Guidelines of Care for Acne Vulgaris Management Technical Report

Guidelines of Care for Acne Vulgaris Management
                Technical Report
2



                                               Acne Vulgaris


Table of Contents                                                                                      Page No.

Introduction ................................................................................................ 3

Clinical questions ....................................................................................... 3

Method of evaluation of evidence .............................................................. 4

Grading and classification systems............................................................ 7

Microbiological and endocrine testing ...................................................... 12

Topical agents.......................................................................................... 18

Systemic agents....................................................................................... 30

Hormonal agents...................................................................................... 36

Isotretinoin ............................................................................................... 42

Miscellaneous therapies .......................................................................... 49

Complementary/alternative therapies ...................................................... 53

Dietary restriction ..................................................................................... 58

Graded References.................................................................................. 60
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Introduction

Approximately 40-50 million people in the United States have acne vulgaris. It is the
most common skin disease, especially in adolescents and young adults. Acne affects
more than 85% of teenagers. There is no mortality associated with acne disease, but
there is often significant physical and psychological morbidity such as permanent
scarring, poor self-image, depression and anxiety. The direct cost of acne is estimated to
exceed $1 billion per year, with $100 million spent on over-the-counter acne products in
the United States.
Acne is a multifactorial disease affecting the pilosebaceous follicles of the skin. Some
factors that play an important role in the pathogenesis of acne are follicular
hyperkeratinization, microbial colonization, sebum production inflammation following
chemotaxis and the release of various pro-inflammatory mediators. Appropriate
evaluation and management of acne vulgaris are important. At present there are many
topical and systemic therapeutic options available for the treatment of acne because of
the multifactorial etiology of acne vulgaris. Various therapies are discussed in the
“Guidelines of care for acne vulgaris management” (J Am Acad Dermatol. 2007
Apr;56(4):651-63).

Clinical Questions

This is a comprehensive search of the peer-reviewed biomedical literature and analysis
of the evidence regarding therapies for acne as a basis for the development of the
American Academy of Dermatology (AAD) clinical guidelines of care for the treatment of
acne.
Specific Clinical Questions addressed in the acne guidelines are the following:

   I.   What systems are most commonly used for the grading and classification of adult
        acne and acne vulgaris in adolescents (11 to 21 years) to adults?

   II. What is the role of microbiological and endocrine testing in evaluating patients
        with adult acne and acne vulgaris in adolescents to adults?

   III. What is the effectiveness and what are the potential side effects of the following
        topical agents in the treatment of adult acne and acne vulgaris in adolescents to
        adults including:
            a) retinoids and retinoid-like drugs
            b) benzoyl peroxide
            c) topical antibiotics
            d) salicylic/azelaic acids
            e) sulfur and resorcinol
            f) aluminum chloride
            g) zinc
            h) combinations of topical agents

   IV. What is the effectiveness and what are the potential side effects of the following
       systemic antibacterial agents in the treatment of adult acne and acne vulgaris in
       adolescents to adults including:
          a) tetracyclines: doxycycline, minocycline
          b) macrolides: erythromycin
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            c) clindamycin
            d) trimethoprim
            e) ampicillin/amoxicillin

   V. What is the effectiveness and what are the potential side effects of hormonal
      agents in the treatment of adult acne and acne vulgaris in adolescents to adults
      including:
          a) contraceptive agents, especially oral preparations
          b) spironolactone
          c) antiandrogens
          d) oral corticosteroids

   VI. What is the effectiveness and what are the potential side effects of isotretinoin in
       the treatment of adult acne and acne vulgaris in adolescents to adults?

   VII. What is the effectiveness and what are the potential side effects of miscellaneous
         therapies in the treatment of adult acne and acne vulgaris in adolescents to
         adults including:
           a) chemical peels
           b) comedo removal
           c) intralesional steroids

   VIII. What is the effectiveness and what are the potential side effects of
         complementary/alternative therapies in the treatment of adult acne and acne
         vulgaris in adolescents to adults including:
           a) herbal agents
           b) homeopathy
           c) psychological approaches
           d) massage therapy
           e) hypnosis/biofeedback

   IX. What is the effectiveness of dietary restriction in the treatment of adult acne and
       acne vulgaris in adolescents to adults?



