Acne Therapy With Topical Benzoyl Peroxide,

DOI: 10.1111/j.1610-0387.2006.05931.x Review Article 293

© Blackwell Verlag GmbH • www.blackwell.de • 1610-0379/2006/0404-0293 JDDG | 4˙2006 (Band 4)

Acne therapy with topical benzoyl peroxide,

antibiotics and azelaic acid

Topische Therapie mit Benzoylperoxid, Antibiotika und Azelainsäure

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 • 4:293–300 Submitted: 13.7.2005 | Accepted: 15.12.2005

Keywords• acne

• benzoyl peroxide

• clindamycin

• erythromycin

• tetracycline

• azelaic acid

• chloramphenicol

• nadifloxacin

• evidence-based medicine

SummaryBenzoyl peroxide (BPO) was introduced in the treatment of acne in 1934. De-

spite the fact that only few randomized trials have been published, BPO is con-

sidered the standard in topical acne treatment. Anaerobic bacteria are reduced

by oxidative mechanisms and the induction of resistant strains is reduced.Topi-

cal 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 oxida-

tive 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 lacta-

ting females because it is degraded to benzoic acid. It is a cost-effective treat-

ment for acne grade I–II.

Patients with papulopustular acne grade I–II, particularly with marked inflam-

mation, 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 sug-

gested that topical tetracycline was ineffective in the treatment of acne. Along

with eliminating Propionibacterium acnes, the main mechanism of topical anti-

biotics is their antiinflammatory effect. All three penetrate the epidermal bar-

rier well and are similarly efficacious. Randomized trials have shown that in

concentrations of 2–4 %, 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 to-

pical antibacterial treatment is an increase in drug-resistant resident skin flora

with gram-negative microorganisms prevailing, which can lead to gram-nega-

tive folliculitis. All three antibiotics fluoresce under black light which may pro-

duce interesting effects in a discotheque.There are two reports of topical clin-

damycin causing pseudomembranous colitis after long-term and widespread

usage.

Azelaic acid has a predominant antibacterial action, although it is not conside-

red as an antibiotic in the classical sense.Furthermore, it possesses a modest co-

medolytic effect. Burning upon application is common. Since azelaic acid is na-

turally present, systemic side effects are not likely to occur, making it safe for

acne treatment during pregnancy and lactation.

Benzoyl peroxide (BPO)

IndicationsPapulopustular acne Plewig and Klig-man’s grade I–II, acne in adolescents, inpregnant and lactating females, use inadults and as part of a combinationtherapy with topical retinoids, azelaicacid or systemic antibiotics.

Mechanism of action BPO acts through oxidation and the for-mation of free radicals causing a reduc-

tion of propionibacteria. This mecha-nism helps prevent an induction of resi-stance in Propionibacterium acnes oftenobserved during long-term acne treat-ment with antibiotics. Micromolar BPO concentrations inhibitthe release of reactive oxygen speciesfrom human neutrophils – an importantstep in the inflammatory response inacne. Noticeable drug-induced cytotoxi-city has been observed in neutrophils [1].In cell-free experiments BPO exhibited aslight inhibition of protein kinase C and

no inhibition of calmodulin (known re-gulators of the release of reactive oxygenspecies). Thus the clinical antiinflamma-tory action of BPO is probably not me-diated by protein kinase C or calmodu-lin. As BPO launches a potent oxidativeattack on the stratum corneum (SC), itmight reduce the anti-oxidative defensesof this layer. A recent study concludedthat during BPO therapy of acne [2], �-tocopherol (vitamin E) is lost from theepidermal barrier. This loss and the re-sulting oxidation of lipids and proteins

294 Review Article Acne therapy with topical benzoyl peroxide, antibiotics and azelaic acid

JDDG | 4˙2006 (Band 4)

