Acne Vulgaris Topical Therapy – Topical Antibiotics and Oral Antibiotics

INTRODUCTION

Successful treatment for acne vulgaris is guided by the severity of the acne and is aimed at correcting the altered pattern of follicular keratinization, decreasing sebaceous gland activity, decreasing the follicular bacterial population, and providing an anti-inflammatory effect (1). In many cases, management of acne vulgaris should be approached as a chronic disease with a prolonged course and a pattern of recurrence or relapse that manifests as acute or gradual outbreaks (2,3).

Early and aggressive treatment of acne vulgaris is encouraged to limit the occurrence of physical scarring, persistent hyperpigmentation, and psychological sequelae (4).

Treatment modalities include both local and systemic therapies and may include combinations of both types of therapies. Selection of single versus combination treatment should be made following the determination of the severity of disease, the types of lesions present, the psychological impact of the disease, and the patient’s treatment history (5). Several guidelines have been proposed for the assessment of acne severity; however, currently, there is no single standardized and reproducible grading system. In general, acne severity is determined by the number of lesions, the number and presence of non-inflammatory (e.g., open and closed comedones) versus inflammatory lesions (e.g., papules, pustules, nodules/nodulocystic lesions), and the extent of disease.

Cunliffe et al. have proposed a severity scale based on the number and types of lesions (6). Mild acne is characterized by the predominance of comedones with less than 10 small papules and pustules. The presence of 10 to 40 papules and pustules and 10 to 40 comedones define moderate acne. Mild disease on the trunk may also be present. In moderately severe disease, numerous papules and pustules (40 100), several comedones (40 100), and up to five large and deep nodular inflamed lesions are present with widespread involvement of the face, chest, and back. Severe acne is characterized by the presence of nodulocystic acne and acne conglobata with many large and painful nodular or pustular lesions including several smaller papules, pustules, and comedones.

FIRST-LINE THERAPY

The pathogenesis of acne occurs as a result of four major factors: (i) excess sebum production, (ii) bacterial colonization of the pilosebaceous duct and release of inflammatory mediators, (iii) inflammation, and (iv) abnormal kera-tinization within the follicle. Current treatment modalities are formulated to simultaneously affect these pathogenic factors. The use of topical retinoids is based on their comedolytic and anticomedogenic activity, anti-inflammatory effects, and their ability to normalize desquamation to allow penetration of other topical agents (7). Although the combination of antimicrobials with benzoyl peroxide has been shown to have some effectiveness in the treatment of acne, antibiotics and benzoyl peroxide have only minimal comedolytic or anti-comedogenic effects (7). The anti-inflammatory and antimicrobial properties of antimicrobials and benzoyl peroxide complement the properties of topical reti-noids and have been more effective in combination compared to monotherapy with either antimicrobials or topical retinoids (8). Moreover, the combination of antimicrobials with benzoyl peroxide may help prevent the emergence of resistant strains of Propionibacterium acnes (7,9). No single therapy is able to counter the growth of P. acnes inflammation and comedogenesis as effectively as antibiotics and retinoids in combination (7,9). For most patients, first-line therapy using the combination of a topical retinoid and antimicrobial agent results in faster and more complete clearing of acne lesions compared with monotherapy (4).

TOPICAL RETINOIDS WITH TOPICAL ANTIMICROBIALS

Combination therapy using topical retinoids and topical antibiotics (e.g., clin-damycin and erythromycin) and benzoyl peroxide are most effective in the treatment of patients with mild-to-moderate acne with an inflammatory com-ponent (10 13). A 12-week, randomized study comparing the combination of adapalene gel 0.1% and clindamycin 1% gel versus clindamycin 1% with the adapalene vehicle revealed faster and significantly greater clearance of acne lesions using the combination of adapalene gel with clindamycin (13). In addition, tretinoin gel 0.025% plus clindamycin gel 1% was more effective compared with either treatment alone in an eight-week study involving 64 patients (14). A randomized, parallel-group, investigator-blinded study of clindamycin 1% gel in combination with either tazarotene 0.1% cream or tre-tinoin 0.025% gel in 135 patients with mild-to-moderate acne showed that the tazarotene regimen was associated in greater improvements in overall disease severity and better global assessments (15). Studies comparing the cumulative skin tolerance of topical retinoids (adapalene gel 0.1%, tretinoin cream 0.025%, and tretinoin microsphere gel 0.1% and 0.4%) in combination with topical microbials (clindamycin 1%, erythromycin 2%, benzoyl peroxide 5%, and erythromycin/BPO gel) have demonstrated minimal erythema, dryness, or burning/stinging with adapalene gel compared to other retinoids (15 18). In general, retinoid-based combination therapy with an antimicrobial agent is recommended as first-line therapy for most patients with acne because the combination decreases abnormal desquamation, P. acnes colonization, and inflammation (4).