Method

Evidence evaluated for this report was obtained primarily from a search of MEDLINE
and EMBASE databases spanning the years 1966 to 2006.
The available evidence was evaluated using a unified system called the Strength of
Recommendation Taxonomy (SORT) developed by editors of the US family medicine
and primary care journals (i.e., American Family Physician, Family Medicine, Journal of
Family Practice and BMJ-USA). This strategy was supported by a decision of the Clinical
Guidelines Task Force in 2005 with some minor modifications for a consistent approach
to rating the strength of the evidence of scientific studies.1 Evidence was graded using a
three-point scale based on the quality of methodology as follows:

       I               Good quality patient-oriented evidence
       II              Limited quality patient-oriented evidence
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III   Other evidence including consensus guidelines, extrapolations
      from bench research, opinion or case studies
6


Clinical recommendations were developed based on evidence tabled in the guideline
and explained further in the technical report. These are ranked as follows:

A. Recommendation based on consistent and good-quality patient-oriented evidence
B. Recommendation based on inconsistent or limited quality patient-oriented evidence
C. Recommendation based on consensus, opinion or case studies

For each intervention within the Clinical Questions, an effort was made to identify and
present the best evidence regarding its use in the treatment of acne. Studies of clinical
measurements of outcome were considered for analysis whether or not the clinical
outcome was the primary outcome measured.

Disclosure of Significant Relationships with Relevant Commercial
Companies/Organizations

The Academy must ensure balance, independence, objectivity and scientific rigor in its
evidence-based guidelines of care. The Board of Directors requires that all participating
members of the guidelines of care associated work groups must comply with regulations
governing disclosure.

All participants are expected to disclose in the document “Authors’ Conflict of Interest
Disclosure Statement” any significant financial interest or other relationship with the
manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services
discussed by them. The intent of this disclosure is not to prevent anyone with a
significant financial or other relationship from participating, but rather to provide readers
of the guidelines with information on which to make their own judgments. It remains for
the reader to determine whether any work member’s interests or relationships may
influence the discussion. Following are the Work Group members that developed the
acne guidelines along with their affiliation and disclosure of potential conflict of interest:”

John Strauss, MD, Chair Acne Work Group – the Department of Dermatology, Roy J.
and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
Dr. Strauss was a consultant and investigator for Roche Laboratories receiving
honoraria and grants, and a consultant for Medicis receiving honoraria.

Karl R. Beutner, MD, PhD, Chair Clinical Guidelines Task Force – Anacor
Pharmaceuticals, Inc., Palo Alto, California
Dr. Beutner was an employee of Anacor receiving salary and stock options and a
stockholder of Dow Pharmaceutical Sciences receiving stock.
Daniel Krowchuk, MD – the Departments of Pediatrics and Dermatology, Wake Forest
University School of Medicine, Brenner Children’s Hospital, Winston-Salem, North
Carolina
Dr. Krowchuk had no relevant conflicts of interest to disclose.
James J. Leyden, MD – the Department of Dermatology, University of Pennsylvania
Hospital, Philadelphia, Pennsylvania
Dr. Leyden was a consultant for Stiefel and SkinMedica, receiving honoraria; served on
the Advisory Board and was a consultant for Galderma and Obaj, receiving honoraria;
was on the Advisory Board and was a consultant and investigator for Connetics,
Collagenex, Allergan, and Medicis, receiving honoraria.
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Anne W. Lucky, MD – the Division of Pediatric Dermatology, Cincinnati Children's
Hospital Medical Center and the University of Cincinnati School of Medicine, Cincinnati,
Ohio
Dr. Lucky was an investigator for Connetics, Dow, Galderma, Healthpoint, Johnson &
Johnson, QLT, and Stiefel, receiving grants, and an investigator and consultant for
Berlex receiving grants and honoraria.
Alan R. Shalita, MD – the Department of Dermatology, State University of New York
Downstate Medical Center, Brooklyn, New York
Dr. Shalita was a consultant, investigator, stockholder, and speaker for Allergan,
receiving grants and honoraria; a consultant for Bradley/Doak receiving honoraria;
served on the Advisory Board and was a consultant for Collagenex, receiving honoraria;
was a consultant and investigator for Connetics receiving grants and honoraria; an
Advisory Board member, consultant, investigator, and speaker for Galderma receiving
grants and honoraria; a consultant, speaker, and stockholder for Medicis receiving
honoraria; an Advisory Board member for Ranbaxy receiving honoraria; and a
consultant, investigator, and speaker for Stiefel, receiving grants and honoraria.
Elaine C. Siegfried, MD – the Department of Dermatology, St. Louis University School of
Medicine, St. Louis, Missouri
Dr. Siegfried was an investigator for Atrix receiving salary.