ZusammenfassungBenzoylperoxid wurde bereits 1934 in die Aknetherapie eingeführt und für gut

wirksam befunden. Auch wenn nur sehr wenige randomisierte Doppelblind-

studien 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 Wir-

kung mäßig zunimmt, aber die unerwünschten Wirkungen, wie Brennen, Rö-

tung und Schuppung steigen.5 % BPO ist meist ausreichend, um die Akne Grad

I–II nach Kligman und Plewig unter Kontrolle zu halten. Da BPO aufgrund seiner

starken Oxidationsfähigkeit ein potentes Bleichmittel ist, muss der Patient dar-

auf hingewiesen werden, dass bei einer Aknetherapie mit BPO farbige oder

dunkle Kleidung, dunkle Haare und Bettwäsche gebleicht werden können. BPO

ist das kostengünstigste Mittel bei der Akne Grad I–II, und da es in der Haut zu

Benzoesäure abgebaut wird, ist es auch bei Schwangeren und in der Stillperi-

ode angezeigt.

Die Akne papulopustulosa vom Grad I–II, insbesondere die stärker entzündete,

kann suffizient mit topischen Antibiotika behandelt werden. Hierbei stehen fol-

gende effektive Substanzen zur Verfügung: 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 Pro-

pionibacterium acnes, sondern vorwiegend in den allgemein antiinflammatori-

schen Eigenschaften dieser Präparate.Alle drei Antibiotika sind in ihren Wirkun-

gen gleichwertig, und randomisierte Studien haben ergeben, dass sie in einer

Dosierung von 2–4 % auch gleichwertig zu oralen Tetrazyklinen und Minozy-

klin sind. Die Penetration ist von allen Substanzen etwa gleich gut. Eine Wir-

kungsverstärkung erhalten sie durch die Kombination mit Retinoiden und Ben-

zoylperoxid (BPO).Die Kombination mit Retinoiden ist bei der Komedonenakne

deshalb sinnvoll, da Antibiotika vorwiegend nur die Entzündungen verringern,

Retinoid aber auch die Penetration verbessert und vermehrt die Komedonen

eliminiert. Eine unerwünschte Wirkung ist die Resistenzausbildung der Haut-

flora mit Überwucherung von gramnegativen Bakterien,was zur Ausbildung ei-

ner gramnegativen Follikulitis führen kann. Die genannten Antibiotika fluores-

zieren bei Bestrahlung mit UV-Licht. Diese Tatsache ist den Patienten

mitzuteilen, wenn sie sich einer solchen Beleuchtung, zum Beispiel in einer Dis-

kothek, aussetzen. In 2 Fällen wurde bei großflächiger, längerer topischer Clin-

damycin-Therapie eine pseudomembranöse Kolitis beschrieben.

Azelainsäure wirkt vorwiegend antimikrobiell, auch wenn es sich nicht um ein

Antibiotikum handelt. Sie kann auch in geringem Maße Komedonen eliminie-

ren. Häufig wird ein leichtes Brennen bei der Therapie angegeben. Da Aze-

lainsäure natürlicherweise im Organismus gebildet wird, sind Nebenwirkungen

nicht zu erwarten.Dieses macht diese Substanz bei der Aknebehandlung in der

Schwangerschaft und in der Stillperiode einsetzbar.

Schlüsselwörter• Akne

• Azelainsäure

• Benzoylperoxid

• Clindamycin

• Chloramphenicol

• Erythromycin

• Evidenz-basierte Medizin

• Tetrazyklin

• Nadifloxacin

might explain the common side effectsof skin dryness and desquamation.Corneocyte plugs in the follicular ostiaare loosened in a dose-dependent fas-hion but to a lesser extent than with re-tinoids. There is no reduction in sebumsecretion.

Evidence-based dataDespite the existence of only very fewrandomized, double-blind studies, BPOis viewed as the “standard” in acne trials.Even though the first therapy report in1934 only achieved EBM level 5, in laterstudies in which BPO was compared toclindamycin or erythromycin or azelaicacid and even with placebo vehicle, anEBM level of 2b was reached [3–5]. Onlyone study exists in which BPO (20 %)was directly compared to placebo (EBMlevel 2b) [6, 7].

