work shows the great importance of vehicle effects in topical therapy; in some cases this effect approached 90%. The potential significance of the above findings in the development of more effective topical anti-acne drugs was discussed.     

Contact allergy to topical drugs: prevalence in a clinical setting and estimation of frequency at the population level

OBJECTIVES: To estimate the prevalence of contact allergy (CA) to a set of topical drugs patch tested in the research network IVDK (Information Network of Departments of Dermatology; www.ivdk.org) between 1995 and 2004, and to extrapolate these clinical data to the German population. METHODS: Clinical data comprised results of allergy patch tests with topical drugs in patients with suspected CA. Clinical epidemiology and drug utilization research (CE-DUR) methods were employed to grossly estimate the incidence of CA to these topical drugs during two 5-year periods (1995-1999 and 2000-2005) in the German general population. To estimate the number of persons eligible for patch testing (with the topical drugs) on a general population level, sales data of patch test material were obtained. By relating this denominator to the CA frequency observed in the IVDK, the incidence of CA to selected topical drugs in the German general population was crudely estimated. RESULTS: In general, topical aminoglycosides showed the highest CA frequencies and, except for gentamicin sulfate, frequencies of CA to all other allergens tested were lower in the 2nd period of analysis. According to the medium model, 1-year incidence rates ranged from 1 (hydrocortisone-17-butyrate) to 29 persons/100,000 (neomycin sulfate) in the general population (1995-1999). CONCLUSION: The CE-DUR approach yielded incidence estimates of CA to relevant topical drugs in the German general population, which, despite their limited precision in absolute terms, illustrate the relative frequency of this particular adverse effect. However, comparative risk assessment should preferably take exposure information into account.     

Study results of benzoyl peroxide 5%/clindamycin 1% topical gel, adapalene 0.1% gel, and use in combination for acne vulgaris

Combination therapy is the standard of care in the management of acne vulgaris. It is essential to treat as many aspects of acne pathogenesis as possible. Due to increasing insensitivity of Propionibacterium acnes to antibiotics, the concomitant use of other topical agents that exhibit other modes of antibacterial and anti-inflammatory activity is integral to the successful treatment of acne. The combination of topical benzoyl peroxide and clindamycin gel has been shown to be more effective than either agent alone. The addition of a topical retinoid may further enhance therapeutic results. This 12-week study evaluated the safety and efficacy of initial topical benzoyl peroxide 5%/clindamycin 1% gel as monotherapy and in combination with adapalene gel versus adapalene gel monotherapy in the management of acne.     

Novel drug delivery systems: potential in improving topical delivery of antiacne agents

Acne is the most common cutaneous disorder of multifactorial origin with a prevalence of 70-85% in adolescents. The majority of the acne sufferers exhibit mild to moderate acne initially, which progresses to the severe form in certain cases. Topical therapy is employed as first-line treatment in mild acne, whereas for moderate and severe acne, systemic therapy is required in addition to topical therapy. Currently, several topical agents are available that affect at least one of the main pathogenetic factors responsible for the development of acne. Although topical therapy has an important position in acne treatment, side effects associated with various topical antiacne agents and the undesirable physicochemical characteristics of certain important agents like tretinoin and benzoyl peroxide affect their utility and patient compliance. Novel drug delivery strategies can play a pivotal role in improving the topical delivery of antiacne agents by enhancing their dermal localization with a concomitant reduction in their side effects. The current review emphasizes the potential of various novel drug delivery strategies like liposomes, niosomes, aspasomes, microsponges, microemulsions, hydrogels and solid lipid nanoparticles in optimizing and enhancing the topical delivery of antiacne agents.     

