EVIDENCE-BASED REVIEW ARTICLE
`
`Am J Clln Dermatol 2012; 13 (3): 141-152
`l l76-056 l/l2/0003-0l4 l/$49.95/0
`
`© 2012 Adls Data Information BV. All rights reserved.
`
`American Journal of Clinical Dermatology
`June 2012, Volume 13, Issue 3, pp 141–152
`
`Topical Antimicrobial Treatment of Acne Vulgaris
`An Evidence-Based Review
`
`Ryan Gamble,1 Jeff Dunn,1 Annelise Dawson,1 Brian Petersen,1 Lauren McLaughlin} Alison Small,3 Scott Kindle4
`and Robert P. Dellavalle1
`5
`•
`
`1 School of Medicine, University of Colorado, Aurora, CO, USA
`2 College of Osteopathic Medicine, Rocky Vista University, Parker, CO, USA
`3 College of Medicine, University of Arizona, Tucson, AZ, USA
`4 College of Medicine, University of Nebraska, Omaha, NE, USA
`5 Dermatology Service, Department of Veterans Affairs Medical Center, Denver, CO, USA
`
`Contents
`
`Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 l
`l. Literature Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
`2. Mechanisms of Action of Anti-Acne Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
`3. Benzoyl Peroxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
`4. Topical Antibiotics ............................................................................................... 143
`5. Benzoyl Peroxide and Antibiotic Combinations ....................................................................... 143
`6. Retinoid and Antibiotic Combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
`7. OtherTopicalTreatmentOptions ................................................................................... 143
`8. Bacterial Resistance .............................................................................................. 145
`9. Treatment Selection .............................................................................................. 146
`9. l Expert Guidelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
`9.2 Comparing Combination Therapies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
`9.3 Adverse Effects ............................................................................................. 148
`9.4 Cost ....................................................................................................... 148
`9.5 Practical Considerations ...................................................................................... 149
`9.6 Conflicts of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
`l 0. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
`
`Abstract
`
`Topical antimicrobial treatment is indicated for mild to moderate acne vulgaris. Our literature review
`includes searches of Ovid, MED LINE, EMBASE, and the databases of the Cochrane Library. A detailed
`search strategy is included. All searches were limited to controlled trials and systematic reviews. No year
`limits were applied to the searches, but we focused on trials, guidelines, and reviews published since 2004, the
`year that the last review of topical antimicrobials was published in this journal. Several controlled trials
`demonstrate that benzoyl peroxide, topical antibiotics, and topical retinoids used in combination provide
`the greatest efficacy and safety profile for the treatment of mild to moderate acne, but there are few trials
`directly comparing different combinations of these topical therapies with one another. Additionally, robust
`studies comparing cost and efficacy of generic combinations of the above agents with proprietary fixed-dose
`combination therapies that may increase compliance are also lacking. Although they have not been exten(cid:173)
`sively studied, alternative agents including dapsone, salicylic acid, azelaic acid, and zinc are safe and effi(cid:173)
`cacious when combined with traditional therapies.
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`142
`
`Gamble et al.
`
`Acne vulgaris is a highly prevalent skin disease and the most
`common skin disorder in adolescents. Numerous treatment
`options are available, but topical antimicrobial therapy re(cid:173)
`mains a mainstay for the management of mild to moderate acne
`because it offers localized treatment with less risk of systemic
`adverse effects_[ll We review recent trials evaluating topical
`antimicrobial therapy and assess current evidence relevant to
`the development of treatment suggestions and guidelines.121
`
`1. Literature Search
`
`The literature review conducted for this paper includes
`searches in the following databases: Ovid, MEDLINE,
`EMBASE, and the databases of the Cochrane Library, includ(cid:173)
`ing the Cochrane Database of Systematic Reviews, Central Reg(cid:173)
`ister of Controlled Trials (CENTRAL), Database of Abstracts of
`Reviews of Effects (DARE), Methodology Register, Technology
`Assessment Database, and Economic Evaluation Database.
