DOI: 10.1111/j.1610-0387.2006.05931.

Review Article 293

Acne therapy with topical benzoyl peroxide, antibiotics and azelaic acid
Topische Therapie mit Benzoylperoxid, Antibiotika und Azelainsure bei der Akne
Wolf-Ingo Worret1, Joachim W. Fluhr2
(1) Department of Dermatology and Venereology, Technical University of Munich, Germany (2) Department of Dermatology and Allergology, Friedrich Schiller University, Jena, Germany

JDDG; 2006 4:293300

Submitted: 13.7.2005 | Accepted: 15.12.2005

Keywords
acne benzoyl peroxide clindamycin erythromycin tetracycline azelaic acid chloramphenicol nadifloxacin evidence-based medicine

Summary
Benzoyl peroxide (BPO) was introduced in the treatment of acne in 1934. Despite the fact that only few randomized trials have been published, BPO is considered the standard in topical acne treatment. Anaerobic bacteria are reduced by oxidative mechanisms and the induction of resistant strains is reduced.Topical formulations are available at concentrations of 2.5, 5, 10 and 20 %.The effect is dose-dependent, but the irritation increases with higher concentrations. Usually 5 % BPO is sufficient to control acne grade I-II. Due to its strong oxidative potential, patients should be advised that BPO may bleach colored and dark clothing, bedding and even hair. BPO is safe for use in pregnant and lactating females because it is degraded to benzoic acid. It is a cost-effective treatment for acne grade III. Patients with papulopustular acne grade III, particularly with marked inflammation, show satisfactory improvement with topical antibiotic treatment. The following compounds are available and effective: erythromycin, clindamycin and tetracycline (the latter being less frequently used). A review in 1990 suggested that topical tetracycline was ineffective in the treatment of acne. Along with eliminating Propionibacterium acnes, the main mechanism of topical antibiotics is their antiinflammatory effect. All three penetrate the epidermal barrier well and are similarly efficacious. Randomized trials have shown that in concentrations of 24 %, their effects are comparable to oral tetracycline and minocycline. Combination therapy with retinoids or benzoyl peroxide (BPO) increases efficacy. Retinoids increase penetration and reduce comedones, while topical antibiotics primarily address inflammation. One side effect of topical antibacterial treatment is an increase in drug-resistant resident skin flora with gram-negative microorganisms prevailing, which can lead to gram-negative folliculitis. All three antibiotics fluoresce under black light which may produce interesting effects in a discotheque. There are two reports of topical clindamycin causing pseudomembranous colitis after long-term and widespread usage. Azelaic acid has a predominant antibacterial action, although it is not considered as an antibiotic in the classical sense.Furthermore, it possesses a modest comedolytic effect. Burning upon application is common. Since azelaic acid is naturally present, systemic side effects are not likely to occur, making it safe for acne treatment during pregnancy and lactation.

Blackwell Verlag GmbH www.blackwell.de 1610-0379/2006/0404-0293

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Schlsselwrter
Akne Azelainsure Benzoylperoxid Clindamycin Chloramphenicol Erythromycin Evidenz-basierte Medizin Tetrazyklin Nadifloxacin