The utility of benzoyl peroxide in hydrophase base (Brevoxyl) in the treatment of acne vulgaris

Available for more than 5 decades, benzoyl peroxide has been a "workhorse" of acne therapy. The benefits of this agent include reduction in Propionibacterium acnes (P. acnes) with decrease in inflammatory lesions, efficacy as both "leave on" and cleanser formulations and reduced emergence of antibiotic-resistant P. acnes strains. As the effect of benzoyl peroxide on P. acnes is a direct toxic effect rather than as a "true" antibiotic, resistance to benzoyl peroxide does not occur and has never been reported. Benzoyl peroxide in hydrophase base (Brevoxyl Creamy Washes and Gels) has shown significant efficacy in the treatment of acne, with lower irritancy than other benzoyl peroxide preparations. It is felt that the low irritancy of this product is related to a unique delivery vehicle containing dimethyl isosorbide, which dissolves benzoyl peroxide crystals on the skin. Clinical studies demonstrating the efficacy and safety of benzoyl peroxide in hydrophase base will be reviewed.     

Tazarotene versus tazarotene plus clindamycin/benzoyl peroxide in the treatment of acne vulgaris: a multicenter, double-blind, randomized parallel-group trial

Topical retinoids offer highly effective treatment for both inflammatory and non-inflammatory acne, with tazarotene demonstrating greater efficacy than other topical retinoids. A multicenter, double-blind, randomized, parallel-group trial has been performed to evaluate whether the adjunctive use of clindamycin/benzoyl peroxide could enhance the efficacy of tazarotene still further. Patients with moderate to severe inflammatory acne applied tazarotene 0.1% cream each evening and were randomly assigned to morning applications of vehicle gel or a ready-to-dispense formulation of clindamycin 1%/benzoyl peroxide 5 % gel containing 2 emollients. Tazarotene/clindamycin/benzoyl peroxide achieved a significantly greater reduction in comedo count than tazarotene monotherapy and, among patients with a baseline papule plus pustule count of > or =25 (the median value), a significantly greater reduction in inflammatory lesion count. The combination therapy was also at least as well-tolerated as tazarotene monotherapy. The adjunctive use of clindamycin/benzoyl peroxide gel with tazarotene cream promotes greater efficacy and may also enhance tolerability. Any improvements in tolerability could be due to the emollients in the clindamycin/benzoyl peroxide gel formulation.     

A new treatment for acne vulgaris combining benzoyl peroxide with clindamycin

Topical acne therapies are widely used for the treatment of mild to moderately severe acne vulgaris. However, many available treatments have limitations associated with their use, including lengthy time to response, cosmetic acceptability, and photosensitivity. Combinations of topical antibiotics and comedolytics are especially useful, but some formulations have stability challenges. A new combination formulation that contains 1% clindamycin and 5% benzoyl peroxide (BenzaClin Topical Gel) is currently available. In clinical trials, clinical improvement occurred at the first two follow-up visits and continued throughout treatment. In addition, combination therapy with clindamycin/benzoyl peroxide gel rapidly reduces Propionibacteria acnes counts and suppresses the emergence of clindamycin-resistant P. acnes. This formulation is stable at room temperature for up to 2 months after compounding. The aqueous gel vehicle is less drying, and there is no photosensitivity associated with its use. This study compares the combination treatment of 1% clindamycin and 5% benzoyl peroxide topical gel with other therapeutic options for mild to moderately severe acne vulgaris.     

Benzoyl peroxide: a review of its current use in the treatment of acne vulgaris

Background: Owing to the use of topical and systemic antibiotics for acne vulgaris, the incidence of antibiotic-resistant Propionibacterium acnes is increasing worldwide. Topical benzoyl peroxide (BPO) is an alternative to antibiotics in the treatment of acne vulgaris. Objective: This review describes and evaluates recent clinical literature regarding the efficacy and tolerability of BPO. Methods: A PubMed literature search was conducted using the keywords benzoyl peroxide, acne, and combination therapy. Results: BPO is equally effective at concentrations of 2.5, 5.0 and 10%. However, a concentration-dependent irritant dermatitis can occur with higher concentrations. The efficacy of BPO can be enhanced when used in combination with topical retinoids, antibiotics and tertiary amines. BPO-containing combinations do not induce bacterial resistance and are important first-line treatments for mild to moderate acne vulgaris.     

