BPO is still the gold standard for mild-to-moderate acne. It is the leading OTC antiacne agent (in the United States) and it is available in several formulation types including gels, creams, lotions, soap bars, and liquid cleansers, at a concen- tration ranging from 2.5% to 10% in strength.
Why Is Benzoyl Peroxide So Successful in Acne Therapy?
Antibacterial formulations that suppress P. acnes are a mainstay in the treatment of acne. As BPO’s activity is primarily antibacterial against P. acnes, its use in acne therapy is corollary. The mechanism of action is presumably due to its strong oxi- dizing action, as explained further in Figure 2. The release of free radical oxygen causes oxidation of bacterial proteins and the development of oxygen creates a milieu in the follicle, where anaerobic bacteria like P. acnes cannot survive. The anti- bacterial efficacy is reported in a large body of literature (13,33 – 36) and is proven in numerous studies. BPO has a broad-spectrum activity and rapid bactericidal effects. It is active against gram-positive and gram-negative bacteria, yeasts, and various fungi (34). In vitro investigations using the agar diffusion method demonstrated strong antibacterial efficacy against gram-positive bacteria
(Table 3). The minimal inhibitory concentration (MIC) of BPO was found to be about
100 mg/mL (35,36).
In addition to this in vitro data, antibacterial action within the sebaceous follicle was also shown in vivo using the cyanoacrylate technique. After a seven-week treatment with a 5% BPO-gel, reduction of propionibacteria was demonstrated (37). Further studies have revealed a very fast antibacterial action that, however, does not increase with the continued use of BPO. After application of 5% BPO in an aqueous gel (daily use on the face), mean numbers of propioni- bacteria recovered from the skin surface and follicular casts were significantly reduced after two days of treatment. In the following days, the population was maintained, but no further decrease was observed (38). The same rapid effects could be observed in another study where the effect of BPO against P. acnes after only three days was proven, but no further decrease was observed at day 7 (39).
One major advantage of BPO over common antibiotics, used in acne therapy, is its full activity against antibiotic-resistant propionibacteria as well as sensitive strains (36). This might be due to its mechanism of antibacterial action, which is probably mediated by its powerful oxidizing property. This nonspecific mode of antibacterial action means that BPO does not induce resistance like antibiotics during long-term therapeutic use (38). Therefore, in order to preserve the efficacy of antibiotics in the therapy of acne, one obvious way could be to treat patients either concomitantly or sequentially with a broad-spectrum antibacterial agent such as BPO.
As acne is not only caused by bacterial colonization, efficacy of BPO against other factors is also of interest and has been investigated. One question is whether BPO has any impact on sebum production or secretion. It was found that BPO has a lack of direct effect on sebum production per se and does not reduce skin surface lipids, but it is effective in reducing the free fatty acids, known as comedogenic agents, and triggers of inflammation, in sebum. It inhibits hydrolysis of fatty esters and dramatically lowers the free fatty acid content in
sebum, concomitantly leading to an increase of triglycerides (Table 4) (37,40,41). This was also found in a further study (42). The same study revealed contrary results in the way that a sebo-suppressive effect was demonstrated by investi- gations on cell kinetics. A prolongation of the S-phase of sebaceous follicle cells and a diminution of the sebum glands were observed, which would be regarded as a direct sebo-suppressive effect and, therefore, the skin surface lipids would need to be reduced in consequence. As this, however, was not observed, the prac- tical relevance of these data remains uncertain. Therefore, due to these contrary results, the impact of BPO on sebo-suppression in acne therapy is still under discussion.
Having discussed the questions of antibacterial and sebo-suppressive activity of BPO, it is still open whether BPO can also act against another factor of acne—the comedolytic activity. Before going on, it is necessary to define the terms comedoly- tic, keratolytic, or corneodesmolytic. Although these terms are often used for the same action, they are, strictly speaking, not identical. Comedolytic means lysis of a comedo caused by loosening of sticked corneocytes, whereas keratolytic is defined as lyses of superficial corneocytes, nails, or hair due to lyses of keratin. Cor- neodesmolytic is a newer terminology, which expresses nearly the same action, as it results in desquamation due to degradation of corneodesmosomes, which are pro- teinaceous complexes that effectively rivet corneocytes together. As a keratolytic action, however, can be defined as reducing cohesion between corneocytes in a broader sense, the terms comedolytic, corneodesmolytic, and keratolytic will be used for the same action from here on.
