Acne therapy: old wine in new vessels – the promise (and pitfalls) of new drug deliveries and regimens

Therapy in acne vulgaris has undergone significant advances in the new millennium. While the standard menu of therapeutic options has changed little, the delivery/application options have steadily increased effectiveness and patient tolerance and acceptance. These advances have occurred in both systemic and topical therapy and, as I discuss later, therapeutic success as well as patient satisfaction, has reached new heights. There are few conditions for which we have such in-depth understanding of the pathophysiologic mechanisms which has resulted in focused therapy that is so successful [1,2]. While standard drugs have changed little, their usage has been dramatically enhanced by newer low-dose, sustained-release systemic preparations and better targeting with topical agents, essentially accelerating and broadening the response to time-honored agents. Owing to the size of the market (i.e., dermatologists and not generalists who usually prescribe generically), major ‘breakthrough’ or ‘blockbuster’ drugs are not anticipated.

Drugs

Systemic

Retinoids

Retinoids remain the mainstay of therapy as they are the only modalities capable of acting on all of the operative mechanisms in the pathologic cascade of acne vulgaris [2]. No other agents directly correct the keratinization abnormality that is key to the process. While hormones can affect sebum production and antibiotics downregulate inflammation, systemic retinoids do all three. The teratogenicity, mental depression and other systemic side effects are the major limitations to more extensive use, especially in the USA where the US FDA/American Academy of Dermatology ‘I-pledge program’ mandates extensive documentation and in-depth registration, along with a very restrictive schedule of visits, laboratory testing and oversight of prescriptions. Even without this extensive regulatory oversight, for some patients, the usual physiologic side effects including elevation of triglyceride level, mucous membrane dryness and epistaxis are challenging to manage. Rarer serious side effects, such as depression/suicide potential, and even rarer problems, such as drug interactions and ‘pseudotumor cerebri’, further mandate careful patient selection in addition to intensive follow-up. For some time, a new class of drugs has been under investigation that modulates the metabolism of endogenous retinoids by interfering with usual catabolism, elevating them and ideally achieving the same effect as dosing isotretinoin. This evolved from studies on the metabolism of imidazoles, which require cytochrome P450 (CYP450)/3a for this process and, therefore, compete with many other drugs for this pathway. This is seen with the retinoid/antifungal–imidazole interaction, resulting in a potential for serious toxic interactions. The retinoid metabolism inhibition was initially reported with the imidazole liarazole and is now also reported with R115866 (rambazole) [3]. Initial reports are encouraging, showing significant retinoid effects without many of the troublesome side effects (e.g., dryness/cracking of the skin – especially the mucous membranes). Since these are endogenous retinoids that were elevated by blocking the metabolic degradation and elevating the skin retinoid concentration, presumably the problems of depression and teratogenicity would be significantly less; however, this is an area of uncertainty that will require further long-term studies to clarify. The rationale here is most exciting and promising for future therapeutic approaches.

Antibiotics

Macrolides

There has been few additions in the choice of antibiotics for acne. Of greater significance has been the steady accumulation of bacterial resistance reported in patients on both systemic and topical antibiotics. While few alternate choices have been developed, other approaches have been operative to address the problem. First, concern has been raised regarding the choice of other macrolides, as some have unique effectiveness in other areas (i.e., clarithromycin for other atypical acid fast bacterial diseases). Another concern has been drug interactions, as macrolides share the CYP450 involved in metabolism of statins, triazoles and imidazoles that are widely used. Systemic erythromycin has been used much less frequently owing to the gastrointestinal (GI) side effects, but topical forms have wide usage after the demonstration of the anti-inflammatory effect of the topical preparations of erythromycin/benzoyl peroxide (BPO) versus topical agents of BPO without the antibiotic.

Tetracyclines

Tetracyclines, the group of antibiotics longest used in acne, has perhaps succumbed to the generic switch, which has resulted in variability in results as well as the growing problem of antibiotic resistance. GI side effects, a problem with the generics, has been addressed by newer formulations that delay absorption in the upper portions of the GI tract. Cost maintains the generic predominance, even with the aforementioned problems of patient symptoms. Perhaps the most significant advance in the use of tetracyclines in acne has been the newer low-dose, timed-release forms of doxycycline and minocycline. This new approach was first introduced in oral surgery with low-dose (20 mg) doxycycline for oral inflammatory conditions [3,4]. This approach was primarily found to downregulate inflammation with little bacteriostatic/bacteriocidal effect. Further studies demonstrated that this formulation minimized the risk for common side effects, such as photosensitivity and monilial infection. This was adopted off-label by dermatologists for acne and acne rosacea. The usage, for over a decade, in analysis seems to have avoided significant increases in bacterial resistance, also suggesting a major advance in therapy. More recently, the 40 mg form was approved for rosacea (one per day or 20 mg twice daily), and it is now also used in acne and will most likely be well accepted, although cost is a barrier.