`Concepts searched included acne vulgaris and topical anti(cid:173)
`biotics. Terms that describe the concepts include 'acne vulgaris,'
`'topical anti-microbial,'
`'anti-infective agents,'
`'anti-bacterial
`agents,' 'dermatologic agents,' 'benzoyl peroxide,' 'sodium sulfa(cid:173)
`cetamide,' 'azelaic acid,' 'clindamycin,' and 'erythromycin.' These
`terms were searched both as text words and as subject headings.
`All searches were limited to controlled trials and systematic
`reviews. No year limits were applied to the searches and they
`therefore extend as far back as the year range of each database
`up to April 2011 when they were conducted. Retrievals in Ovid
`MEDLINE go back to 1976, EMBASE to 1985, and the Co(cid:173)
`chrane Library to 1966. The Cochrane Library retrievals derive
`primarily from the CENTRAL database, supplemented by a
`handful from the DARE and the Economic Evaluation data(cid:173)
`bases. For further details of the literature search strategy and
`citations retrieved, see Supplemental Digital Content 1, http://
`links.adisonline.com/DYZ/ A3.
`
`2. Mechanisms of Action of Anti-Acne Agents
`
`Several factors contribute to development of acne includ(cid:173)
`ing increased sebum production, abnormal keratinization with
`subsequent blockage of pilosebaceous ducts, microbial colo(cid:173)
`nization most often by Propionobacterium acnes, and inflam(cid:173)
`mation. Increased androgen levels at puberty result in greater
`sebum production contributing to the development of acne in
`this age group.131
`Benzoyl peroxide acts through three primary mechanisms
`in the control of acne: it is bactericidal to P. acnes and also
`exhibits comedolytic as well as mild anti-inflammatory ac-
`
`tivity.14-91 Benzoyl peroxide is lipophilic and concentrates inside
`sebaceous follicles to produce benzoic acid and reactive oxygen
`species. These products are thought to oxidize bacterial proteins
`thereby inhibiting protein and nucleotide synthesis, metabolic
`pathways, and mitochondrial activity.19-111 Benzoyl peroxide
`does not appear to select for resistant P. acnes primarily due
`to its mechanism of action.19-111 Antibiotics represent another
`primary drug category in the treatment of acne vulgaris.
`Erythromycin, a macrolide antibiotic, clindamycin, a lincosamide
`derivative, and tetracycline are the primary antibiotics utilized.
`All are bacteriostatic and interact with ribosomal subunits
`to inhibit protein synthesis.112-141 These antibiotics inhibit syn(cid:173)
`thesis of lipase, which is utilized by P. acnes for hydrolyzing
`serum triglycerides to glycerol (a bacterial growth substrate)
`and proinflammatory free fatty acids. Antibiotics also inhibit
`complement pathways and impair neutrophil chemotaxisPSJ
`Topical antibiotics are most effective in the treatment of in(cid:173)
`flammatory lesions but demonstrate mild activity against
`non-inflamed lesions and their use may contribute to the de(cid:173)
`velopment of bacterial resistance.116,171
`Retinoids are derivatives of vitamin A (retinol) that act by
`binding retinoic acid receptors and retinoic X receptors. Reti(cid:173)
`noids are desquamating agents that regulate differentiation and
`proliferation of keratinocytes and modulate keratinocyte ad(cid:173)
`hesion molecules_[l 7, 18l Retinoids also control inflammation by
`inhibiting neutrophil chemotaxis, toll receptor expression, and
`reactive oxygen species production on leukocytes_[1 8l Systemic
`retinoids also reduce sebum production, but topical retinoids
`do not.1161 The newer retinoids, adapalene and tazarotene, are
`receptor selective and may be more efficacious than older ret(cid:173)
`inoid agents.118•191 Adapalene is thought to be better tolerated
`than other drugs in the retinoid category.1191
`Antibiotics, retinoids, and benzoyl peroxide have comple(cid:173)
`mentary mechanisms of action that may contribute to their
`synergistic activity when used in combination_[l7,zo,zi1 In gen(cid:173)
`eral, retinoids are more effective at reducing sebum production
`and keratinization, while antibiotics and benzoyl peroxide have
`greater effects at reducing
`inflammation and P. acnes
`counts.117•20,211 The desquamating effect of retinoids also in(cid:173)
`creases the penetration of antibiotics.122•231 Interestingly, use of
`benzoyl peroxide with retinoids may decrease retinoid activity
`although newer retinoids such as adapalene are more stable and
`may be used in combination with benzoyl peroxideP8,24l
`
`3. Benzoyl Peroxide
`
`Treatment of acne vulgaris with benzoyl peroxide alone or in
`combination with other topical treatments at concentrations of
`
`© 2012 Adis Data Information BV. All rights reserved.