TOPICAL RETINOIDS WITH ORAL ANTIBIOTICS

The use of topical retinoids in combination with oral antibiotics is very effective for the treatment of moderate-to-severe or persistent acne. Two multicenter, randomized, investigator-blinded studies comparing the efficacy and tolerability of oral antibiotics (lymecycline, doxycycline) in combination with topical reti-noids (adapalene) demonstrated significant decreases in the total number of inflammatory and noninflammatory lesions in a short amount of time compared to monotherapy (6,19). Topical tretinoin in combination with oral tetracycline also has increased efficacy and faster therapeutic response in reducing P. acnes than with either agent alone (8,12). The Global Alliance cautions against pro-longed antibiotic treatment to prevent the emergence of resistant strains of P. acnes and recommends no more than three to four months of antibiotic treatment in combination with retinoids followed by maintenance therapy with a topical retinoid (4). If inflammatory lesions are still present, then the use of benzoyl peroxide or a benzoyl peroxide/antibiotic combination should be used in addition to a topical retinoid.

FIXED-DOSE COMBINATION PRODUCTS

Fixed-dose combination products were developed with the goal of increasing patient compliance and have shown enhanced efficacy and speed of treatment of acne. Studies comparing fixed-dose combination products with BPO (adapalene 0.1%/BPO 2.5%) or topical antibiotics (tretinoin 0.025%/clindamycin 1.2% gel, tretinoin 0.025%/clindamycin 1% hydrogel, and erythromycin 4%/tretinoin 0.025% gel) have also shown increased effectiveness of fixed-dose combination products compared to treatment without topical retinoids (20 22). Adapalene gel 0.1% combined with BPO 2.5% in a fixed-dose product has been carefully studied in a multicenter, randomized, double-blind study in 517 patients with moderate to moderately severe acne (23). The 12-month study consisted of 452 patients with acne using the once-daily fixed-dose combination of adapalene/ BPO and showed sustained reduction of inflammatory and noninflammatory lesions and improved cutaneous tolerability (24). Use of adapalene treatment in combination with a clindamycin/BPO fixed-dose product was evaluated in a randomized, multicenter, parallel group study and showed the greatest reduction in lesion counts in patients treated with adapalene in combination with the fixed-dose clindamycin/BPO product (25).

Moreover, the combination of tazarotene plus a clindamycin/BPO fixed-dose product in the treatment of moderate-to-severe inflammatory acne showed significant global improvement, reduced number of inflammatory lesions, and reduced skin irritation (26,27). A multi-center case series evaluated efficacy and tolerability of the fixed-dose combi-nation of tretinoin 0.025%/erythromycin 4% product and showed improvement with rapid onset and good tolerability in 85% of patients with acne (28). Comparison of tretinoin 0.025%/erythromycin 4% with erythromycin 3%/BPO 5% in patients with moderate acne showed comparable efficacy; however, the erythromycin 3%/BPO 5% product was preferred and had better cutaneous tolerability (21). Additionally, two randomized, double-blind, active-drug and vehicle-controlled studies of tretinoin/clindamycin fixed combination product in 2219 patients with mild-to-moderate acne showed greater reductions in the number of inflammatory and noninflammatory lesions and there were a greater number of patients at the end of the study with clear or almost clear skin on Investigator Global Assessment in patients who received the combination treatment (22). The irritancy potential of various fixed-dose combinations has also been studied. Comparisons between adapalene gel 0.1%, tazarotene cream 0.05%, and tretinoin microsphere 0.04% in combination with clindamycin/ benzoyl peroxide products have shown that adapalene resulted in the least amount of irritation compared to tretinoin and tazarotene (29).