Zusammenfassung
Benzoylperoxid wurde bereits 1934 in die Aknetherapie eingefhrt und fr gut wirksam befunden. Auch wenn nur sehr wenige randomisierte Doppelblindstudien existieren, wird BPO als Standard bei Aknestudien angesehen. Der Vorteil besteht zum einen in der Verminderung anaerober Bakterien durch starke Oxidation und zum andern in einer Resistenzvermeidung. BPO wird in 2, 5, 5, 10 und 20 % angeboten, wobei bei zunehmendem Prozentsatz die Wirkung mig zunimmt, aber die unerwnschten Wirkungen, wie Brennen, Rtung und Schuppung steigen. 5 % BPO ist meist ausreichend, um die Akne Grad III nach Kligman und Plewig unter Kontrolle zu halten. Da BPO aufgrund seiner starken Oxidationsfhigkeit ein potentes Bleichmittel ist, muss der Patient darauf hingewiesen werden, dass bei einer Aknetherapie mit BPO farbige oder dunkle Kleidung, dunkle Haare und Bettwsche gebleicht werden knnen. BPO ist das kostengnstigste Mittel bei der Akne Grad III, und da es in der Haut zu Benzoesure abgebaut wird, ist es auch bei Schwangeren und in der Stillperiode angezeigt. Die Akne papulopustulosa vom Grad III, insbesondere die strker entzndete, kann suffizient mit topischen Antibiotika behandelt werden. Hierbei stehen folgende effektive Substanzen zur Verfgung: Erythromycin, Clindamycin und, nach Datenlage weniger eingesetzt, Tetrazyklin. In einer Beurteilung aus dem Jahre 1990 wird jedoch dem topischen Tetrazyklin eine Wirkung auf die Akne abgesprochen. Der Mechanismus besteht nicht nur in der Elimination von Propionibacterium acnes, sondern vorwiegend in den allgemein antiinflammatorischen Eigenschaften dieser Prparate.Alle drei Antibiotika sind in ihren Wirkungen gleichwertig, und randomisierte Studien haben ergeben, dass sie in einer Dosierung von 24 % auch gleichwertig zu oralen Tetrazyklinen und Minozyklin sind. Die Penetration ist von allen Substanzen etwa gleich gut. Eine Wirkungsverstrkung erhalten sie durch die Kombination mit Retinoiden und Benzoylperoxid (BPO).Die Kombination mit Retinoiden ist bei der Komedonenakne deshalb sinnvoll, da Antibiotika vorwiegend nur die Entzndungen verringern, Retinoid aber auch die Penetration verbessert und vermehrt die Komedonen eliminiert. Eine unerwnschte Wirkung ist die Resistenzausbildung der Hautflora mit berwucherung von gramnegativen Bakterien, was zur Ausbildung einer gramnegativen Follikulitis fhren kann. Die genannten Antibiotika fluoreszieren bei Bestrahlung mit UV-Licht. Diese Tatsache ist den Patienten mitzuteilen, wenn sie sich einer solchen Beleuchtung, zum Beispiel in einer Diskothek, aussetzen. In 2 Fllen wurde bei groflchiger, lngerer topischer Clindamycin-Therapie eine pseudomembranse Kolitis beschrieben. Azelainsure wirkt vorwiegend antimikrobiell, auch wenn es sich nicht um ein Antibiotikum handelt. Sie kann auch in geringem Mae Komedonen eliminieren. Hufig wird ein leichtes Brennen bei der Therapie angegeben. Da Azelainsure natrlicherweise im Organismus gebildet wird, sind Nebenwirkungen nicht zu erwarten. Dieses macht diese Substanz bei der Aknebehandlung in der Schwangerschaft und in der Stillperiode einsetzbar.

Benzoyl peroxide (BPO) Indications Papulopustular acne Plewig and Kligmans grade III, acne in adolescents, in pregnant and lactating females, use in adults and as part of a combination therapy with topical retinoids, azelaic acid or systemic antibiotics. Mechanism of action BPO acts through oxidation and the formation of free radicals causing a reduc-

tion of propionibacteria. This mechanism helps prevent an induction of resistance in Propionibacterium acnes often observed during long-term acne treatment with antibiotics. Micromolar BPO concentrations inhibit the release of reactive oxygen species from human neutrophils an important step in the inflammatory response in acne. Noticeable drug-induced cytotoxicity has been observed in neutrophils [1]. In cell-free experiments BPO exhibited a slight inhibition of protein kinase C and

no inhibition of calmodulin (known regulators of the release of reactive oxygen species). Thus the clinical antiinflammatory action of BPO is probably not mediated by protein kinase C or calmodulin. As BPO launches a potent oxidative attack on the stratum corneum (SC), it might reduce the anti-oxidative defenses of this layer. A recent study concluded that during BPO therapy of acne [2], tocopherol (vitamin E) is lost from the epidermal barrier. This loss and the resulting oxidation of lipids and proteins

