Management of Acne Using a Fixed Dose Clindamycin/Tretinoin Preparation

Sam Hanna, MD, DABD
Managing Physician, Dermatology on Bloor, Toronto, ON, Canada

Introduction

The new Canadian acne guidelines were published in the Canadian Medical Association Journal in 2016.¹ An excellent summary of the new guidelines was published in the April 2017 issue of Skin Therapy Letter, Family Practice Edition.² The focus of this review is to delve deeper into the use of Biacna^® Gel, a fixed-dose clindamycin/tretinoin combination product, for the treatment of acne.

Background

• Acne is a common skin disease affecting more than 90% of Canadian teens. As acne can persist into adulthood in up to half of patients, treatment may need to be continued for years to maintain control.
• The mainstay of comedonal acne therapy is topical retinoids (vitamin A derivatives), which primarily serve to normalize follicular keratinisation.
• Inflammatory (papulopustular) acne, which can lead to scarring, often requires the addition of anti-inflammatory topical or oral antibiotics.
• Severe acne (nodulocystic acne, conglobate acne or acne fulminans) is best treated with isotretinoin, an oral retinoid.
  • Isotretinoin is a potent teratogen and has a more challenging side effect profile for patients.
  • Labratory monitoring of patients is necessary while on isotretinoin therapy.
  • Women of child-bearing potential must be on a concomitant primary form of birth control.
• Hormonal acne in females typically presents as monomorphic inflammatory acne of the lower face and submental area and can be managed with agents like spironolactone or specific oral contraceptives.
• In the new Canadian acne guidelines,¹ the recommended first-line therapy for comedonal and papulopustular acne is benzoylperoxide (BPO) or Topical Retinoids or both or Fixed Dose Combinations BPO/ Clindamycin (clinda) or BPO/Adapalene or, after failure of above, Clinda/Tretinoin.
• As should be expected, these guidelines were developed based on the strength of the available data at the time they were written.
• The guidelines’ authors required 2 randomised controlled trials for inclusion in the first “tier”. At the time of their development, there were 2 pooled RCTs for Biacna^® Gel. The decision was made by the co-authors to consider this as a single RCT, hence the positioning of Biacna in the guidelines. Given this and the discussion that follows, physicians should be comfortable considering Biacna^® Gel as a first line agent in acne.

Clindamycin/Tretinoin

• Biacna^® Gel is an aqueous-based, alcohol-free gel consisting of solubilized clindamycin phosphate and two forms of tretinoin; one immediately available and one which solubilizes slowly. The tretinoin is stable and is not degraded by sunlight or by benzoyl peroxide.³ Tretinoin particle size is ≤10 μm to improve entry into the pilosebaceous unit.⁴
• The clindamycin in Biacna^® Gel is a water-soluble ester of the semi-synthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent antibiotic lincomycin. It binds to susceptible bacteria and suppresses bacterial protein synthesis. It is primarily bacteriostatic with demonstrated in vitro activity against P. acnes.
• Tretinoin occurs as a yellow to light orange crystalline powder, insoluble in water, slightly soluble in alcohol and chloroform. It decreases the cohesiveness of follicular epithelial cells and decreases microcomedone formation. This increases turnover of follicular epithelial cells, causing extrusion of comedones.
• The tretinoin in Biacna^® Gel occurs in two forms, solubilized and crystalline.
• The solubilized form affords rapid delivery of the tretinoin on the skin surface leading to rapid follicular penetration.
• Progressive solubilization of the crystalline tretinoin on the skin surface results in slower and prolonged follicular penetration, accounting for the improved tolerability of this form of tretinoin.⁵ This may also provide improved, deeper penetration of clindamycin into the follicles, which could lead to increased concentration of clindamycin where P. acnes is located.

Clinical Data

Efficacy

• In the pivotal trials, Biacna^® Gel demonstrated a statistically significant increase in efficacy compared with clindamycin alone or tretinoin alone or vehicle. Mean reduction in total lesion count of 41% was noted in the Biacna^® Gel group as compared to 34% and 34% in the clindamycin and tretinoin groups respectively.
• Dreno et al⁶ looked at the efficacy of Biacna^® Gel in adolescents as compared to an overall study population. They demonstrated statistically significant reductions at 12 weeks in both inflammatory and non-inflammatory lesions both in adolescents and the general study population.

Safety and Tolerability

• While retinoids are a staple of topical acne management, their use is often accompanied by varying degrees of irritation.
• While irritation was reported at a low rate with Biacna^® Gel, it occurred at a lower rate than with other fixed-dose retinoid-containing topical properties.
• This is likely due to several factors:
  • Biacna^® Gel’s aqueous gel base is likely less irritating than an alcohol based gel.
  • The two forms of tretinoin in Biacna^® Gel likely limit retinoid-related irritancy. The clindamycin component may have anti-inflammatory properties that reduce retinoid induced irritation. This is supported by lower levels of irritation with the clinda/tretinoin combination versus tretinoin alone.⁷
• As with all topical retinoids, the long-term safety of these products has yet to be established and, given the teratogenicity of oral retinoids, the use of Biacna^® Gel in pregnancy should be avoided.

Improving Penetration of Clindamycin

• The presence of a retinoid may enhance the penetration of clindamycin into the follicles. This was demonstrated by Jain et al. 2007 when clindamycin and a retinoid were applied together to both rat skin and to human volunteer hand skin. They demonstrated that the concentration of clindamycin applied in conjunction with a retinoid was almost double that seen when the antibiotic was applied alone.⁸

Antibiotic Resistance

• A study⁹ examining the antimicrobial effect of the clindamycin/tretinoin combination enrolled 22 healthy patients whose cheek samples exhibited high P. acnes MIC levels of at least ≥10,000 colonies per cm² and MIC of ≥8μg/mL for clindamycin, to ensure the presence of resistant organisms.
• Using a split-face design, each patient was treated with 1.2% clindamycin gel on one cheek and clindamycin 1.2%/tretinoin 0.025% gel on the other cheek once daily for 6 weeks.
• In the split-face design study,⁶ quantitative bacteriologic cultures were obtained from left and right cheeks at baseline and at weeks 3 and 6.
• In patients with low/moderate clindamycin resistance (MIC ≤256 μg/mL), both treatments were equally effective at reducing P. acnes at Weeks 3 and 6.
• In patients with high clindamycin resistance (MIC ≥<512 μg/mL), there was no difference at week 3, but the clindamycin/tretinoin combination demonstrated significantly greater mean 6-week log/cm²
• Since there is no known antimicrobial effect of tretinoin, this suggests that the presence of the tretinoin component allows more effective and prolonged penetration of clindamycin enabling more robust control of P. acnes.
• Available data indicate that, unlike use of clindamycin monotherapy, use of Biacna^® Gel for up to 16 weeks demonstrated no increase in clindamycin-resistant P. acnes.^{10, 11}
• However, if more prolonged maintenance therapy with Biacna^® Gel is undertaken, the addition of a benzoyl peroxide gel or wash may be prudent as this has been shown to significantly mitigate the development of antibiotic resistance.
• Biacna^® is also more effective at reducing clindamycin-resistant P. acnes than clindamycin monotherapy as noted above.

Conclusion

Biacna^® Gel represents an excellent addition to the primary treatment options for patients with acne, as indicated. In addition, it offers an effective, well tolerated topical maintenance option once control is achieved.