Combining BPO or antibiotics with retinoids is guided by the bactericidal properties of BPO and antimicrobials and the comedolytic and anticomedogenic properties of retinoids. Moreover, retinoids have been shown to downregulate the expression of TLR-2, thereby decreasing cytokine production and blocking the AP-1 inflammatory pathway. Retinoids have also been shown to increase CD-1d expression and decrease IL-10 expression on keratinocytes, which may enhance dendritic and T-cell interaction and antimicrobial activity against P. acnes (30). However, it should be noted that combination formulations con-sisting of topical antibiotics without benzoyl peroxide (e.g., fixed-dose retinoid/ antibiotic formulations) may increase the prevalence of resistant strains of P. acnes. According to the Global Alliance, any retinoid/antibiotic combination should also include benzoyl peroxide or should be changed to a retinoid with or without benzoyl peroxide to decrease the incidence of resistant strains of P. acnes (4).

MAINTENANCE THERAPY

The chronic nature of acne merits continued therapy, as this disease tends to recur when treatment is withdrawn following successful initial therapy (31,32). For most types of acne, topical retinoids are recommended because of their anticomedogenic and comedolytic properties. There have been many studies evaluating the efficacy of topical retinoids as maintenance therapy, usually following initial treatment with a topical retinoid and topical antimicrobial. In a study involving patients with moderate to moderately severe acne following combination therapy, patients con-tinued on adapalene maintenance therapy had a significant reduction in lesion counts and had less rebound of acne lesion compared to those who did not receive maintenance therapy (33). Similarly, in a randomized, vehicle-controlled mainte-nance study of patients who showed improvement following combination treat-ment, more than half of patients were able to maintain 90% of their clearing while on their adapalene maintenance therapy compared to those using the vehicle control (34).

In both studies, patients who were untreated or treated with vehicle eventually developed rebound of acne lesions, whereas those treated with adapalene mainte-nance therapy had stable or decreased lesion counts. Using patients who showed improvement after combination treatment, a randomized, parallel-group, double-blind, 12-week study assessed the efficacy of three different maintenance therapy regimens including tazarotene gel, minocycline, and tazarotene gel with minocy-cline. All three groups showed no significant differences in mean overall disease score, reductions in acne lesions from baseline, or percent of patients with good or excellent maintenance (35). This study not only indicates that topical retinoids are effective but also indicates that the use of antibiotics does not provide additional benefit. In general, long-term use of topical or oral antibiotics should be dis-couraged to reduce the potential for antimicrobial resistance (4,5).

The anticomedogenic property of topical retinoids is the basis for use of these agents as maintenance therapy. An assessment of microcomedone forma-tion in patients with mild-to-moderate acne treated with adapalene maintenance therapy was done using cyanoacrylate stripping. Using computer-assisted den-sitometric analysis, cyanoacrylate stripping allows for analysis of the lipid composition in the sebaceous follicular infundibulum and surface lipids. Patients treated with topical retinoids show increased ceramide subfractions, and this is correlated with decreased microcomedone formation (32). At baseline, week 8 and week 20, cyanoacrylate strip analysis showed a significant decrease in microcomedone formation in patients treated with adapalene maintenance therapy compared to the vehicle (36).

CONCLUSIONS

Several treatment algorithms have been proposed based on acne severity. The use of combination therapies as first-line treatment of acne has been shown to have the most significant effect with faster onset than other treatment modalities. In general, mild acne can be treated with topical retinoids with the addition of antibiotics or benzoyl peroxide containing products if inflammatory lesions are present. Mild-to-moderate acne (e.g., mild-to-moderate popular/pustular acne) can best be treated with combination therapy composed of the following regi-mens: (i) a topical retinoid combined with a topical or oral antibiotic, (ii) a topical retinoid combined with benzoyl peroxide or benzoyl peroxide/antibiotic fixed-dose product, or (iii) a fixed-dose topical retinoid/benzoyl peroxide in combination with a topical antibiotic. Moderate-to-severe acne (e.g., severe nodulocystic) can also be treated with combination therapy composed of topical retinoids combined topical or oral antibiotics. Additional benefit can be achieved using systemic isotretinoin alone; however, the side effects profile of oral iso-tretinoin may prohibit its use in some patients. Following successful treatment with combination therapy, maintenance therapy with topical retinoids can be initiated.

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Jean-Paul Marat

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