Abstract
Topical clindamycin Phosphate Gel has been accepted as being effective, safe and well tolerated in the treatment of acne for decades. Topical clindamycin comes in various vehicles, including gel, lotion, solution and foam. Choosing the proper vehicle is dependent on patient preference, tolerability and application site. Widespread usage of topical antibiotics has led to a greater proportion of resistant strains of Propionibacterium acnes. As a result of the increasing resistance, clindamycin monotherapy is no longer considered a first-line acne treatment. Currently, combination treatment with benzoyl peroxide has helped to prevent antibiotic resistance. In addition, novel combinations, such as clindamycin phosphate 1.2% or tretinoin 0.025% gel, have been proven to be superior to clindamycin monotherapy in reducing acne lesion counts.
Background
Acne is the most common skin disorder affecting teenagers in the USA. Currently, it is estimated that 85% of the US population will suffer from acne at some point in their lives. Excessive sebum production, abnormal desquamation of the intrafollicular epithelium, overgrowth of Propionibacterium acnes and subsequent P. acnes-mediated inflammation have been implicated in the pathogenesis of acne.Antimicrobial therapy not only decreases the number of P. acnes bacteria present in the skin, but also works by decreasing the P. acnes-related inflammatory mediators. Topical therapy is usually the preferred treatment for mild acne. It allows direct contact with the sebaceous follicles without exposing a patient to the possible adverse effects that systemic drugs may have. Currently, clindamycin is the most common topical antimicrobial used in the treatment of acne. Other topical antimicrobials include topical erythromycin, dapsone, benzoyl peroxide and azelaic acid.
Current acne guidelines recommend topical retinoids as first-line therapy in all acne cases, except for the most severe . For inflammatory acne (papules and pustules), the addition of topical antimicrobials is required. Antimicrobial therapy should include topical benzoyl peroxide, with or without the addition of topical antibiotics (i.e., clindamycin and erythromycin). Moderate acne may require the addition of oral antibiotics (i.e., tetracycline, doxycycline and minocycline). Female patients may additionally benefit from hormonal therapy, even in the absence of endocrine abnormalities. Patients with the most severe type of acne may require oral isotretinoin. Maintenance therapy for all types of acne should involve a topical retinoid with or without the addition of benzoyl peroxide. Long-term antibiotic use should be avoided owing to the potential for resistance development.
Mechanism
Clindamycin is a semi-synthetic derivative of the natural antibiotic lincomycin. Since clindamycin is chlorinated, it has greater lipophilicity, allowing better penetration into bacterial cells than lincosamides. It inhibits bacterial protein biosynthesis by irreversibly binding to the 50S subunit of the bacterial ribosome, producing the bacteriostatic effect. This prevents translocation of the peptidyl-tRNA from the A site to the P site, resulting in early chain termination. Clindamycin is most effective against aerobic Gram-positive cocci and anaerobic Gram-negative bacilli. Clindamycin has enjoyed something of a renaissance since it has also been found to be valuable in treating methicillin-resistant Staphylococcus aureus in skin and soft tissue infections. Along with its bacteriostatic effects, clindamycin also has action against some protozoa. For the treatment of acne, clindamycin targets P. acnes, a slow-growing, Gram-positive, anaerobic rod-shaped bacterium.
Antimicrobial Resistance
Widespread usage of topical and oral antimicrobials has resulted in the proliferation of less sensitive strains of P. acnes. Usually, this is a result of transposons and plasmids transferring between strains. However, with P. acnes, mobile genetic elements are not found. With macrolides, lincosamides and streptogramins, point mutations in 23S rRNA result in varying degrees of sensitivity. Since lincosamides and macrolides share the same binding site on the bacterial ribosome, most resistance that develops from clindamycin and erythromycin is a result of crossresistance. The high resistance rates that have developed over the past 25 years have led to the current recommendation to avoid clindamycin and erythromycin monotherapy in the treatment of acne.
Simonart and Dramaix reviewed the results of clinical studies conducted between 1974 and 2003 in order to evaluate whether there was in fact a decreased efficacy of topical erythromycin and clindamycin over time. Their analysis shows that erythromycin was less effective over time in reducing the number of inflammatory and noninflammatory lesions by annual percentage decreases of 2.14 (p = 0.001) and 2.03% (p = 0.001), respectively. By contrast, clindamycin efficacy has remained stable over the time period, with any changes being nonsignificant.
It is unclear why efficacy of clindamycin has remained steady while P. acnes resistance has continued to increase. It is well known that P. acnes produces chemotactic factors that attract polymorphonuclear leukocytes. Once polymorphonuclear leucocytes reach the sebaceous follicles, they release reactive oxygen species and other inflammatory mediators that damage the follicular epithelium. Clindamycin has been shown to have a nonantimicrobial effect against acne through suppression of polymorphonuclear leukocyte chemotaxsis, thereby reducing inflammation.