Minocycline, long considered the gold standard in acne antibiotic therapy, is now also available in three dosage forms (45, 90 and 135 mg). This allows flexibility to approach the ideal dosing of 1 mg/kg/day. It is noteworthy that this extended-release formulation was developed with the first dose-ranging studies in acne, since all of the previous studies were directed at clinical response rather than dosing. The dose (1 mg/kg/day) now recommended showed significant benefit, while significantly reducing the vestibular side effects observed in usual dosing [5]. The same benefits prevail and will probably be the standard of care for difficult cases (the last step before using isotretinoin). It is not clear whether this subantimicrobial dosage avoids the resistance phenomenon, but this is a hoped-for benefit.

Topical therapy advances

Perhaps the major advance in topical therapy has been the newer gel, microsponge and foam vehicles, which are showing greater tolerability and enhanced drug penetration, ideally avoiding the possibilities of systemic drug toxicities and interactions. Most studies of percutaneous penetration with these vehicles have been in topical steroids, but there are some acne products available with seemingly adequate penetration and effectiveness [1]. The ease and convenience of new preparations (e.g., pumps and canisters) have resulted in acceptance even though the cost is generally higher than the traditional formulations. Many of the original formulations are now displaced to over-the-counter (OTC) status, or in some instances generic availability, leaving the new vehicle delivery systems as the prescription-only agents for the present and the future.

Retinoids/topicals: first & third generation

Retinoids still remain the keystone for acne therapy, as they alone act on all three pathophysiologic mechanisms of acne: sebum production, follicular dyskeratinization and bacterial-induced inflammation. While the first-generation forms had significant inflammatory sequellae, refinement on the vehicles has produced better tolerated forms of retinoic acid. However, generic availability has essentially prevented further development and except for some minor changes in delivery systems and some unique dispensers, such as pumps, the generic shift has been the major determining factor of therapy and, unfortunately, there has been a return to the significant irritative side effects that come with these inexpensive generics. The greater tolerability of the third-generation retinoid adapalene led to its rapid acceptance, while the other third-generation retinoid tazarotene was slower to be accepted owing to its much higher irritative potential, similar to the first-generation products and the inexpensive generics.

With no newer agents in the pipeline, the advances for the future seem to focus on the combination agents (vide infra). The combination agents rely on new vehicle technology to minimize irritation (especially with the retinoids) and provide longer stability/shelf life and absorption. It is currently safe to assume that generic substitution (except for in a couple of instances, which again cost more) results in decreased compliance because of increased irritation and decreased tolerability. The combination agents also simplify the treatment schedule to once daily instead of twice daily.

Combination preparations

Compliance is always a challenge, especially with busy teens, as the usual regimen of topical therapy may include:

• • Antibiotic/BPO in the morning

• • Retinoid at bedtime

• • Several applications of keratolytic cleansers (e.g., salicylic acid and BPO) daily in addition to oral antibiotics (once- to four-times daily)

Many of the topical agents are sometimes reactive with a short shelf life. The first combination BPO/erythromycin was reconstituted when dispensed and refrigeration was recommended. Shelf life was an even greater concern with retinoids in any preparation until now. Such combinations allow the use of the principal anti-acne agent (retinoids) with other agents (BPO or ABX) to allow a simplified once-daily use, which thus far appears to greatly enhance compliance and, thus, clinical improvement. The new tretinoin 0.025%/clindamycin 1.2% gel was the first available and meets all the expectations, especially the daily hour of sleep application, greatly improving acceptance and compliance [6]. Next available, the adapalene 0.1%/BPO 2.5% had great results in early studies but is too new for wider clinical impressions [7]. However, this newest agent has the known tolerability of adapalene and, coupled with the BPO, sidesteps the concerns of antibiotic resistance totally. Therefore, it would also seem a great advance with the once-daily application. Comparisons between the tolerability of the new tretinoin vehicle and the known tolerability of adapalene may be the key in choice of either. The concern of growing antibiotic resistance could also favor the choice of the adapalene/BPO combination.

The only new agent that has been approved by the FDA is the gel formulation of diamino-diphenyl sulfone (DDS [Dapsone]) [8,9]. This drug was originally, and still is, used in the treatment of leprosy. When I reviewed the literature as a resident, 12 million persons worldwide were using DDS daily for Hansen’s disease, which attests as a ‘Phase 4’ assurance of safety. Even with this record, the greater utilization of the drug for conditions from acne to Zumbusch’s psoriasis resulted in higher dosage uses and increasing reports of reactions. These include agranulocytosis (in malarial prophylaxis), the dapsone syndrome (a Stevens–Johnson-like syndrome reported prominately in the treatment of Loxosceles envenomation), common hematologic effects/anemia and hepatic toxicity.