The keratolytic efficacy of BPO has widely been investigated in the past. On the one hand, this drug was considered to be moderately comedolytic in the rabbit ear model, whereas it looked rather inactive in the human assay. Using the rabbit ear model, which is used for comedonegicity assessment, BPO was shown to moderately reduce the development of comedones (24). Recent studies, using a new technique for quantifying the number and size of microcomedones, also demonstrated comedolytic activity of BPO (43). However, using the follicular biopsy technique, the anticomedogenic effect is only comparatively slight in con- trast to tretinoin or SA (4,22). One explanation for this mismatch may reside in
TABLE 4 Thin-Layer Chromatographic and Densitometric Analysis of Skin Surface Lipids (Volunteers n ¼ 5) Before and After Application of 5% Benzoyl Peroxide and Placebo (Half-Faced Comparison). Ratio of Triglycerides to Free Fatty Acids
the nature of comedones. In the follicular biopsy technique, native microcomedones were studied, which may well be different from the tar- or azetulen-induced come- dones used in the rabbit studies (43). Overall, a weak comedolytic activity of BPO can be stated.
Another supplementary benefit of BPO in acne therapy is its anti- inflammatory action. BPO, however, does not have significant direct in vivo anti-inflammatory potency. It had been suggested that protein kinase C might serve as an additional pharmacological target of BPO. Therefore, the effects of BPO were investigated on the release of reactive oxygen species, regulated by protein kinase C and calmodulin, from human neutrophils, a potential important step in acne inflammation. Micromolar concentrations of BPO were found to inhibit the release of reactive oxygen species from human neutrophils but associ- ated with a marked drug-induced cytotoxicity. When, in cell-free assays, the effects of BPO on protein kinase C and calmodulin as regulators of the release of reactive oxygen species were investigated, there was only a marginal inhibition of protein kinase C and no detectable inhibition of calmodulin. Thus, the inflamma- tory activity of BPO is unlikely to be mediated by protein kinase C or calmodulin (44,45). A potential explanation for the anti-inflammatory effects of BPO could be the mediation by the antibacterial or oxidizing action of BPO. Following the decrease in the population of P. acnes in the follicles and the reduction of free oxygen radicals, one source of inflammation is cut and therefore inflammatory reac- tions are suppressed (4,22).
The anti-inflammatory benefit of BPO, regardless of being direct or indirect, is reflected in several studies (37,46,47). BPO products are indicated for mild-to- moderate acne with occurrence of predominantly inflamed lesions.
One study tested gel formulations with different concentrations of BPO (3, 5, or 10%) depending on the skin condition. After four weeks of treatment, the differ- ent BPO formulations were proven to be effective in the treatment of moderate acne. BPO was shown to decrease the number of papules and pustules and, to a smaller degree, the number of comedones (48).
Interestingly, not only efficacy in mild-to-moderate acne but also a quick onset of action can be observed after BPO application, which accompanies the quick antibacterial action. A double-blind study showed that a 5% BPO lotion used topically for only five days significantly reduced the number of inflamed lesions (49). Since acne usually responds slowly to treatment, these results are
very surprising. Another study also demonstrated the effect of short-duration treatment with a BPO aqueous gel. Compared to baseline, a statistically signifi- cant reduction of inflamed-lesions was determined after nine days and a reduction of noninflamed lesions after four days of treatment. Over the whole study period (28 days), improvement in the reduction of inflamed lesions could be observed (50).
Is There a Difference in Efﬁcacy Between Various Benzoyl Peroxide Levels?
As mentioned earlier, BPO products are not only available in a variety of formu- lations such as gel, cleanser, or emulsion but also in a variety of concentrations. But is a higher level of active really more efficacious than a lower one? In general, one would expect superior efficacy from a product with the higher concen- tration. Surprisingly, a 2.5% gel formulation of BPO was proven to be equivalent in
reducing the number of inflammatory lesions to 5% or 10% BPO gel preparations. With respect to the side effects, however, a difference could be observed. Desqua- mation, erythema, and symptoms of burning with the 2.5% gel were less frequent than with the 10% preparation but equivalent to the 5% gel. The 2.5% formulation also significantly reduced P. acnes and the percentage of free fatty acids in the surface lipids after two weeks of topical application (51). So why are not the lowest strengths in favor? The answer is probably consumer psychology. Folklore has established the belief that products with higher levels of active are generally better and more efficacious than those with a lower concentration (52). Which prep- aration should be used then? In practical use, people with delicate or irritable skin should start with preparations of lower strength and, when this preparation is tolerated, can continue with higher strength formulations.