P. acnes produces a lipase that cleaves sebaceous triglycerides, thus releasing free fatty acids. Free fatty acids are both comedogenic and proinflammatory, exerting chemotactic effects. Clindamycin has been shown to inhibit P. acnes-related extracellular lipase production, whereas erythromycin did not inhibit enzyme production. Interestingly, despite changes seen in lipase production, clindamycin has little effect on P. acnes growth.
Compared with other topical antibiotics, clindamycin also has an effect on comedonal acne. Some of the first clindamycin studies showed an unexplained reduction of total comedo counts in the clindamycin-treated group (50%) compared with the placebo group (21%). Further investigation of the horny layer using cyanoacrylate follicular biopsy was used to analyze topical therapy-induced changes in lipid composition. This study showed a statistically significant reduction of the microcomedo counts, with a 21% reduction after 12 weeks of treatment with topical clindamycin 1%. This declined further to 31% during the 4-week follow-up period. Topical tretinoin 0.025% gel and combination tretinoin 0.025% gel and clindamycin 1% showed a 28.3 and 36.1% reduction in the follow-up period, respectively. Furthermore, there was a significant decrease in free fatty acid proportions and an increase in triglycerides, as well as an increase in ceramides in cast lipids. These results point to the distinctive quality of clindamycin in targeting noninflammatory lesions.
Safety
Although clindamycin phosphate and clindamycin hydrochloride are efficacious in the treatment of acne, the phosphate form is used more commonly . Clindamycin phosphate has been shown to have low bioavailability, giving it a good side-effect profile. Topical clindamycin phosphate does not penetrate the skin as easily as topical clindamycin hydrochloride. Systemic bioavailabilty of clindamycin phosphate salt was lower than the hydrochloride form – 2 versus 8%, respectively. In addition, clindamycin was not detected in the urine of subjects treated with topical clindamycin phosphate 1%.
Clindamycin phosphate structural formula.
Currently, topical clindamycin preparations maintain a US FDA pregnancy category B level, indicating that, although there are no controlled studies in pregnant women, animal-reproduction studies have not demonstrated fetal risk. With monitoring, oral clindamycin may be used to treat infections in children and, thus, topical application is also likely to be safe. Pseudomembranous enterocolitis is a known adverse side effect with oral administration of clindamycin. There have been case reports of Clostridium difficile colitis with topical clindamycin hydrochloride, but few with clindamycin phosphate. Therefore, in patients with a history of regional enteritis, inflammatory bowel disease or a history of antimicrobial-associated colitis, clindamycin is contraindicated. Clindamycin has also been shown to have neuromuscular blocking properties and should be used with caution if taken concurrently with a neuromuscular blocking agent. Clindamycin should also not be used with erythromycin as they have been shown to be antagonistic in vitro, probably because both share the same binding site.
Vehicle
Topical clindamycin is currently available in a variety of different vehicles, including lotion, solution, gel and foam (various branded and generic products). It is also found in combination with benzoyl peroxide and tretinoin. Vehicles differ in the amount of alcohol, water and oil they contain .
Clindamycin Phosphate: Ingredients of Various Preparations
The chemical formulations lead to differences in the alcohol-related drying effects, skin irritation, amount of residue and compatibility with other topical products. Factors that influence absorption include the dosage, frequency, duration and location of application, as well as the vehicle itself. Generally, gels, solutions and foams provide the easiest media for spreading and are the most efficient for drug delivery, whereas a cream or lotion will probably not penetrate the skin as effectively. Choosing the right product should also be based on the patient’s skin type (i.e., oily, normal or dry), application site (i.e., face, beard, hair, chest or back) and tolerability. Conjoint analysis comparing patient preference to topical antimicrobials found that patients preferred gel formulations, those that are stored at room temperature, those with a long product life, those that involve application with fingers and formulations that are used in once-daily regimens.
Of course, these preferences do hold not true for each patient and it may be unrealistic to clear acne with these parameters. At the same time, patient preference and convenience are the limiting factors in ensuring compliance and, therefore, treatment success.
Studies comparing clindamycin phosphate 1% solution, lotion and gel have demonstrated equal reductions in lesion count; however, the lotion and gel preparations were found to be less drying and irritating to the skin. A study comparing different topical antimicrobials found clindamycin gel to be preferred over clindamycin lotion, benzoyl peroxide/erythromycin gel and erythromycin/zinc solution. In this 4-week crossover study, patients applied each of the topical antimicrobials once or twice daily for 1 week. Acceptable texture, easy absorption and tolerability were qualities that made a product favorable for patients to use. In addition, easy application of make-up and skin care products after medication application also made the product more acceptable. Dry skin was the side effect most frequently associated with the gel; however, this side effect was more common in the benzoyl peroxide/erythromycin gel and erythromycin/zinc solution groups. Patients also report that, although the lotion vehicle was well tolerated and had an acceptable smell, it was absorbed less compared with the gel formulation.