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might explain the common side effects of skin dryness and desquamation. Corneocyte plugs in the follicular ostia are loosened in a dose-dependent fashion but to a lesser extent than with retinoids. There is no reduction in sebum secretion. Evidence-based data Despite the existence of only very few randomized, double-blind studies, BPO is viewed as the standard in acne trials. Even though the first therapy report in 1934 only achieved EBM level 5, in later studies in which BPO was compared to clindamycin or erythromycin or azelaic acid and even with placebo vehicle, an EBM level of 2b was reached [35]. Only one study exists in which BPO (20 %) was directly compared to placebo (EBM level 2b) [6, 7]. Adverse effects Typical adverse effects Redness, desquamation and burning of treated skin are the dose-dependent major symptoms of therapy. High BPO concentrations (see below) can exhibit significant irritative effects, especially in gels with a relatively high alcohol concentration. The major common side effect of BPO is skin irritation which is strongly linked to concentration and formulation. In high concentrations it is an obligatory side effect preventable by choosing relative low BPO concentrations (35 %). Using a 2.5 % BPO gel redness, desquamation and burning will occur more rarely than with 10 % BPO formulations but at a similar rate compared to a 5 % gel [8]. As BPO, based on its high oxidative capacity, is a potent bleaching agent, patients should be warned that acne therapy with BPO can lead to bleaching of colored or dark clothing, bedding, and even dark hair. Rare side effects BPO can sensitize and cause allergic contact dermatitis. Incidence has been estimated at 1 : 500 [9]. Since BPO is now only rarely used in the antibacterial therapy of leg ulcers, these numbers are declining. Phototoxicity towards UVB occurred in 8 to 24 tested volunteers [10]. Duration of therapy Usually no mention of duration of therapy is made in the studies. Various BPO formulations are available (gel,

rinse-off products, shampoo, cream, emulsion and lotion). Strengths ranging from 2.5 % to 10 % are offered (2.5 %, 3 %, 4 %, 5 % and 10 %) with 2.5 %, 5 % and 10 % BPO preparations are most common. Effects are quickly visible (12 weeks) and a 48 week course is generally adequate in mild acne. The entire involved area should be treated with a thin film of BPO gel one to three times daily. Long-term treatment or short contact therapy with a BPO rinse-off product can follow to prevent relapse. Combination therapy Combination therapies with topical antibiotics (erythromycin, clindamycin, miconazole) have been well-studied and show an increase in efficacy (EBM level 2a). Studies of the combination of BPO and tretinoin as well as BPO and topical isotretinoin exist. These combinations are superior to monotherapy, but with the combination of BPO and tretinoin as well as adapalene, side effects such as burning, redness and desquamation increase significantly. A randomized, controlled study showed increased efficacy by adding miconazole in cases with simultaneous presence of Malassezia furfur [11]. Commentary BPO can be viewed as standard therapy for papulopustular acne grade I-II. Combination therapy, for example with retinoids, should be strived for. BPO is available in 2.5, 5, 10 and 20 % strengths with efficacy increasing with higher concentrations as do the adverse irritative effects such as burning, redness and desquamation [12]. A controlled study shows that 2.5 % and 5 % are equally efficacious as 10 %, the side effects being less. Papulopustular acne grade I-II can usually be controlled by 5 % BPO. Topical antibiotics Erythromycin Indications Inflammatory papulopustular acne grade I-II. Mechanism of action Erythromycin, a typical representative of the macrolide group, acts primarily through antibacterial mechanisms. It is bacteriostatic via inhibition of bacterial ribosomal protein synthesis. Sensitive bacteria, especially propionibacteria, are