Investigation of degradation products in a topical gel containing erythromycin and benzoyl peroxide by liquid chromatography-mass spectrometry

Benzamycin, combining benzoyl peroxide and erythromycin, is a topical gel used in the treatment of acne vulgaris. Because of the reactivity of benzoyl peroxide, preparations containing both erythromycin and benzoyl peroxide might be unstable and degradation products could be formed. To investigate and identify these latter products, a gradient-based liquid chromatographic method using volatile mobile phase constituents was developed. Mass spectrometry data were acquired on solutions containing erythromycin and benzoyl peroxide and on freshly prepared, 2-month-old and 18-month-old samples of Benzamycin. With the reference spectra as interpretative templates, it was concluded that erythromycin undergoes oxidation, followed by benzoylation.     

Contact allergy to neomycin sulfate: results of a multifactorial analysis

PURPOSE: To perform a comprehensive, multifactorial analysis of potential risk factors (demographic and clinical) for contact allergy to neomycin sulfate, a common adverse reaction resulting from the topical use of this drug; especially in some subgroups of the population. METHODS: Retrospective analysis of allergy test data of the Information Network of Departments of Dermatology (IVDK, www.ivdk.org) between 1998 and 2003, including all patients patch tested with a standard screening series because of suspected allergic contact dermatitis (ACD). As one outcome, a positive (allergic) test reaction to neomycin sulfate was considered. An alternative outcome included only those patients with a positive test to neomycin sulfate and a final diagnosis of ACD. The association between outcome and potential risk factors was analyzed with Poisson regression analysis, deriving prevalence ratios (PR) as risk estimates. RESULTS: Of the 47,559 patients tested, 2.5% had positive reactions to neomycin sulfate, while in 1.1% ACD was additionally diagnosed. The results of the multifactorial analysis indicated that the risk of both outcomes decreased slightly during the period covered; was higher among patients with leg dermatitis; varied significantly with age and increased progressively with the number of additional positive reactions to other standard series allergens. Cross-reactivity to other, selectively tested, aminoglycoside antibiotics was substantial (kappa = 0.67; 95%CI: 0.63-0.71) for framycetin sulfate, to low (kappa = 0.33; 95%CI: 0.27-0.37) for gentamicin sulfate. CONCLUSIONS: The prevalence of contact sensitization to neomycin sulfate was noteworthy among patients patch tested in the IVDK centers. Supplementing clinical epidemiology, neomycin contact allergy has been estimated to be relatively common even on the level of the unselected population (prevalence approx. 1%). Hence, the topical use of neomycin sulfate by patients should be carefully monitored, considering its potential to induce ACD, with emphasis on subgroups at risk.     

The formulation and stability of erythromycin-benzoyl peroxide in a topical gel

The combination of benzoyl peroxide and erythromycin is used for the local treatment of acne and available as a commercial preparation. Because of the stability problems of erythromycin an extempore preparation is required. The influence of storage temperature and non active ingredients on the stability of benzoyl peroxide and erythromycin in topical gel preparations for extempore compounding is described. A microbiological and an HPLC method were used to determine the erythromycin and the benzoyl peroxide concentrations, respectively. For a formulation compounded with hydroxyethylcellulose no stability problems were observed. For the formulation containing Carbopol 940, the levels of erythromycin varied over a wide range due to precipitation and aggregation of the drug during compounding.     

PROTEIN ALLERGENS: THE IMPORTANCE OF SKIN AS A ROUTE OF EXPOSURE

Protein contact with skin is associated with a number of clinical conditions, including protein contact dermatitis and immunologic contact urticaria. This article reviews the clinical, in vivo, and in vitro evidence that proteinaceous materials penetrate skin. It is concluded that while penetration of intact proteins through normal skin is extremely low and normally without consequence, any damage to the skin barrier may allow penetration. As a result, risk assessment for contact of protein with skin must take into account potential barrier impairment and thus the possibility of both the induction and the elicitation of allergic skin reactions.     