Clindamycin Foam
Clindamycin foam is composed of clindamycin phosphate 1% in a stable, fragrance-free, nonstaining triphasic (organic, aqueous and lipid) foam vehicle (VersaFoam™). This vehicle is an excellent option for hair-bearing areas as it is easy to spread and leaves no residue behind.
In an in vitro human skin penetration study, twice as much clindamycin phosphate was recovered from foam than the gel formulation. In addition, the foam preparation delivered clindamycin phosphate three-times faster than the gel. Despite its penetration potential, the foam preparation showed a low systemic absorption, which was equivalent to its gel counterpart. A 12-week, multicenter, randomized, double-blind vehicle-controlled study found clindamycin phosphate 1% foam to be more effective than gel at reducing total, inflammatory and noninflammatory acne lesion counts. The most common adverse effects were headache and application site reaction, the most frequent being burning. Overall, it was well tolerated and efficacious in the treatment of acne.
Clindamycin & Benzoyl Peroxide Combination
As stated previously, acne is caused by excess sebum production, dyskeratinization, P. acnes and its inflammatory response. Therefore, combination treatment targeting several of these mechanisms appears to be the logical approach in the treatment of acne. Additionally, data suggest that combination treatment is superior to single agent usage. Combination products that contain benzoyl peroxide help prevent antimicrobial resistance. In patients who have already developed resistance, this combination continues to improve acne. Benzoyl peroxide is a powerful antimicrobial with broad-spectrum coverage. It is a lipophilic molecule that is able to infiltrate into the sebaceous follicle, where it propagates free radicals to oxidize proteins in the bacterial cell membrane. Furthermore, tertiary amine-containing antimicrobials, such as erythromycin and clindamycin, may work synergistically with benzoyl peroxide by increasing free-radical formation. In addition to its anti-inflammatory properties, benzoyl peroxide is also mildly comedolytic, reducing the noninflammatory lesion counts.
Unlike topical antibiotics, microorganisms, including P. acnes, cannot develop resistance to benzoyl peroxide. Combining benzoyl peroxide with clindamycin reduces resistant strains and permits longer effective therapy. In fact, several clinical studies have pointed to the superiority of combination clindamycin/benzoyl peroxide gel over clindamycin monotherapy . In addition, topical benzoyl peroxide monotherapy was inferior to the combination clindamycin/benzoyl peroxide gel. Tolerability has been shown to be similar for all groups. When examining the microbiologic activity of clindamycin gel monotherapy compared with combination clindamycin phosphate 1%/benzoyl peroxide 5% gel, P. acnes counts increased by more than 1600% from baseline in the clindamycin monotherapy-treated group. By contrast, the combination clindamycin phosphate/benzoyl peroxide-treated group showed reductions relative to baseline in clindamycin-resistant P. acnes counts.
Reductions in Propionibacterium acnes with topical treatment. BP: Benzoyl peroxide; Clinda: Clindamycin; Ery: Erythromycin. Reprinted from with permission. Copyright (2001) Elsevier.
Unlike combination benzoyl peroxide/erythromycin, benzoyl peroxide/clindamycin combinations are stable at room temperature and do not require refrigeration. Some benzoyl peroxide/clindamycin formulations, however, require reconstitution by a pharmacist and must be discontinued 2 months after compounding.
Clindamycin & Tretinoin Combination
Inflammatory acne responds to topical and oral antimicrobial treatments, whereas comedonal acne responds better to retinoids, such as tretinoin, adapalene or tazarotene. Retinoids inhibit the formation of the microcomedo, promote normal desquamtion of the follicular epithelium and enhance the penetration of other topicals. By inhibiting comedo rupture, retinoids also decrease inflammatory events. Further anti-inflammatory properties of retinoids are likely to be due to their ability to block Toll-like receptor 2. Retinoids should be used as first-line and maintenance therapy in all cases of acne.