Diane M. Thiboutot, MD – the Department of Dermatology, Pennsylvania State
University College of Medicine, Milton S. Hershey Medical Center, Hershey,
Pennsylvania
Dr. Thiboutot served on the Advisory Board and was an investigator and speaker for
Allergan and Galderma, receiving honoraria; was on the Advisory Board and was a
consultant and investigator for Collagenex receiving honoraria; was on the Advisory
Board and was an investigator for Connetics, Dermik, and QLT, receiving honoraria; and
was a consultant, investigator, and speaker for Intendis, receiving honoraria.

Abby S. Van Voorhees, MD – the Department of Dermatology, University of
Pennsylvania Hospital, Philadelphia, Pennsylvania
Dr. Van Voorhees served on the Advisory Board and was an investigator and speaker
for Amgen, receiving grants and honoraria; was an investigator for Astellas, Bristol
Myers Squibb, and GlaxoSmithKline, receiving grants; was an Advisory Board member
and investigator for Genentech and Warner Chilcott, receiving grants and honoraria; was
on the Advisory Board for Centocor receiving honoraria; was a speaker for Connetics
receiving honoraria; and was a stockholder of Merck, owning stock and stock options.

Carol Sieck, RN, MSN – the American Academy of Dermatology, Schaumburg, Illinois
C. Sieck had no relevant conflicts of interest to disclose.

Reva Bhushan, PhD - the American Academy of Dermatology, Schaumburg, Illinois
Dr. Bhushan had no relevant conflicts of interest to disclose.
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I.    Grading and classification systems of adult acne and acne vulgaris in
      adolescents (11 to 21 years) to adults


Many acne grading and classification systems have been proposed but at present there
is not any one system universally accepted for assessing and grading acne severity. The
grading and classification of acne is essential for the initial evaluation as a base of
comparison during treatment and as a method to assess clinical trials. Acne severity is
generally considered the most important patient characteristic used in determining
individual treatment profiles. There are several grading/classification systems; most
include lesion counting combined with some type of global severity assessment. Global
evaluation takes into account the total impact of the disease. Grading systems are
mainly used in clinical studies for the evaluation of acne treatment. Comparing
therapeutic efficacy in different studies because of the lack of a validated classification
system becomes difficult. It is important to standardize a specific and reproducible
method to grade the severity of acne.
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       Table 1. Acne Grading/Classification Systems


Level
                  Author/Date/
of Evi-                                     Type of scale                 Method of Assessment                                  Conclusions
                  study design
dence

          Lehmann et al., J Am Acad     Review of acne             The target population for the review     250 papers were reviewed. There were more than
  II      Dermatol 2002; 47: 231-40.2   clinical trials to         was all patients with acne who did not   25 different methods of assessment of acne
                                        provide clinicians the     have complicating co-morbidities such    severity and 19 methods of counting lesions. There
          Methodological review of
                                        background needed          as endocrinopathies.                     were many different ways the outcomes were
          literature and
                                        to interpret current                                                expressed. There was no standard approach to
          recommendations.
                                        and future clinical        The search was an expert-advised         describing side effects, and no standard follow-up
                                        trials, and scientists a   structured literature synthesis.         times.
                                        basis for further
                                                                                                            The authors made recommendations for the
                                        studies.
                                                                                                            scientists for future clinical trials.

          Pochi et al.,                 Global evaluation of       Includes a total evaluation of lesions   Panel recommendations:
  II      J Am Acad Dermatol 1991;      lesions.                   and complications; categorizes
                                                                                                            Dividing acne into 4 grades of severity was overly
          24: 495-500.3                                            inflammatory lesions as mild, moderate
                                                                                                            simplistic.
                                                                   or severe.
          AAD Consensus conference
                                                                                                            It is the opinion of the consensus panel that acne
          on acne classification.
                                                                                                            grading can be accomplished by the use of a
                                                                                                            pattern-diagnosis system, which includes a global
                                                                                                            (total) evaluation of lesions and their complications.
                                                                                                            A strictly quantitative definition of acne severity
                                                                                                            cannot be established because of the variable
                                                                                                            expression of the disease.
                                                                                                            The clinical diagnosis of acne severity should be
                                                                                                            based on persistent or recurrent inflammatory
                                                                                                            nodules, papulopustular disease, ongoing scarring,
                                                                                                            drainage from lesions or the presence of sinus
                                                                                                            tracks and psychological factors.
                                                                                                            The consensus panel recommendations did not
                                                                                                            include non-inflammatory lesions.
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Level
                  Author/Date/
of Evi-                                     Type of scale             Method of Assessment                                  Conclusions
                  study design
dence