Adverse effectsTypical adverse effectsRedness, desquamation and burning oftreated skin are the dose-dependent ma-jor symptoms of therapy. High BPOconcentrations (see below) can exhibitsignificant irritative effects, especially ingels with a relatively high alcohol con-centration. The major common side ef-fect of BPO is skin irritation which isstrongly linked to concentration and for-mulation. In high concentrations it is anobligatory side effect preventable bychoosing relative low BPO concentrati-ons (3–5 %). Using a 2.5 % BPO gelredness, desquamation and burning willoccur more rarely than with 10 % BPOformulations but at a similar rate compa-red to a 5 % gel [8]. As BPO, based onits high oxidative capacity, is a potentbleaching agent, patients should be war-ned that acne therapy with BPO can leadto bleaching of colored or dark clothing,bedding, and even dark hair.

Rare side effectsBPO can sensitize and cause allergiccontact dermatitis. Incidence has beenestimated at 1 : 500 [9]. Since BPO is nowonly rarely used in the antibacterialtherapy of leg ulcers, these numbers aredeclining. Phototoxicity towards UVBoccurred in 8 to 24 tested volunteers [10].

Duration of therapyUsually no mention of duration oftherapy is made in the studies. VariousBPO formulations are available (gel,

rinse-off products, shampoo, cream, emul-sion and lotion). Strengths ranging from2.5 % to 10 % are offered (2.5 %, 3 %, 4 %, 5 % and 10 %) with 2.5 %, 5 % and10 % BPO preparations are most com-mon. Effects are quickly visible (1–2weeks) and a 4–8 week course is generallyadequate in mild acne. The entire invol-ved area should be treated with a thinfilm of BPO gel one to three times daily.Long-term treatment or short contacttherapy with a BPO rinse-off productcan follow to prevent relapse.

Combination therapyCombination therapies with topical anti-biotics (erythromycin, clindamycin, mi-conazole) have been well-studied andshow an increase in efficacy (EBM level2a). Studies of the combination of BPOand tretinoin as well as BPO and topicalisotretinoin exist. These combinations aresuperior to monotherapy, but with thecombination of BPO and tretinoin as wellas adapalene, side effects such as burning,redness and desquamation increase signi-ficantly. A randomized, controlled studyshowed increased efficacy by adding mi-conazole in cases with simultaneous pre-sence of Malassezia furfur [11].

CommentaryBPO can be viewed as standard therapyfor papulopustular acne grade I-II. Com-bination therapy, for example with reti-noids, should be strived for. BPO is avai-lable in 2.5, 5, 10 and 20 % strengthswith efficacy increasing with higher con-centrations as do the adverse irritative ef-fects such as burning, redness and des-quamation [12]. A controlled studyshows that 2.5 % and 5 % are equally ef-ficacious as 10 %, the side effects beingless. Papulopustular acne grade I-II canusually be controlled by 5 % BPO.

Topical antibiotics

Erythromycin

IndicationsInflammatory papulopustular acne gradeI-II.

Mechanism of actionErythromycin, a typical representative ofthe macrolide group, acts primarilythrough antibacterial mechanisms. It isbacteriostatic via inhibition of bacterialribosomal protein synthesis. Sensitivebacteria, especially propionibacteria, are

eliminated. Erythromycin penetrateswell into the comedo. It exhibits mildantiinflammatory effects.

Evidence-based data (Table 1)In the literature 7 randomized, double-blind studies show improvement of acne(EBM level 2b) [3, 13–15]. Two rando-mized, double-blind studies show effi-cacy similar to clindamycin (EBM level2b) [16–17].

Adverse effectsTypical adverse effectsInduction of resistance in the residentskin flora with overgrowth of gram-nega-tive bacteria, which can lead to gram-nega-tive folliculitis. The increase of antibiotic-resistant propionibacteria (especiallytowards erythromycin) is an ever-gro-wing problem [18–22]. As fluorescenceunder UV light can occur, patients mustbe informed before exposure, as in a dis-cotheque.

Rare adverse effectsDryness of the skin and burning, usuallyresulting from the often employed gelformulation.

Duration of therapyLittle information is available in the lite-rature. In the prescribing information forone product, a total duration of therapyof 3 months is mentioned. Longer treat-ment is also inadvisable considering thedevelopment of resistance in P. acnes.Treatment should only continue untilthe pustular stage has resolved.