The newest addition to the topical clindamycin preparations is the clindamycin phosphate 1.2% tretinoin 0.025% gel, which was approved by the FDA in 2006 for the treatment of acne vulgaris in patients older than 12 years of age. This formulation combines clindamycin phosphate 1.2% solution, which is equivalent to 1% clindamycin, with a crystalline suspension of tretinoin in an alcohol-free, aqueous-based gel. Clinical studies have shown it to be efficacious, with a low incidence of irritation. In addition, clindamycin phosphate 1.2%/tretinoin 0.025% gel had a lower incidence of flaring than tretinoin 0.025% gel in the early phase of treatment. It is postulated that the reduced irritation may be due to the fact that tretinoin is released in a rate-controlled manner. In addition, the aqueous-based, alcohol-free vehicle allows greater tolerability. It has also been postulated that the anti-inflammatory effects of clindamycin may reduce flaring. The efficacy of the clindamycin phosphate 1.2%/tretinoin 0.025% gel was evaluated in three randomized, double-blind, 12-week, Phase III studies in more than 4500 patients with mild, moderate or severe acne. It was demonstrated that the clindamycin phosphate 1.2%/tretinoin 0.025% gel was superior to clindamycin phosphate 1.2% gel, tretinoin 0.025% gel and vehicle gel alone in reducing the number of inflammatory, noninflammatory and total lesion counts (p < 0.001). This combination treatment is well tolerated, has a convenient once-daily application and targets several mechanisms in the pathogenesis of acne. However, a benzoyl peroxide agent should be added in the morning to avoid the development of resistance against P. acnes.
Conclusion
Clindamycin is the most common topical antimicrobial used for treating acne. Although antimicrobial resistance has increased over the last 20 years, clindamycin still retains valuable anti-inflammatory properties for controlling acne. Along with reducing inflammatory lesion counts, clindamycin also has an effect on reducing noninflammatory lesions (comedones). Clindamycin phosphate 1% comes in a solution, lotion, gel and foam vehicle. Factors such as skin type, application site, tolerability, ability to apply make-up after application and convenience are all considerations when prescribing a certain vehicle. Novel combinations, such as clindamycin phosphate 1% benzoyl peroxide gel or clindamycin phosphate 1.2%/tretinoin 0.025% gel, have been proven to be superior to clindamycin monotherapy in reducing acne lesion counts. Combination treatments have also shown equivalent tolerability to monotherapy. Combination therapy should be the standard in management of acne in order to decrease P. acnes-related resistance.
Expert Commentary
Owing to the decreased sensitivity of P. acnes, topical clindamycin should not be used alone. It should always be used in combination with benzoyl peroxide, either as a leave-in product or in conjunction with a benzoyl peroxide wash. Solution and foam preparations may be preferable for hair-bearing areas, including the chest and back in men. Lotions may be helpful for acne patients who complain of dry skin or peeling from retinoids. In our experience, clindamycin phosphate 1.2%/tretinoin 0.025% gel has also been well tolerated by patients, probably because it is alcohol-free. However, for inflammatory acne, a benzoyl peroxide product should be added in the morning to minimize the emergence of resistant organisms.
Five-year View
There are very few new topical agents at this time that could take the place of topical clindamycin. It is currently the most widely used topical antimicrobial for the treatment of acne in the USA. The emergence of less-sensitive organisms and the concern over the development of methicillin-resistant S. aureus suggest that the combination of clindamycin and benzoyl peroxide will gain increased use. There is also a new combination of adapalene and benzoyl peroxide that may gain popularity. A new emerging topical antimicrobial in the treatment of acne is dapsone 5% gel. In a double-blind, randomized trial, dapsone gel was found to be superior to vehicle gel. It is unclear what future role dapsone gel will have in the treatment of acne. There are no head-to-head studies comparing topical clindamycin with dapsone. Further study of dapsone alone or in combination with other drugs is needed to define its role in acne management.
Topical taurine bromide (TauBr), the product of taurine and hypobromous acid, may also gain popularity in acne therapy. It exerts anti-inflammatory and antimicrobial effects against P. acnes. In a double-blind study, TauBr and clindamycin showed similar reductions in acne lesions of 65 and 68%, respectively. No adverse effects were observed in either group. However, how TauBr will be utilized in clinical practice is yet to be determined.
Sidebar: Key Issues
• Acne is the most common skin disorder affecting teenagers in the USA.
• Acne is caused by excessive sebum production, abnormal desquamation of the intrafollicular epithelium, overgrowth of Propionibacterium acnes and subsequent P. acnes-mediated inflammation.
• Topical clindamycin not only decreases the number of P. acnes present in the follicle, but also works by suppressing polymorphonuclear leukocyte chemotaxsis and inhibiting P. acnes extracellular lipase production.
• Topical clindamycin has also been shown to reduce comedonal acne, probably through the effect of free fatty acids.
• Widespread usage of clindamycin is implicated in the spread of cross-resistant strains of P. acnes. As a result, clindamcyin monotherapy is no longer considered a first-line topical treatment. Combination clindamycin phosphate 1% benzoyl peroxide is more effective at reducing acne lesion count.
• Combination clindamycin phosphate 1.2% and tretinoin 0.025% gel has also been shown to be superior to clindamycin monotherapy in reducing both inflammatory and noninflammatory lesion counts.