          Doshi et al., Int J Dermatol   Global Acne Grading   The GAGS considers 6 locations on the     This system is accurate and reproducible. Grading
          1997; 36: 416-8.4              System (GAGS)         face and chest/upper back, with factor    with the GAGS system takes under 1 minute in an
  II
                                                               for each location based on surface        office setting.
          This paper proposed a new
                                                               area, distribution and density of
          grading system called Global                                                                   The authors suggest that time saved in grading can
                                                               pilosebaceous units. Each of the six
          Acne Grading System                                                                            be spent on counseling patients.
                                                               locations is graded separately on a 0-4
          (GAGS).
                                                               scale. The global score is a summation    Includes both inflammatory and non-inflammatory
                                                               of each factor.                           lesions.
                                                                                                         Patients with numerous lesions confined to only 1
                                                                                                         or 2 locations may end up with a lower total score
                                                                                                         and less severe classification than observed
                                                                                                         clinically.
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Level
                  Author/Date/
of Evi-                                        Type of scale                Method of Assessment                                    Conclusions
                  study design
dence

          Allen and Smith, Arch             Acne severity and       Study 1. Physicians and research             The authors concluded that acne grading scales
          Dermatol 1982; 118: 23-5.5        comedo grading scale    technician evaluated 190 subjects -          and papule counts are equally reproducible
  II
                                            including lesion        male college students with acne at           methods of grading inflammatory acne. The
          Randomized, double-blinded,
                                            counts.                 baseline and every two weeks                 comedo grading scale and comedo count are
          placebo-controlled trial to
                                                                    independently for 12 weeks. All              equally reproducible.
          evaluate grading of acne
                                                                    subjects at each visit received a
          severity.                                                                                              This study does not include the back and chest. It
                                                                    severity grade, papule count, pustule
                                                                                                                 uses half of the face for comedo and papule
                                                                    count and comedo grade. Comedo
                                                                                                                 counts; both sides of the face for pustule counts
                                                                    counts were not performed in this
                                                                                                                 and severity grades.
                                                                    study.
                                                                    Study 2. Physicians and research
                                                                    technician evaluated 141 male college
                                                                    students with acne at baseline and
                                                                    every two weeks independently for 10
                                                                    weeks. All subjects at each visit
                                                                    received a severity grade, papule
                                                                    count, pustule count and comedo
                                                                    grade. Comedo count was also done.
                                                                    Severity scale ranges from 0 (no or few
                                                                    comedones) to 8 (all of facial area
                                                                    involved with large, prominent
                                                                    nodules). This study used the acne
                                                                    grading scale devised by Cook et al.7
                                                                    Photographs of all the subjects were
                                                                    also used for evaluations.
          Cook et al., Arch Dermatol        Acne severity grading   Double-blinded, controlled clinical trial.   The overall severity grade based on the 0 to 8
  II      1979; 115: 571-5.7                scale.                  Ranges from 0 (no or few comedones)          scale with the photographic reference standards
                                                                    to 8 (all of facial area involved with       showed to be useful, reliable and sensitive.
          Double-blinded, placebo-
                                                                    large, prominent nodules).
          controlled trial to determine a                                                                        The photograph creates a permanent record.
          method of grading of acne                                 Uses photographic reference
                                                                                                                 This method includes both inflammatory and non-
          severity.                                                 standards; photographs taken at each
                                                                                                                 inflammatory lesions.
                                                                    visit become part of patient’s clinical
                                                                    record.
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Level
                   Author/Date/
of Evi-                                         Type of scale          Method of Assessment                                  Conclusions
                   study design
dence

          Lewis-Jones and Finlay,            Children’s         This study was conducted on 169           The CDLQI is based on the Dermatology Life
  II      Br J Dermatol 1995; 132:           Dermatology Life   children aged 3-16 years in a pediatric   Quality Index (DLQI).
          942-9.11                           Quality Index      dermatology clinic for 1 year.
                                                                                                          CDLQI provides a new technique for comparative
                                             (CDLQI).
          The aim of the study was to                           A 10-item questionnaire was used in       purposes.
          create and validate a simple                          this study, similar to the adult DLQI
                                                                                                          This is a simple scoring method. This method can
          questionnaire to measure the                          questions. The questionnaire was
                                                                                                          be used for clinical trials and clinical practice.
          quality of life in children with                      designed for a child. It may sometimes
          skin disease.                                         require parent’s help. Each question
                                                                was scored individually. The CDLQI
                                                                score was calculated by adding the
                                                                scores of the 10 questions. Scores
                                                                range from 0-30, 0 being the best
                                                                score.
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II.   The role of microbiological and endocrine testing in evaluating patients with
      adult acne and acne vulgaris in adolescents to adults