Treatment considerations for inflammatory acne: clinical evidence for adapalene 0.1% in combination therapies

Acne vulgaris is an exceptionally common, chronic, and recurring disease. It involves multiple etiological factors including follicular hyperkeratinization, increased sebum production, Propionibacterium acnes proliferation, and inflammation. Presently, oral isotretinoin is the only single agent that is effective against all 4 major pathophysiologic features. However, this drug is also responsible for several serious side effects, including teratogenicity. Therefore, it should be used in only the most severe cases and alternative treatment approaches for inflammatory acne, such as initial combination therapy, should be considered first. Combination therapy in inflammatory acne simultaneously targets multiple pathogenic factors. Current guidelines recommend early initiation of combination therapy with a topical retinoid and antimicrobials for mild to moderate inflammatory acne and topical retinoids with oral antibiotics (with or without the use of benzoyl peroxide) for moderate to severe cases of acne, followed by maintenance therapy with topical retinoids. This review evaluates the rationale and clinical evidence for the use of adapalene in combination therapy for inflammatory acne.     

Optimizing topical combination therapy for the treatment of acne vulgaris

Given the multifactorial and complex contributors to acne development, combination therapy is standard of care. By addressing multiple pathogenic factors, combination therapy provides a quicker and more efficacious treatment outcome than monotherapy. Topical retinoids normalize follicular keratinocyte differentiation and are anti-inflammatory. Their use is limited by the potential for cutaneous irritation. Antimicrobials reduce Propionibacterium acnes colonization on the skin and reduce the bacteria's proinflammatory effects. Topical antibiotics and benzoyl peroxide (BPO) are commonly employed in fixed-dose combination products or two separate medications. BPO has the added benefit of being comedolytic and can minimize the risk for bacterial antibiotic resistance. Like topical retinoids, BPO may cause skin irritation, burning, erythema, and peeling. Managing cutaneous side effects when using multiple products that cause irritation can be a challenge. Careful product selection, dose titration, and patient-directed regimens can help to optimize outcomes. This review presents the latest data on two topical acne products that have demonstrated excellent efficacy and tolerability profiles. In addition, their in vitro profiles suggest the potential for combination use, affording greater dosing flexibility.     

Topical antibiotic therapy: current status and future prospects

As we enter a new decade, topical antibiotics are the subject of much renewed interest and are being used on a wider scale than ever before. The reasons for using topical rather than oral therapy for a variety of dermatoses include the reduced risk of systemic side effects, the avoidance of resistance selection in the gut microflora, the higher achievable concentration of antibiotic at the site of action and the overall usage of less drug. Somewhat surprisingly, treatment costs are not reduced by the use of topical therapy. The number of antibiotics licensed for topical use has increased in recent years and now includes representatives of the tetracycline, macrolide, lincosamide, aminoglycoside and peptide families of antibiotics in addition to fusidic acid, chloramphenicol and pseudomonic acid. Opinions regarding the clinical efficacy of topical antibiotics are conflicting, and for most indications alternative oral therapies are available. Topical antibiotics are the drugs of choice for the elimination of nasal carriage of Staphylococcus aureus and for the therapy of eye and external ear infections. They are also effective in the treatment of impetigo and other superficial pyodermas and in the management of localised infected eczema. Topical preparations of erythromycin, clindamycin and tetracycline are widely prescribed for the therapy of acne and are of clinical benefit in mild--moderate cases. However, they are no more effective against inflamed lesions than benzoyl peroxide and are less effective against non-inflamed lesions. They are not as effective as oral tetracycline in moderate to severe acne and should not be considered as a therapy for severe acne, for which 13-cis-retinoic acid is the drug of choice. It is well known that many antibiotics, when used topically, especially for prolonged periods, select for antibiotic-resistant staphylococci at the skin surface. Tetracyclines, erythromycin and clindamycin also select for resistant staphylococci on the surface of intact skin when delivered by the oral route. The contribution of topical antibiotic usage to the current high level of antibiotic resistance in coagulase-negative staphylococci, which are increasingly implicated in infections of compromised hosts, has not been quantified, although it is known that cutaneous staphylococci possess a large pool of transferable resistance genes.(ABSTRACT TRUNCATED AT 400 WORDS)