Combination therapyIncreased efficacy in combination withBPO [3]. A randomized, double-blindtrial of the combination with zinc on 122patients showed increased efficacy. Thecombination contained 4 % erythromy-cin while the control only contained 2 %which weakens the comparison [23].

CommentaryTopical erythromycin products are indi-cated for inflammatory, pustular formsof grade I–II acne. They compare to sy-stemic tetracycline in strength, but ef-fects are slower to appear. They shouldalways be combined with tretinoin orBPO in order to adequately reduce co-medos. One disadvantage is the increa-sing occurrence of resistant P. acnesstrains, so that other topical antibiotics

Acne therapy with topical benzoyl peroxide, antibiotics and azelaic acid Review Article 295

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have to be substituted. Possibly the addi-tion of zinc and BPO can reduce the de-velopment of resistance, where antibac-terial and clinical effects of zinc alonehave been shown [24].

Chloramphenicol

IndicationsHighly inflammatory papulopustularacne grade II–III.

Mechanism of actionIn topical application little chloram-phenicol is resorbed. It acts in a bacte-riostatic manner on extra- and intracellu-lar bacteria, penetrating the cell throughdiffusion and binding reversibly to the50-S subunit of the bacterial ribosomepreventing protein synthesis. Inhibitionof leukocyte chemotaxis causes antiin-flammatory effects.

Evidence-based dataOnly few randomized studies in the lite-rature compare combination therapy in-cluding chloramphenicol with chloram-phenicol-free products [25–27]. Theefficacy of a chloramphenicol-containingcombination is comparable to that of aBPO gel [28].

Adverse effectsTypical adverse effectsIn contrast to older data [29], new stu-dies of chloramphenicol in the context ofacne treatment show no problems resul-ting from an increased rate of sensitiza-tion. Chloramphenicol is today classifiedas a weak sensitizer [30].

Rare adverse effectsTopical application of chloramphenicolleads to only very low plasma levels (mean 25 �g/l [27] . No evidence for he-matopoietic problems, especially for in-duction of aplastic anemia, exists for to-pical cutaneous use of chloramphenicol[31]. As not a single case of bone marrowdamage has been reported in the litera-ture, the topical cutaneous application ofchloramphenicol can be viewed as safe.

Duration of therapyNo specific recommendations can be fo-und in the literature. An older study sho-wed that three months of treatment witha product containing chloramphenicolled to significant improvement in mode-rate acne [26].

Combination therapyThe combination of chloramphenicol andpale sulfonated shale oil appears sensible asthe antibacterial effect of chloramphenicolsupplements the anti-comedogenic andsebosuppressive effects of pale sulfonatedshale oil in the treatment of papulopustu-lar acne. A double-blind study showed thesuperiority of the combination of pale sul-fonated shale oil with chloramphenicolcompared with topical chloramphenicolmonotherapy and vehicle alone in papulo-pustular acne [27]. Interactions betweenboth agents are not known.

CommentaryOf clinical relevance is the fact thatchloramphenicol is the only topical anti-biotic in acne treatment for whom no re-sistance is yet known, in contrast to highresistance towards other alternatives(clindamycin, tetracycline, erythromy-cin) [31]. In long-term therapy, theblood count should be controlled on aregular basis.

Nadifloxacin

IndicationsNadifloxacin can be used to treat multi-ple inflammatory lesions in acne (papu-lopustular acne grade II-III).

Mechanism of actionNadifloxacin is a synthetic antibiotic de-veloped for topical use only. As withother quinolones, antimicrobial action isthe result of preventing formation of su-perspiralized bacterial DNA via inhibi-tion of bacterial topoisomerase II (DNAgyrase) and topoisomerase IV. The sub-stance shows activity towards a broadspectrum of gram-positive and gram-ne-gative bacteria including anaerobes. Ad-ditional clinical effects may be due todecreased production of O2- and OH.by neutrophils, leading to reduced oxida-tive tissue damage.