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`Topical Antimicrobial Treatment of Acne Vulgaris
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`143
`
`2-5% is the standard of care for mild to moderate papular(cid:173)
`pustular acne_l4,7-9,2o,25,26l Use of benzoyl peroxide 2.5% ap(cid:173)
`pears to offer similar benefit to the 5% and 10% concentrations
`with fewer associated adverse effects.l9,27J Benzoyl peroxide
`monotherapy has been shown to have greater activity than topi(cid:173)
`cal tretinoin or isotretinoin against inflammatory lesions,117,28,291
`although two smaller trials demonstrated similar efficacy for
`both agents.117,3o,3i1
`Benzoyl peroxide is available in a variety of preparations
`including gels, washes, lotions, and creams. There is no clear
`superiority of these different preparations in terms of effec(cid:173)
`tiveness.14,321 Newer delivery systems to enhance efficacy and
`tolerability are also being investigated but have not been rig(cid:173)
`orously evaluated in comparison with current benzoyl peroxide
`formulations.111,33-37J
`
`4. Topical Antibiotics
`
`Topical antibiotics are most effective for treating inflam(cid:173)
`matory acne, with limited efficacy against non-inflammatory
`lesionsP81 The most commonly available antibiotics for topical
`treatment of acne are erythromycin and clindamycin. Bacterial
`resistance is a persistent problem with antibiotics, especially
`when they are used as monotherapyP91 The efficacy of
`erythromycin, in particular, may be declining due to bacterial
`resistance.16,16·17J Increasing bacterial resistance has led many
`experts to recommend against the use of antibiotics as mono(cid:173)
`therapy. Nevertheless, topical antibiotics continue to play an
`important role in the treatment of acne in combination with
`other topical treatments including benzoyl peroxide, topical
`retinoids, or azelaic acid.
`
`5. Benzoyl Peroxide and Antibiotic Combinations
`
`The benefit of combining topical antibiotics with benzoyl
`peroxide over using either as monotherapy has been demonstrated
`in several trials_l25,4o-431 Two large randomized, double-blind,
`controlled studies from 2008 showed that benzoyl peroxide 2.5%
`and clindamycin 1.2% gel significantly reduced lesion counts
`and demonstrated similar tolerability compared with clinda(cid:173)
`mycin or benzoyl peroxide monotherapy.1431 A smaller study
`from 2009 found that a novel solubilized form of benzoyl per(cid:173)
`oxide 5% alone showed greater reduction of non-inflammatory
`lesions compared with combined benzoyl peroxide 5% and
`clindamycin 1 %. Both groups showed comparable reduction of
`inflammatory lesions although benzoyl peroxide displayed
`more early adverse cutaneous effects than combination ther(cid:173)
`apy1441 (see table I).
`
`A recent meta-analysis determined that combination ben(cid:173)
`zoyl peroxide 2.5% or 5% with clindamycin outperformed benzoyl
`peroxide and clindamycin monotherapy in treating inflamma(cid:173)
`tory lesions and that reduction of non-inflammatory lesions
`with benzoyl peroxide 2.5% and clindamycin was significantly
`greater than any of the other treatments.1471 A study by another
`group1481 also showed that benzoyl peroxide 2.5% and clindamycin
`preparation demonstrated similar efficacy to benzoyl peroxide 5%
`and clindamycin preparation but was better tolerated.