eliminated. Erythromycin penetrates well into the comedo. It exhibits mild antiinflammatory effects. Evidence-based data (Table 1) In the literature 7 randomized, doubleblind studies show improvement of acne (EBM level 2b) [3, 1315]. Two randomized, double-blind studies show efficacy similar to clindamycin (EBM level 2b) [1617]. Adverse effects Typical adverse effects Induction of resistance in the resident skin flora with overgrowth of gram-negative bacteria, which can lead to gram-negative folliculitis. The increase of antibioticresistant propionibacteria (especially towards erythromycin) is an ever-growing problem [1822]. As fluorescence under UV light can occur, patients must be informed before exposure, as in a discotheque. Rare adverse effects Dryness of the skin and burning, usually resulting from the often employed gel formulation. Duration of therapy Little information is available in the literature. In the prescribing information for one product, a total duration of therapy of 3 months is mentioned. Longer treatment is also inadvisable considering the development of resistance in P. acnes. Treatment should only continue until the pustular stage has resolved. Combination therapy Increased efficacy in combination with BPO [3]. A randomized, double-blind trial of the combination with zinc on 122 patients showed increased efficacy. The combination contained 4 % erythromycin while the control only contained 2 % which weakens the comparison [23]. Commentary Topical erythromycin products are indicated for inflammatory, pustular forms of grade III acne. They compare to systemic tetracycline in strength, but effects are slower to appear. They should always be combined with tretinoin or BPO in order to adequately reduce comedos. One disadvantage is the increasing occurrence of resistant P. acnes strains, so that other topical antibiotics

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have to be substituted. Possibly the addition of zinc and BPO can reduce the development of resistance, where antibacterial and clinical effects of zinc alone have been shown [24]. Chloramphenicol Indications Highly inflammatory papulopustular acne grade IIIII. Mechanism of action In topical application little chloramphenicol is resorbed. It acts in a bacteriostatic manner on extra- and intracellular bacteria, penetrating the cell through diffusion and binding reversibly to the 50-S subunit of the bacterial ribosome preventing protein synthesis. Inhibition of leukocyte chemotaxis causes antiinflammatory effects. Evidence-based data Only few randomized studies in the literature compare combination therapy including chloramphenicol with chloramphenicol-free products [2527]. The efficacy of a chloramphenicol-containing combination is comparable to that of a BPO gel [28]. Adverse effects Typical adverse effects In contrast to older data [29], new studies of chloramphenicol in the context of acne treatment show no problems resulting from an increased rate of sensitization. Chloramphenicol is today classified as a weak sensitizer [30]. Rare adverse effects Topical application of chloramphenicol leads to only very low plasma levels (mean 25 g/l [27] . No evidence for hematopoietic problems, especially for induction of aplastic anemia, exists for topical cutaneous use of chloramphenicol [31]. As not a single case of bone marrow damage has been reported in the literature, the topical cutaneous application of chloramphenicol can be viewed as safe. Duration of therapy No specific recommendations can be found in the literature. An older study showed that three months of treatment with a product containing chloramphenicol led to significant improvement in moderate acne [26].

Combination therapy The combination of chloramphenicol and pale sulfonated shale oil appears sensible as the antibacterial effect of chloramphenicol supplements the anti-comedogenic and sebosuppressive effects of pale sulfonated shale oil in the treatment of papulopustular acne. A double-blind study showed the superiority of the combination of pale sulfonated shale oil with chloramphenicol compared with topical chloramphenicol monotherapy and vehicle alone in papulopustular acne [27]. Interactions between both agents are not known. Commentary Of clinical relevance is the fact that chloramphenicol is the only topical antibiotic in acne treatment for whom no resistance is yet known, in contrast to high resistance towards other alternatives (clindamycin, tetracycline, erythromycin) [31]. In long-term therapy, the blood count should be controlled on a regular basis. Nadifloxacin Indications Nadifloxacin can be used to treat multiple inflammatory lesions in acne (papulopustular acne grade II-III). Mechanism of action Nadifloxacin is a synthetic antibiotic developed for topical use only. As with other quinolones, antimicrobial action is the result of preventing formation of superspiralized bacterial DNA via inhibition of bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. The substance shows activity towards a broad spectrum of gram-positive and gram-negative bacteria including anaerobes. Additional clinical effects may be due to decreased production of O2- and OH. by neutrophils, leading to reduced oxidative tissue damage. Evidence-based data A double-blind, vehicle-controlled study shows nadifloxacin cream to be superior to vehicle alone [32]. The minimal inhibitory concentration of topically applied nadifloxacin towards P. acnes appears lower than that of tetracycline or minocycline. This points to the fact that this topical antibiotic is potently bactericidal [32]. Compared to seven other tested antibiotics (ciprofloxacin, penicillin, erythromy-