The most prevalent bacterium implicated in the clinical course of acne is
Propionibacterium acnes (P. acnes), a gram-positive anaerobic bacterium that normally
inhabits the skin. Studies have found that in patients affected with acne, the population
of P. acnes is higher than in the unaffected general population. Routine microbiologic
testing is unnecessary in the evaluation and management of patients with acne. In
patients who exhibit acne-like lesions, microbiologic testing may be helpful. Gram-
negative folliculitis is an uncommon complication often observed following long-term
systemic treatment of acne.
Adrenal and gonadal androgens play an integral role in the pathogenesis of acne.
Laboratory evaluation is indicated for those with acne and additional signs of androgen
excess. Most people with acne have normal levels of androgenic hormones, despite the
importance of androgens in this disorder. However, in females, acne severity and other
virilizing signs are associated with subtle differences in circulating androgens. These
include elevated free testosterone and DHEA-S, and reduced sex hormone-binding
globulin (SHBG). Presently, routine endocrinologic testing is not indicated for the
majority of patients with acne. Laboratory tests like free testosterone DHEA-S, LH and
FSH may be helpful.
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       Table 2a. Microbiological Testing

Level
  of     Author(s)/Date/                                           Method of
                                            Study Population                              Results                                Conclusions
 Evi-    Study Design                                              Assessment
dence
         Cove et al., Br J Dermatol         Ages 18-20 years.      Degree of acne         This study showed no difference in     There is no co-relationship
  II     1980; 102: 277-80.16               (1) 35 patients with   was graded on a        the number of microorganisms           between the severity of acne
         2 separate studies to determine    mild acne and 35       simple scoring         between mild and moderate study        and the number of bacteria.
         levels of P. acnes and             patients with          system:                groups.                                There is no direct relationship
         Micrococcaceae.                    moderate acne          bacteria sampled       There was no significant decrease in   between the size of the
                                            were compared for      using scrub            bacterial populations after 3 months   bacterial population and the
         (1) This study compared
                                            level of P. acnes      method.                of tetracycline.                       extent of acne severity.
         bacterial populations on
                                            and Micro-             CFU (colony-           There was not a significant decrease   Greater numbers of bacteria
         foreheads of patients with mild
                                            coccaceae.             forming units) were    in the number of P. acnes or           are not associated with
         to moderate acne.
                                            (2) 12 patients on     determined by          Micrococcaceae after the 3 months of   increasing severity of acne. The
         (2) This study compared
                                            250 mg of              plating out ten-fold   treatment of either bacterium.         effectiveness of oral
         bacterial populations and acne
                                            tetracycline twice     serial dilutions.      There was a significant decrease in    tetracycline in treating acne
         grade pre-treatment and post-
                                            daily for 3 months     Colonies were          the acne grade in patients after 4     cannot be explained by the
         treatment with tetracycline
                                            were compared for      counted after 7        weeks of therapy.                      reduction in the number of
         250 mg twice daily for 3 months.
                                            bacterial              days or 48 hours                                              viable bacteria.
                                            populations of P.      anaerobically for P.
                                            acnes and              acnes and
                                            Micrococcaceae.        Micrococcaceae.
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Level
  of    Author(s)/Date/                                        Method of
                                          Study Population                      Results                                  Conclusions
 Evi-   Study Design                                           Assessment
dence
        Bojar et al., Drugs 1995; 49      86 volunteers with   Used the scrub   Significant reduction in the number of   It was demonstrated that topical
  II    Suppl 2: 164-7.17                 mild/moderate        technique.       propionibacteria with both 1%            1% nadifloxacin is clinically as
        Double-blinded, randomized        acne:                                 nadifloxacin and 2% erythromycin         effective as and
        clinical study to assess 1%       1% nadifloxacin                       after 12 weeks.                          microbiologically superior to 2%
        nadifloxacin compared to 2%       (n=43);                               The carriage of Micrococcaceae was       erythromycin.
        erythromycin to determine the     2% erythromycin                       reduced in the nadifloxacin treated      Widespread incidence of
        susceptibility of all cutaneous   (n=43).                               group only.                              erythromycin-resistant
        microorganisms isolated before                                                                                   propionibacteria may limit future
        and after treatment of patients                                         Minimum inhibitory concentration
                                                                                (MIC)values were determined.             usefulness of erythromycin as a
        with mild/moderate facial acne.                                                                                  therapeutic agent.
                                                                                After 12 weeks of treatment with
                                                                                nadifloxacin, no resistant bacteria
                                                                                were isolated.
                                                                                Erythromycin-resistant P. acnes and
                                                                                erythromycin-resistant
                                                                                Micrococcaceae were isolated from
                                                                                27.9% and 97.7% erythromycin-
                                                                                treated subjects respectively.
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Level
  of    Author(s)/Date/                                         Method of
                                         Study Population                             Results                                 Conclusions
 Evi-   Study Design                                            Assessment
dence
        Eady et al., Br J Dermatol       51 patients on oral    Bacterial samples     42-51 bacteria were isolated from the   This study showed that the use
  II    1989; 121: 51-7.18               erythromycin and       were obtained by      skin surface of both erythromycin-      of oral erythromycin has
        Controlled study to determine    53 patients on         detergent scrub       and clindamycin-treated patients        developed more resistant
        the incidence of erythromycin-   topical clindamycin    technique.            compared to 3% of controls.             bacteria than the use of topical
        resistant propionibacteria in    were included in the   MIC of each           Patients responding to erythromycin     clindamycin.
        various groups treated with      study; 100 control     antibiotic was        carried less erythromycin-resistant
                                                                                                                              This study suggests that use of
        antibiotics for acne.            subjects.              recorded as the       bacteria compared to patients who
                                                                                                                              oral erythromycin should be
                                                                lowest                did not respond or those who had
                                                                                                                              limited to patients with no
                                                                concentration         relapsed.
                                                                                                                              previous exposure to the drug
                                                                yielding no growth.
                                                                                      There was an increased incidence of     and therapy should be
                                                                                      erythromycin-resistant bacteria in      discontinued after 6 months to
                                                                                      clindamycin patients who had used       allow any resistant bacteria to
                                                                                      erythromycin previously compared to     be overgrown by sensitive
                                                                                      those who received no erythromycin.     bacteria. The use of benzoyl
                                                                                                                              peroxide alone for a short
                                                                                                                              period may eradicate resistant
                                                                                                                              bacteria.
17