`A randomized controlled trial of patients with mild to moderate
`inflammatory acne with a 4-week washout prior to trial entry,
`showed that topical treatment regimens containing erythromycin
`and benzoyl peroxide outperformed oral tetracycline regimens for
`treating resistant acne with fewer systemic adverse effects.146,491
`Benzoyl peroxide monotherapy produced similar results to com(cid:173)
`bined erythromycin and benzoyl peroxide treatment in both pri(cid:173)
`mary outcome measures, although it produced greater skin irrita(cid:173)
`tion than the erythromycin and benzoyl peroxide combination.146,491
`
`6. Retinoid and Antibiotic Combinations
`
`Topical retinoid and antibiotic combination therapies are
`also indicated for the treatment of patients with mild to moderate
`inflammatory acne. Several studies have demonstrated that
`combination therapy with topical retinoids and antibiotics pro(cid:173)
`duces significantly faster and greater clearance of acne than
`topical antibiotics or topical retinoids alone.15o-541 The combina(cid:173)
`tion ofretinoids with antibiotics may be less irritating to the skin
`compared with monotherapyl52·53·55·561 although one groupl501
`noted that adapalene and clindamycin combination therapy was
`more irritating than either agent used alone.
`Combining clindamycin with the newer topical retinoids
`adapalene and tazarotene is more efficacious than clindamycin
`and tretinoin combination therapy.1571 Adapalene also causes
`significantly less skin irritation than tretinoin when used in
`combination with topical clindamycin.1581 Unfortunately, these
`agents are also more costly. As with benzoyl peroxide and anti(cid:173)
`biotic preparations, topical retinoids and antibiotics combi(cid:173)
`nation therapy can be prescribed as separate products that are
`used together or fixed combination preparations that exist as a
`single product, the former being less expensive, with the latter
`being easier to use.
`
`7. Other Topical Treatment Options
`
`Additional options for topical treatment of acne include
`dapsone, zinc, sodium sulfacetamide, salicylic acid, azelaic acid,
`and allylamines. Topical dapsone 5%, alone or in combination
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`© 2012 Adis Data Information BV. All rights reserved.
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`144
`
`Gamble et al.
`
`Table I. Trials of BPO and antibiotic combination therapy published since 2004
`
`Study
`(no. of patients)
`
`Kircik et al.I441
`(n=65)
`
`Design
`
`Treatment
`
`Results
`
`Adverse effects
`
`Twice daily for 4 or 12 wk:
`Randomized, investigator-
`blind, multicenter 4 or 12 wk solubilized BPO 5% gel to one
`side of face; CL 1 % and BPO
`split-face study in patients
`aged 11-45 y with
`5% gel to contralateral side of
`moderate acne
`the face
`
`Well tolerated; less than mild dryness,
`Solubilized BPO gel showed
`erythema, peeling, stinging and
`greater reduction in non-
`inflammatory lesion count than did burning and itching; significantly
`CL and BPO at wk 1 and 2
`higher for solubilized BPO within the
`(p ~ 0.01) as well as at wk 3, 4, and
`first 3 wk of treatment but comparable
`12 (p ~ 0.05); comparable
`between both regimens by wk 4
`reductions in inflammatory lesion
`count at all timepoints
`
`Two, randomized, double- Once daily: CL 1.2% and BPO The absolute and percentage
`Thiboutot
`et al.I431 (n = 2813) blind, controlled,
`2.5% gel; CL 1.2% gel; BPO
`reduction in inflammatory, non-
`multicenter, parallel, 12wk 2.5% gel; vehicle control gel