Additionally, a more problematic adverse reaction to DDS is a neuropathy that is of unclear significance, since many reports were in the treatment of Hansen’s disease where there is significant neurological damage with the disease. The recording of such reactions is complicated by the fact that they have occurred in the tropics where laboratory backup to document/confirm the reaction is often lacking. When used in severe acne (usually grade 4; now treated with isotretinoin) doses of up to 400 mg/day had significant hematologic sequellae, but this was usually tolerated in the treated population of young healthy adults, being a more significant side effect in the elderly who were treated for mechanobullous diseases such as bullous pemphigoid. These considerations led to caution concerning the use of the anti-inflammatory effects of DDS in acne. In many ways, it has great potential as the anti-inflammatory effects do not come with the concern of antibiotic resistance. Preliminary reports suggest that this approach has few, if any, of the systemic effects and the formulation gel seems to give equivalent results to most other treatment modalities. If early results are maintained this could be a major new tool for therapy, with vehicle advances made for the enhanced absorption and stability of the gel.

Devices

Dermabrasion

This is perhaps the oldest device for the treatment of the scarring sequellae, although it is not used as part of concurrent therapy but when the acne is in remission, so that resurfacing can be used to correct the scarring. When used while the acne was still active there was a possibility of worsening of the long-term cosmetic results, perhaps by compounding the inflammatory levels. By contrast, lasers in some instances seem to downregulate inflammation and ameliorate the process [10]. Laser dermabrasion offers advantages, including less blood loss and splattering and, in some reports, more rapid healing. As with the previous wire brush and diamond fraize tools, the procedure is very operator-specific and excellent results can be expected from the experts – in my mind the ‘artists’ – in the field. With the laser a new variable is introduced – the multiplicity of instruments; another operator variable – but the right combinations and surgeons can provide excellent results. There are few comparison studies in the literature so evidence-based information is not available at the present time, and may never be, as the variablility in operator/surgeon skills and different instruments make the data in careful studies nearly nonexistent. The pace of innovation in laser therapy would make it a major tool in skin cosmetic therapy and, ultimately, newer machines will provide more standardization in treatment to provide more predictable results with less operator dependence.

Phototherapy

Light therapy was another early physical modality in skin care for acne and other inflammatory skin conditions. The instruments were used in the home largely with low power and low risk for complications; however, even these early tools had complications that led to greater regulation, largely eliminating home treatments. Photodynamic therapy has come to the forefront of the field and intense pulsed light (IPL) for differing skin conditions first for premalignant conditions such as actinic keratoses and early cancer in situ as well, as for very superficial conditions such as superficial multicentric basal cell carcinoma. Here again comparison and double-blind studies are insufficient to compare different protocols (e.g., blue light, red light and photosensitizers) [11]. The phototoxicity of some light sources on resident bacteria is thought to be important in the downregulation of the inflammation causing the flares. Some of these bacteria produce porphyrins, which are the usual exogenous photosensitizers in the actinic keratosis and acne treatment protocols. As a result, the usual photodynamic therapy treatments using aminolevulinic acid, as well as methylaminolevulinic acid have been extended to studies utilizing the endogenous porphyrins. Here again comparison or double-blind studies need to be performed to provide evidence-based conclusions on the optimal therapy. Red, blue and yellow light systems at the very least may affect the bacteria, as well as secondarily diminish the inflammation that seems to be the precursor to scarring

Lasers

There are many proprietary reports of therapeutic use of 1320-nm (cool touch), 1450-nm (smooth beam) and 1540-nm lasers in acne [12], but few prospective comparison studies to determine any preferential indications. Clinically, it seems that usage is primarily determined by the instrument available. The reports suggest that all wavelengths affect the sebaceous glands and possibly have some effect on dermal collagen that might alter inflammation and scarring. Long-term follow-ups are thus far unavailable. It is difficult to project future trends as protocol innovation continues without the time for retrospective review.

In the long-term view, the dynamic nature of the device development has, thus far, precluded the necessary comparison studies to show definitive therapeutic trends in specific devices, and many are yet to have the proper studies in acne, so usage remains often ‘off-label’ and conclusions of efficacy and long-term utilization are speculative at present. There are many instruments at the lower price range, including microdermabrasion, infrared (and other heat-type instruments) and IPL – a veritable alphabet of tools reported to be efficacious – but all currently lack comparison studies. It is safe to say that more will appear in the future and it seems that those targeting the bacteria, or collagen (i.e., scarring) and inflammation will be the most likely to eventually be accepted.

The next 5 years should be a time of further development of systemic drugs targeting the pilosebaceous unit with greater specificity and lower dosing. Topicals will enhance skin penetration with newer gels, fullerenes, emulsion liposomes and foams to achieve skin levels equaling systemic administration [13]. Various newer devices will also find enhanced and cost-effective usage for photodynamic therapy, as well as furthered directed lasers.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.