Level
  of    Author(s)/Date/                                       Method of
                                        Study Population                           Results                                  Conclusions
 Evi-   Study Design                                          Assessment
dence
        Harkaway et al., Br J Dermatol 60 subjects (30        Cultures obtained    After 12 weeks of treatment with the     These results showed that
  II    1992; 126: 586-90.19            male, 30 female)      from the forehead    erythromycin group, the aerobic flora    topical erythromycin excretes a
                                        ages 18-30 years.     at 0, 4, 8, 12 and   dominated by S. epidermis (2/3)          selective pressure.
        Controlled trial to examine the 2% erythromycin       16 weeks of          which was completely erythromycin-       Erythromycin-resistant strains
        development of antibiotic       (n=20)                treatment.           resistant.                               were suppressed the same as
        resistance in coagulase-        5% benzoyl                                 There was also an increased              sensitive strains.
        negative staphylococci during   peroxide (n=20)                            resistance to tetracycline and           The use of benzoyl peroxide
        treatment with of erythromycin, 5% benzoyl                                 clindamycin.                             interferes with the selection or
        benzoyl peroxide or combination peroxide + 3%                                                                       the induction of erythromycin-
        of the two for 16 weeks.        erythromycin (n=20)                        Treatment with benzoyl peroxide and
                                                                                                                            resistant bacteria.
                                                                                   the combination of benzoyl peroxide
                                                                                   + erythromycin resulted in significant
                                                                                   decrease in the number of aerobic
                                                                                   bacteria without any change in
                                                                                   resistance pattern to erythromycin or
                                                                                   other antibiotics.
18