`inflammatory, and total lesion
`studies in patients with
`counts in the CL and BPO
`combination group was
`moderate to severe acne
`significantly higher than the other
`groups (p < 0.001)
`
`Well tolerated; mild to moderate
`erythema, scaling, burning,
`itching, and stinging
`
`Langner et al.1451
`(n=130)
`
`Randomized, investigator- Once daily: CL 1 % and BPO
`blind, multicenter, parallel-
`5%; adapalene 0.1 %
`group 12 wk study of
`patients aged 12-39 y with
`mild to moderate acne
`
`CL and BPO had an earlier onset Well tolerated; mild dryness,
`of action and showed greater
`erythema, scaling, burning, and
`reductions in inflammatory lesions pruritus; CL and BPO generally had
`(p~0.001) as well as total lesions
`fewer reports of adverse effects
`(p~0.004)
`
`Ozolins et al.I46I
`(n=649)
`
`Randomized, investigator(cid:173)
`blind 18wktrial in patients
`with mild to moderate acne
`
`Oral oxytetracycline 500 mg
`Topical BPO and topical ERY plus Adverse systemic effects more likely
`to occur with oral antibiotics; local
`twice daily plus topical placebo BPO were as effective as oral
`irritation more likely with topical
`twice daily; minocycline 100 mg oxytetracycline and minocycline;
`treatments (especially BPO)
`once daily plus topical placebo BPO was the most cost-effective
`twice daily; topical BPO 5%
`treatment; the topical regimens
`were most effective in treating
`twice daily plus oral placebo
`once daily; topical ERY 3% and
`resistant Propionobacterium
`BPO 5% combination twice
`acnes
`daily plus oral placebo once
`daily; topical ERY 3% in the
`morning and BPO 5% at night
`plus oral placebo once daily
`BPO = benzoyl peroxide; CL= clindamycin; ERV= erythromycin.
`
`with adapalene 0.1 % or benzoyl peroxide 4%, has been shown
`to be safe and efficacious, but may be more irritating to the skin
`than other topical agents[59-611 (see table II).
`Topical antibiotics are also available in combination with
`zinc acetate. While zinc is ineffective as mono therapy, [41 a small,
`single-blind study of patients with mild to moderate acne treated
`with benzoyl peroxide 5% plus clindamycin 1 % or erythromycin
`4% plus zinc acetate 1.2% once daily found that, although both
`regimens improved total lesion count, clindamycin plus benzoyl
`peroxide had an earlier onset of action and showed significantly
`greater reductions of inflammatory lesions as well as total
`lesions.[641
`A small observational study demonstrated that 20% sodium
`sulfacetamide, when used in combination with a 50% sulfur
`
`foam, decreases acne, rosacea, and seborrheic dermatitis lesions
`without adverse effects.[65J Limited evidence also shows that sali(cid:173)
`cylic acid alone,[41 or in combination with benzoyl peroxide[661
`can improve acne. While limited safety data exist, it has been
`suggested as an alternative for patients who cannot tolerate
`topical retinoid therapy.[41 An Iranian trial of patients randomly
`assigned to combination azelaic acid 5% and clindamycin 2%,
`or either agent alone, showed that the combination gel sig(cid:173)
`nificantly reduced total lesion count compared with baseline, as
`well as clindamycin 2% or azelaic acid 5% monotherapy.[621 The
`same group found similar results when combining azelaic acid
`with erythromycin and noted that the combination was more
`tolerable than either agent used alone.[631 Other studies have
`shown that azelaic acid at concentrations of 15-20% demon-
`
`© 2012 Adis Data Information BV. All rights reserved.