Evidence-based dataA double-blind, vehicle-controlled studyshows nadifloxacin cream to be superiorto vehicle alone [32]. The minimal inhi-bitory concentration of topically appliednadifloxacin towards P. acnes appears lo-wer than that of tetracycline or minocyc-line. This points to the fact that this topi-cal antibiotic is potently bactericidal [32].Compared to seven other tested antibio-tics (ciprofloxacin, penicillin, erythromy-

cin, tetracycline, clindamycin, fusidic acidand gentamicin) nadifloxacin is effectiveagainst propionibacteria as well as sta-phylococci and exhibits the lowest rate ofresistant pathogens [33–34], probablydue to the fact that it has only recentlybeen available commercially.

Adverse effectsTypical adverse effectsSide effects of topical 1 % nadifloxacincream are local erythema and pruritus.Data on systemic absorption / pharma-cokinetics (with the side effects typicalfor other quinolones such as nausea, vo-miting, diarrhea, phototoxicity) are notavailable.

Rare adverse effectsSlight and negligible signs of skin irrita-tion, itching, dryness and desquamationmay occur in rare cases.

Duration of therapyNo statements in the literature. A signifi-cant reduction in the number of lesionsand crusts after 7–14 days of topical treat-ment of patients with bacterial skin disea-ses could be observed. Topical antibacterialtherapy should be discontinued a soon asgood clinical healing has occurred.

Combination therapyNo data available. Based on the assump-tion that combinations of topical anti-biotics with BPO and tretinoin createadditive and synergistic effects on in-flammatory acne, it can be assumed thatnadifloxacin can also be employed in to-pical combination therapy.

CommentaryAs nadifloxacin exhibits an excellent an-tibacterial effect on aerobic and anaero-bic bacteria while having only minimalside effects, it appears to be an alternativein topical antibacterial treatment of acneand bacterial skin infections. Large scaleuse of the quinolone nadifloxacin maylead to an increase in bacteria resistant tothis substance class and resistant to syste-mic therapy. Topical application of 0.25,0.5 and 1 % nadifloxacin cream shows aconcentration-dependent antimicrobialactivity.

Clindamycin

IndicationsHighly inflammatory papulopustularacne grade I–II.


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Mechanism of actionPredominantly general antiinflammatoryproperties. Elimination of sensitive bacte-ria including P. acnes. Clindamycin dis-plays bacteriostatic to bactericidal effectsvia inhibition of bacterial protein synthe-sis. Clindamycin possesses good tissuepenetration and enters the comedo.

Evidence-based dataIn the literature 6 randomized, double-blind studies show improvement of acne(EBM level 2b) [35–37, 5]. Two rando-mized, double-blind studies show thesame efficacy as erythromycin (EBM le-vel 2b). One randomized, double-blindstudy showed that clindamycin was as ef-ficacious as oral tetracycline or 4 % nico-tinamide, respectively.

Adverse effectsTypical adverse effectsInduction of resistance in resident skinflora with overgrowth of gram-negativebacteria, which can lead to gram-nega-tive folliculitis. Fluoresces upon irradia-tion with UV light.

Rare adverse effectsDryness of the skin and burning, whichcan be attributed to the vehicle. In widespread long-term topical applica-tion of clindamycin isolates cases ofpseudomembranous colitis have been re-ported [38, 39].

Duration of therapyNo statements in the literature. Long-term treatment is not advisable due tothe development of resistance by P. acnes.Treatment should only last until the pu-stular stage ceases.

Combination therapyThree randomized, double-blind studieson a total of 1101 patients showed signi-ficantly increased efficacy in combina-tion with BPO [5, 37–40].

CommentaryTopical clindamycin products are indica-ted for inflammatory pustular forms ofacne grade I–II. They are similarly effec-tive as systemic tetracycline but not as ra-pidly. They should always be combinedwith tretinoin or BPO, so that comedoscan adequately be reduced. Long-termuse of clindamycin in topical therapyshould be avoided due to the increase inresistant propionibacteria [21] and be-

cause of the fact that clindamycin, an an-tibiotic with good tissue penetration,plays an important role in systemictherapy, as in osteomyelitis.

Tetracycline

IndicationsHighly inflammatory pustular acnegrade I–II.