  Table 2b. Endocrine testing

Level
  of      Author(s)/Date/           Study Population/
                                                                 Method of Assessment                                   Results                           Conclusion
 Evi-      Study Design                Intervention
dence
        Lawrence et al.,         Moderate to severe acne      Testosterone concentration           29% of women with acne had elevated               This study shows
        Clin Endocrinol          (simple acne) (n=24);        was measured by                      testosterone levels and 41% had free testosterone that a deficiency in
  I
        (Oxf) 1981; 15: 87-                                   chromatography and RIA.              elevated values.                                  SHBG and an
                                Moderate to severe acne
        91.20                                                                                                                                        elevation in derived
                                and with hirsutism and/or                                          Testosterone concentrations were higher in both   free testosterone is
        Controlled cohort trial irregular menstrual cycles                                         acne groups compared with controls.               a frequent finding in
        to determine levels of (complicated acne)
                                                                                                   There was no correlation between the              women with severe
        SHBG, testosterone      (n=23);
                                                                                                   concentration of testosterone and SHBG.           acne.
        and free testosterone
                                Unaffected women as
        in women with
                                controls (n=15);
        moderate to severe
        acne and hirsutes.      No patients or controls
                                were receiving oral
                                contraceptives.
        Lucky et al., J          871 fourth and fifth grade   The degree of facial acne            No racial differences in acne or hormonal levels   The results suggest
        Pediatr 1997; 130:       girls were in this study     was classified annually as           were found.                                        that the early
  I
        30-9.22                  Black (n=439)                mild, moderate or severe.                                                               development of
                                                                                                   There were more comedones at early age in girls
                                 White (n=432)                                                                                                        comedonal acne
        5-year longitudinal                                   Blood samples were obtained          who later developed severe acne.
                                                                                                                                                      may be the best
        cohort study to          Subjects were placed in 3    at first, third and fifth years of
                                                                                                   Those who developed severe inflammatory acne       predictor of later
        determine which          groups based on severity     study.
                                                                                                   had more inflammatory and comedonal lesions        more severe
        factors in early         of acne at year 5.
                                                              Facial comedonal and                 from -36 months to +36 months from menarche        disease.
        pubertal girls might
                                 Mean acne scores, level      nodular inflammatory lesions         compared with girls who developed mild acne.
        be predictive of later                                                                                                                        The DHEAS
                                 of sex steroid hormones      were recorded in the following
        severe facial acne.                                                                  Girls who developed mild acne had significantly          concentration is
                                 and testosterone-estrogen    way:
                                                                                             later menarche than girls who developed severe           higher in those girls
                                 binding globulin (TEBG)
                                                              Mild – up to 10 lesions; given acne.                                                    destined to have
                                 were compared among
                                                              a numerical value of 5.                                                                 severe acne.
                                 the 3 groups.                                               Girls who developed severe comedonal acne had
                                                              Moderate – 11-25 lesions;      significantly increased DHEAS and somewhat
                                                              given a numerical value of 17. increased testosterone and free testosterone.
                                                              Severe – more than 25                There were no differences in estradiol,
                                                              lesions; given a numerical           progesterone and TEBG.
                                                              value of 25.
19




III.   Topical agents in the treatment of adult acne and acne vulgaris in
       adolescents and adults

The effectiveness of topical therapy for acne is well-known. Topical retinoids are the
most effective comedolytic agents and since the microcomedo is thought to be the
precursor of all other acne lesions, they are appropriate for comedonal and inflammatory
acne. The effectiveness of topical retinoids (adapalene, tazarotene, tretinoin and
isotretinoin) is well documented. Topical retinoids such as tretinoin and adapalene
correct abnormalities in follicular keratinocytes. Topical isotretinoin is not available in the
United States. Salicylic acid and azelaic acid are weaker comedolytic agents, but may
be useful when retinoids are not tolerated. Topical antimicrobials include benzoyl
peroxide and topical antibiotics. Topical antibiotics such as clindamycin, tetracycline, and
erythromycin are bacteriostatic for P. acnes and are effective for mild to moderate
inflammatory acne. Benzoyl peroxide is bactericidal and improves both inflammatory and
non-inflammatory lesions. It is an oxidizing agent that works by introducing oxygen into
follicles, which then kills P. acnes. This is why P. acnes does not develop resistance to
benzoyl peroxide. In addition, there is increasing resistance to antibiotics by P. acnes.
Combining benzoyl peroxide with antibiotics reduces or eliminate this resistance. Sulfur,
resorcinol, aluminum chloride and sodium sulfacetamide are weaker antimicrobial
agents which can be useful in selected circumstances. Topical zinc alone is ineffective
but may enhance the activity of antimicrobial agents. Combination therapy, involving
benzoyl peroxide or retinoids and oral antibiotics, is effective treatment for acne.
20



Table 3a. Use of Topical Retinoids

 Level of         Author(s)/Date/                  Study Population/                Method of
 Evidence          Study Design                       Intervention                 Assessment                           Results                      Conclusions
            Christiansen et al.,            256 patients with acne were         The effect of           There was a statistically significant   Tretinoin is very
            Dermatologica 1974; 148:        randomized to receive 1 of the      treatment was           reduction in comedones and papules      successful in reducing
    I
            82-9.25                         following daily for 12 weeks:       determined by           compared to placebo.                    comedones and
                                                                                counting the                                                    papules.
            Double-blinded,                 Tretinoin 0.02% cream,                                      0.05% cream had a quicker onset of
                                                                                comedones,
            randomized clinical trial to    Tretinoin 0.05% cream,                                      action and had quantitatively greater   A very high rate of
                                                                                papules, pustules
            evaluate the effect of          Placebo vehicle control.                                    effect than 0.02% cream.                adverse effects was
                                                                                and cysts and
            topical tretinoin in patients                                                                                                       seen.
                                            Patients were evaluated at          scoring each type of    Pustule and cyst counts were not
            with of acne.
                                            baseline, 2, 4, and 8 weeks of      acne lesion at          significantly different for all the 3
                                            treatment.                          baseline and at 2, 4,   groups.
                                                                                and 8 weeks.
                                            231 patients completed the                                  Local adverse reactions such as
                                            study.                                                      erythema and peeling were noted by
                                                                                                        40% of placebo group, and 81% and
                                                                                                        86% in the 0.05% and 0.02% groups
                                                                                                        respectively.