cin, tetracycline, clindamycin, fusidic acid and gentamicin) nadifloxacin is effective against propionibacteria as well as staphylococci and exhibits the lowest rate of resistant pathogens [3334], probably due to the fact that it has only recently been available commercially. Adverse effects Typical adverse effects Side effects of topical 1 % nadifloxacin cream are local erythema and pruritus. Data on systemic absorption / pharmacokinetics (with the side effects typical for other quinolones such as nausea, vomiting, diarrhea, phototoxicity) are not available. Rare adverse effects Slight and negligible signs of skin irritation, itching, dryness and desquamation may occur in rare cases. Duration of therapy No statements in the literature. A significant reduction in the number of lesions and crusts after 714 days of topical treatment of patients with bacterial skin diseases could be observed. Topical antibacterial therapy should be discontinued a soon as good clinical healing has occurred. Combination therapy No data available. Based on the assumption that combinations of topical antibiotics with BPO and tretinoin create additive and synergistic effects on inflammatory acne, it can be assumed that nadifloxacin can also be employed in topical combination therapy. Commentary As nadifloxacin exhibits an excellent antibacterial effect on aerobic and anaerobic bacteria while having only minimal side effects, it appears to be an alternative in topical antibacterial treatment of acne and bacterial skin infections. Large scale use of the quinolone nadifloxacin may lead to an increase in bacteria resistant to this substance class and resistant to systemic therapy. Topical application of 0.25, 0.5 and 1 % nadifloxacin cream shows a concentration-dependent antimicrobial activity. Clindamycin Indications Highly inflammatory papulopustular acne grade III.

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Mechanism of action Predominantly general antiinflammatory properties. Elimination of sensitive bacteria including P. acnes. Clindamycin displays bacteriostatic to bactericidal effects via inhibition of bacterial protein synthesis. Clindamycin possesses good tissue penetration and enters the comedo. Evidence-based data In the literature 6 randomized, doubleblind studies show improvement of acne (EBM level 2b) [3537, 5]. Two randomized, double-blind studies show the same efficacy as erythromycin (EBM level 2b). One randomized, double-blind study showed that clindamycin was as efficacious as oral tetracycline or 4 % nicotinamide, respectively. Adverse effects Typical adverse effects Induction of resistance in resident skin flora with overgrowth of gram-negative bacteria, which can lead to gram-negative folliculitis. Fluoresces upon irradiation with UV light. Rare adverse effects Dryness of the skin and burning, which can be attributed to the vehicle. In widespread long-term topical application of clindamycin isolates cases of pseudomembranous colitis have been reported [38, 39]. Duration of therapy No statements in the literature. Longterm treatment is not advisable due to the development of resistance by P. acnes. Treatment should only last until the pustular stage ceases. Combination therapy Three randomized, double-blind studies on a total of 1101 patients showed significantly increased efficacy in combination with BPO [5, 3740]. Commentary Topical clindamycin products are indicated for inflammatory pustular forms of acne grade III. They are similarly effective as systemic tetracycline but not as rapidly. They should always be combined with tretinoin or BPO, so that comedos can adequately be reduced. Long-term use of clindamycin in topical therapy should be avoided due to the increase in resistant propionibacteria [21] and be-