`
`Am J Clin Dermatol 2012; 13 (3)
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`Topical Antimicrobial Treatment of Acne Vulgaris
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`145
`
`strates efficacy and tolerability comparable to tretinoin, benzoyl
`peroxide, and erythromycin monotherapy for the treatment of
`mild to moderate forms of acne.[67·681 Combination therapy
`utilizing benzoyl peroxide in combination with an allylamine
`(an antifungal agent), demonstrated more effective control of
`comedones than benzoyl peroxide monotherapy.[691
`
`8. Bacterial Resistance
`
`The long-term, low-dose antibiotic regimens often pre(cid:173)
`scribed for acne treatment have been associated with increasing
`P. acnes resistance.l17•701 Macrolides, such as erythromycin, are
`most associated with the development of bacterial resistance,
`although resistance to clindamycin, tetracycline, and other anti(cid:173)
`biotics is also quite high.[12·15-17•71•721 A study of P. acnes isolates
`in the UK found that resistance to erythromycin and clinda(cid:173)
`mycin increased from nearly 35% in 1991 to over 55%
`in 2OOOP3l A similar study comparing patterns of resistance
`in several European countries found that resistance to erythro(cid:173)
`mycin and clindamycin may be as high as 90% in some re(cid:173)
`gionsP4l P. acnes and Staphylococcus epidermidis strains can
`
`transfer resistance to Staphylococcus aureus and increase the
`lethality of that organism.[91 These findings have prompted
`scientists to recommend against the use of topical or oral anti(cid:173)
`biotics as monotherapy for acne vulgaris_[4,i5,39,7i,75,76l Data
`indicate that, since 2003, approximately 80% of prescriptions
`for topical antibiotics written by dermatologists are split evenly
`between clindamycin and combination clindamycin and ben(cid:173)
`zoyl peroxide gel medicationsP2•14l
`Benzoyl peroxide appears to be effective in controlling both
`antibiotic-sensitive and antibiotic-resistant P. acnes.[91 Use of
`combined agents may allow for reduced dosages of antibiotics
`and lessen selection pressure for resistance.[91 Use of benzoyl
`peroxide may also help slow the spread of antibiotic-resistant
`S. epidermidis strains, which are associated with resistance in
`S. aureus.[91 One expert panel recommends that if antibiotics
`must be used for longer than 2 months, benzoyl peroxide should
`be utilized for at least 5-7 days between antibiotic courses to
`avoid resistanceP7•20l Combination treatment with different
`types of oral and topical antibiotics should be avoided.[17,771
`Another potential strategy for reducing the spread of anti(cid:173)
`biotic-resistant strains may be to eliminate the use of antibiotics
`
`Table II. Trials of dapsone, azelaic acid, and zinc combination therapy published since 2004
`
`Design
`
`Treatment
`
`Study
`(no. of patients)
`Fleischer et al.I611 Randomized, double-blind, Dapsone 5% gel twice daily plus
`(n = 301)
`12 wk study in patients with
`adapalene 0.1 % gel once daily;
`moderate acne
`dapsone 5% gel twice daily plus
`BPO 4% gel once daily; dapsone
`5% gel twice daily plus moisturizer
`once daily
`
`Pazoki-Toroudi
`et al.162I (n = 130)
`
`Randomized, double-blind, Azelaic acid 5% and CL 2%;
`12 wk study of patients with
`azelaic acid 5%; CL 2%
`mild to moderate acne
`
`Results
`
`Adverse effects
`
`All treatment groups showed a
`decrease in inflammatory lesions
`and were not significantly
`different; dapsone plus adapalene
`showed significantly greater
`improvement in non-inflammatory
`and total lesion count vs dapsone
`plus moisturizer (p<0.001 and
`p<0.004, respectively)
`
`Combination azelaic acid and CL
`significantly reduced lesion
`counts compared with azelaic
`acid (p < 0.01) or CL (p < 0.05)
`
`Well tolerated; more adverse
`events in the dapsone plus
`adapalene group including
`pruritus and burning
`
`Patients significantly more
`satisfied with azelaic acid and
`CL combination; no significant
`difference in adverse effects
`among treatment groups
`
`Pazoki-Toroudi
`et a1.I53I (n = 147)
`
`Combination azelaic acid and
`Randomized, double-blind, Azelaic acid 5% and ERV 2%;
`12 wk study of patients with
`azelaic acid 5%; ERV 2%; placebo ERV significantly reduced lesion
`mild to moderate acne
`counts compared with azelaic
`acid (p<0.05), ERV (p<0.01),
`or placebo (p<0.001)
`
`Azelaic acid and ERV
`combination demonstrated
`fewer adverse effects than
`azelaic acid or ERV
`monotherapy
`
`Langner et al.I641
`(n=148)
`
`Randomized, investigator(cid:173)
`blind, multicenter, parallel(cid:173)
`group, 12 wk study of
`patients aged 12-39 y with
`mild to moderate acne
`BPO = benzoyl peroxide; CL= clindamycin; ERV= erythromycin.