Mechanism of actionActivity is based primarily on general an-tiinflammatory properties but also onthe elimination of sensitive bacteria,among them P. acnes. The bacteriostaticactivity is due to inhibition of bacterialribosomal protein synthesis. There isgood penetration into the comedo.

Evidence-based dataIn the literature one randomized, double-blind study showed improvement of acne(EBM level 2b, 50 patients) [41]. In twostudies, not randomized with certainty,topical tetracycline fared better than pla-cebo (125 patients) [42–43, 17]. Tworandomized, double-blind studies sho-wed equal efficacy as clindamycin (EBMlevel 2b) [44, 17].

Adverse effectsTypical adverse effectsDevelopment of resistance in residentskin flora with overgrowth of gram-nega-tive bacteria, possibly leading to gram-negative folliculitis. Burning and stin-ging of treated areas have been reportedin trials. Tetracycline cream discolors theskin and fluoresces under UV light. Thepatient should be informed of this beforeexposure such as in a discotheque.

Rare adverse effectsAllergic reactions towards the vehicle.

Duration of therapyNo statements in the literature. Long-term treatment is not advisable conside-ring the development of resistance in P. acnes. Therapy should continue onlyuntil the pustular stage ceases.

Combination therapyNo reports exist in the literature. A com-bination with retinoids or BPO seemsadvantageous.

CommentaryTopical tetracycline is indicated for in-flammatory pustular forms of acne grade

I–II. It is equally efficacious as systemic te-tracyclines but not as rapid. It should al-ways be combined with tretinoin or BPOin order to reduce comedos sufficiently.

Azelaic acid

IndicationsHighly inflammatory papulopustularacne grade I–II.

Mechanism of actionAzelaic acid is a dicarbonic acid physio-logically occurring in organisms. Openand closed comedos are reduced signifi-cantly by normalization of the increasedproduction of keratohyaline granules inthe infundibulum [45]. Free fatty acidsare also reduced by about 20 %. A se-cond effect is the reduction in the con-centration of P. acnes in vivo and in vitroby a log [45]. This effect is not as drama-tic as for BPO. The reduction of bacteriaresults from inhibition of bacterial pro-tein synthesis. In vitro antiinflammatoryeffects with reduced release of reactiveoxygen species have been shown.

Evidence-based dataFour randomized, double-blind studiesshowing improvement of acne can befound in the literature (EBM level 2b)[46–49].

Adverse effectsTypical adverse effectsBurning, stinging and tightness of theskin in the treated area. A mild bleachingeffect can be observed.

Rare adverse effectsAllergic reactions towards the vehicle.

Duration of therapyTrials usually lasted for 4–6 months.

Combination therapyAzelaic acid can be combined with hor-monal contraceptives and, in severe casesof acne, with oral tetracyclines to pro-mote more rapid improvement.

CommentaryThe substance lacks toxicity, is somewhatweaker than BPO, but has less side ef-fects. Azelaic acid is indicated for acnegrade I–II, in interval therapy and duringpregnancy or lactation.

Conflict of interestCo-author Joachim W. Fluhr has beeninvolved in clinical studies sponsored


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by Fa. Ichthyol and written expert opi-nions. <<<

Correspondence to Prof. Dr. W.-I. WorretDepartment of Dermatology and AllergologyTechnical University of MunichBiedersteinerstr. 29D-80802 Munich, GermanyTel.: +49-89-41 40-31 89Fax: +49-89-41 40-35 02E-mail:[email protected]

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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).

Recommen- Evidencedation grade level

A 1a Review of randomized, double-blind placebo-controlled studies of high homogeneity

1bLarge, randomized, double-blind placebo-controlled study with small confidence interval

1c Eradication or new appearance of a disease in strong association with a medication

B 2a Review of cohort studies of high homogeneity

2bCohort study or randomized, double-blind placebo-controlled study without follow-up and with larger confidence intervals

2c Study with a statistically significant difference in efficacy between two substances

3a Review of case-control studies with high homogeneity

3b Case-control study

C 4 Case series (as well as cohort study and case-control study of poor quality)

D 5 Expert opinion

prescribers. Am J Clin Dermatol 2003;

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