cause of the fact that clindamycin, an antibiotic with good tissue penetration, plays an important role in systemic therapy, as in osteomyelitis. Tetracycline Indications Highly inflammatory pustular acne grade III. Mechanism of action Activity is based primarily on general antiinflammatory properties but also on the elimination of sensitive bacteria, among them P. acnes. The bacteriostatic activity is due to inhibition of bacterial ribosomal protein synthesis. There is good penetration into the comedo. Evidence-based data In the literature one randomized, doubleblind study showed improvement of acne (EBM level 2b, 50 patients) [41]. In two studies, not randomized with certainty, topical tetracycline fared better than placebo (125 patients) [4243, 17]. Two randomized, double-blind studies showed equal efficacy as clindamycin (EBM level 2b) [44, 17]. Adverse effects Typical adverse effects Development of resistance in resident skin flora with overgrowth of gram-negative bacteria, possibly leading to gramnegative folliculitis. Burning and stinging of treated areas have been reported in trials. Tetracycline cream discolors the skin and fluoresces under UV light. The patient should be informed of this before exposure such as in a discotheque. Rare adverse effects Allergic reactions towards the vehicle. Duration of therapy No statements in the literature. Longterm treatment is not advisable considering the development of resistance in P. acnes. Therapy should continue only until the pustular stage ceases. Combination therapy No reports exist in the literature. A combination with retinoids or BPO seems advantageous. Commentary Topical tetracycline is indicated for inflammatory pustular forms of acne grade

III. It is equally efficacious as systemic tetracyclines but not as rapid. It should always be combined with tretinoin or BPO in order to reduce comedos sufficiently. Azelaic acid Indications Highly inflammatory papulopustular acne grade III. Mechanism of action Azelaic acid is a dicarbonic acid physiologically occurring in organisms. Open and closed comedos are reduced significantly by normalization of the increased production of keratohyaline granules in the infundibulum [45]. Free fatty acids are also reduced by about 20 %. A second effect is the reduction in the concentration of P. acnes in vivo and in vitro by a log [45]. This effect is not as dramatic as for BPO. The reduction of bacteria results from inhibition of bacterial protein synthesis. In vitro antiinflammatory effects with reduced release of reactive oxygen species have been shown. Evidence-based data Four randomized, double-blind studies showing improvement of acne can be found in the literature (EBM level 2b) [4649]. Adverse effects Typical adverse effects Burning, stinging and tightness of the skin in the treated area. A mild bleaching effect can be observed. Rare adverse effects Allergic reactions towards the vehicle. Duration of therapy Trials usually lasted for 46 months. Combination therapy Azelaic acid can be combined with hormonal contraceptives and, in severe cases of acne, with oral tetracyclines to promote more rapid improvement. Commentary The substance lacks toxicity, is somewhat weaker than BPO, but has less side effects. Azelaic acid is indicated for acne grade III, in interval therapy and during pregnancy or lactation. Conflict of interest Co-author Joachim W. Fluhr has been involved in clinical studies sponsored

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Table 1: Recommendation grade and evidence level of therapy studies (according to Sackett et al. 2001). Tabelle 1: Empfehlungsgrad und Evidenzebene von Therapiestudien (nach Sackett et al. 2001). Recommendation grade A Evidence level 1a 1b 1c B 2a 2b 2c 3a 3b C D 4 5 Review of randomized, double-blind placebo-controlled studies of high homogeneity Large, randomized, double-blind placebo-controlled study with small confidence interval Eradication or new appearance of a disease in strong association with a medication Review of cohort studies of high homogeneity Cohort study or randomized, double-blind placebo-controlled study without follow-up and with larger confidence intervals Study with a statistically significant difference in efficacy between two substances Review of case-control studies with high homogeneity Case-control study Case series (as well as cohort study and case-control study of poor quality) Expert opinion

by Fa. Ichthyol and written expert opinions. <<<

Correspondence to
Prof. Dr. W.-I. Worret Department of Dermatology and Allergology Technical University of Munich Biedersteinerstr. 29 D-80802 Munich, Germany Tel.: +49-89-41 40-31 89 Fax: +49-89-41 40-35 02 E-mail: wolf-ingo.worret@lrz.tu-muenchen.de

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