`
`ERV 4% and zinc acetate 1.2%
`twice daily; CL 1 % and BPO 5%
`gel once daily
`
`CL and BPO had an earlier onset Well tolerated, mild and
`of action and showed greater
`intermittent scaling, erythema,
`reductions in inflammatory lesions
`dryness, pruritus, and burning
`(p=0.029) as well as total lesions
`(p=0.017)
`
`© 2012 Adis Data Information BV. All rights reserved.
`
`Am J Clin Dermatol 2012; 13 (3)
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`146
`
`Gamble et al.
`
`Table Ill. Trials comparing BPO, topical antibiotic, and topical retinoid combination therapy published since 2004
`
`Treatment
`
`Results
`
`Design
`
`Study
`(no. of patients)
`Leyden, et al.C811 Open-label, single-center, 4 wk
`Adapalene 0.1 % and BPO 2.5% Mean total P. acnes bacterial
`(n=30)
`study in patients with high levels combination gel applied to
`counts decreased significantly
`of Propionobacterium acnes of
`(p<0.001); resistance to
`forehead once daily
`P. acnes highest for ERV and
`the facial skin including various
`CL; P. acnes resistance to all
`levels of resistance to ERV, CL,
`and tetracycline
`antibiotics was significantly
`decreased at the end of the
`study
`Jackson et al.C82I Randomized, investigator-blind, Once daily: CL 1 % and BPO 5%; CL and BPO had greater
`reductions in P. acnes counts
`(n=54)
`two-center, parallel-group,
`CL 1.2% and tretinoin 0.025%
`(p = 0.0030); CL and BPO
`16 wk study in patients aged
`~12 y with moderate to
`showed earlier onset of action;
`reductions in inflammatory, non-
`moderately severe acne
`inflammatory, and total lesion
`counts were similar between
`groups by wk 16
`
`Adverse effects
`
`Well tolerated; specific adverse
`effects were not commented on
`
`Well tolerated; mild dryness,
`pruritus, burning, and peeling
`
`Gollnick et al.C51 l
`(n=1670)
`
`Randomized, double-blind,
`transatlantic, multicenter,
`controlled, 12 wk study in
`patients aged ~12 y with
`moderate acne
`
`Once daily: adapalene 0.1 % and Adapalene and BPO combination Well tolerated; mild to moderate
`dryness
`BPO 2.5% gel; adapalene 0.1 %; was significantly more effective
`BPO 2.5%; vehicle control gel
`(p<0.001) in decreasing
`percentage lesion count than
`either monotherapy or vehicle
`
`Bowman et al.C83I Randomized, investigator-blind,
`(n=132)
`multicenter, 10wkstudyin
`patients aged 12-30y with mild
`to moderate acne
`
`CL 1 % and BPO 5% gel once
`daily; tretinoin 0.025% gel plus
`CL 1 % gel once daily; CL 1 % and
`BPO 5% gel in the morning and
`tretinoin 0.025% gel plus CL 1 %
`gel in the evening
`
`CL and BPO group and CL and
`BPO plus tretinoin group had
`significantly greater reduction in
`inflammatory lesions than
`tretinoin plus CL group (p=0.05
`and p = 0.02, respectively)
`
`Well tolerated; mild to moderate
`irritation and dryness;
`substantially more adverse
`events reported for combination
`regimen than either regimen
`alone; overall more adverse
`effects with tretinoin-containing
`regimens
`
`BPO = benzoyl peroxide; CL= clindamycin; ERV= erythromycin.
`
`altogether and combine other topical agents. Benzoyl peroxide
`in combination with topical retinoids is one option, as neither
`retinoids nor benzoyl peroxide creates selective pressure for
`resistance. While there have been some trials evaluating the
`efficacy and tolerability of this approach, there is limited evi(cid:173)
`dence of its effect on microbial resistanceP8•791 A randomized,
`double-blind study of combination adapalene and benzoyl
`peroxide therapy in patients with moderate to moderately se(cid:173)
`vere acne found that lesion count was significantly improved in
`the group treated with adapalene 0.1 % and benzoyl peroxide
`2.5% compared with either agent alone or placebo_l75,so1 The
`frequency of adverse events and cutaneous tolerability for
`adapalene and benzoyl peroxide were comparable to that ob(cid:173)
`served with adapalene monotherapy, although resistance was
`not specifically addressed_l75,so1 A small open-label study eval(cid:173)
`uated the effectiveness of combination adapalene 0.1 % and
`
`benzoyl peroxide 2.5% in reducing antibiotic-sensitive and
`-resistant strains of P. acnes on the facial skin of study subjects.
`All subjects had strains sensitive and resistant to erythromycin,
`clindamycin, and tetracyclines at baseline. Mean counts of eryth(cid:173)
`romycin-, clindamycin-, and tetracycline-resistant P. acnes were
`significantly decreased by week 41811 (see table III).
`
`9. Treatment Selection
`
`9.1 Expert Guidelines
`
`There is expert consensus that combination therapies are
`more efficacious and less susceptible to bacterial resistance
`than monotherapy alone.l4,75,s41 All of these guidelines illus(cid:173)
`trate similar approaches in which initial therapy selection is
`
`© 2012 Adis Data Information BV. All rights reserved.
`
`Am J Clin Dermatol 2012; 13 (3)
`
`6 of 12
`
`

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`Topical Antimicrobial Treatment of Acne Vulgaris
`
`147
`
`based on the severity and inflammatory nature of the lesions[t7J
`(see table IV).
`The guidelines differ, however, in their recommendations
`regarding selection of topical medications_[4,3s,75,76,85l Practical
`advice on how to manage acne based upon a systematic search
`of evidence is provided by the NHS Clinical Knowledge Sum(cid:173)
`maries (CKS) guideline138l from the UK, including treatment
`options for mild to severe disease (see table IV).
`
`9.2 Comparing Combination Therapies
`
`As noted in a 2003 expert report, there is a need to perform
`well controlled trials comparing benzoyl peroxide with the
`newer topical retinoids.1201 Indeed, there are few robust studies
`comparing various combination regimens ofbenzoyl peroxide,
`clindamycin, and retinoids (see table III).
`One study[82l evaluated the efficacy of clindamycin 1.2% and
`tretinoin 0.025% gel with clindamycin 1 % and benzoyl peroxide
`5% gel. While the clindamycin and benzoyl peroxide combi(cid:173)
`nation group had a faster reduction in inflammatory and total
`lesion counts compared with the tretinoin combination group,
`
`reduction in inflammatory, non-inflammatory, and total acne
`lesions were similar by the end of the 16-week study.1821 Re(cid:173)
`ductions in clindamycin-resistant P. acnes colonization occurred
`only in the benzoyl peroxide group, but overall reduction in
`disease severity was comparable at 87% for the tretinoin com(cid:173)
`bination group and 80% for the benzoyl peroxide combination
`group.1s21
`A relatively small, single-blind study of patients with mild to
`moderate acne[83·861 compared the efficacy of tretinoin 0.025%
`and clindamycin 1 % gel once daily versus benzoyl peroxide 5%
`and clindamycin 1 % gel once daily versus benzoyl peroxide 5%
`and clindamycin 1 % applied in the morning with tretinoin
`0.025% plus clindamycin 1 % applied in the evening. Treatment
`groups with benzoyl peroxide (benzoyl peroxide and clinda(cid:173)
`mycin, and benzoyl peroxide and clindamycin plus tretinoin)
`had significantly greater reductions in inflammatory lesions as
`well as greater reductions in non-inflammatory lesions at week
`10. All three regimens were safe and generally well tolerated,
`although agents with tretinoin initially caused more irritation,
`dryness, desquamation, and erythema. It has been suggested
`that these results should be viewed with cauti