            Chalker et al., J Am Acad       313 subjects (age range 13-30       Facial inflammatory     At 8 weeks, the non-inflammatory        0.05% isotretinoin gel
            Dermatol 1987; 17: 251-         years) with at least 12             and non-                lesion count was significantly          is effective in the
    I
            4.28                            inflammatory lesions, 12 non-       inflammatory            reduced in the isotretinoin-treated     treatment of acne.
                                            inflammatory lesions, and no        lesions were            group compared to the placebo
            Multicenter, randomized,                                                                                                            More adverse effects
                                            more than 3 facial nodulocystic     counted and overall     group.
            double-blinded, controlled                                                                                                          were observed in the
                                            lesions.                            acne grade
            clinical trial to determine                                                                 Inflammatory and non-inflammatory       treated group than in
                                                                                assigned using
            the efficacy of 0.05%           268 subjects completed the                                  lesion counts were reduced by 55%       the placebo group.
                                                                                Cook’s et al.
            topical isotretinoin gel in the study.                                                      and 46% respectively in the treated
                                                                                method (0-8). 7
            treatment of acne                                                                           group compared to 25% and 14%
                                            Subjects were randomized to
            compared its vehicle.                                                                       reduction in the placebo group.
                                            receive 0.05% isotretinoin or
                                            vehicle gel twice daily for 12-14                           Mean acne severity grade was
                                            weeks.                                                      reduced by 40% after 12 weeks
                                            Subjects were evaluated at 0, 2,                                 isotretinoin treated vs. placebo
                                            5, 8, 10-11, and 12-14 weeks of                             peeling:     71%                51%
                                            treatment.                                                  erythema: 76%                   62%
21


Level of        Author(s)/Date/                  Study Population/               Method of
Evidence         Study Design                       Intervention                Assessment                       Results                       Conclusions
           Shalita et al., Cutis 1999;  446 subjects (14-44 years) with      Percentage of         There was significant reduction in      Tazarotene 0.1% and
           63: 349-54.38                mild to moderate facial acne         change was            non-inflammatory and total lesion       0.05% aqueous gels
   I
                                        were randomized to receive           determined by         count at week 12.                       were safe and effective
           Multicenter, double-blinded,
                                        tazarotene 0.1% gel, tazarotene      lesion count and                                              in reducing acne lesion
           randomized, parallel-group,                                                             0.1% gel tazarotene had of 68%,
                                        0.05% gel, or vehicle-only           global evaluation                                             count.
           controlled trial to evaluate                                                            0.05% gel tazarotene had 51% and
                                        placebo daily for 12 weeks.          response to
           the safety and efficacy of                                                              placebo had 40% reduction of non-       Both concentrations
                                        Patients were evaluated at 0, 4,     treatment methods.
           tazarotene in the treatment                                                             inflammatory and total lesion counts.   had acceptable
                                        8, and 12 weeks of treatment.
           of acne.                                                          Pharmacokinetics                                              tolerability.
                                        333 subjects completed the           and safety analyses
                                                                                                                                           There were few
                                        study.                               were conducted.
                                                                                                                                           adverse events.

           Lucky et al., J Am Acad        215 patient study; patients were   Efficacy              The efficacy of both treatments was     Both treatments
           Dermatol 1998; 38: S17-        randomized to receive any one      assessments were      comparable and more effective than      demonstrated
   I
           23.41                          of the treatments.                 measured by lesion    the control vehicle.                    comparable efficacy.
                                                                             counts and Physical
           Multicenter, double-blinded,   The formulation tested ethanol                           The gel containing polyolprepolymer-
                                                                             Global Evaluation
           randomized, parallel-group,    gel containing 0.025% tretinoin                          2 caused significantly less peeling
                                                                             (PGE).
           vehicle-controlled trial to    gel and polyolprepolymer-2, (n-                          and drying than the commercially-
           evaluate the safety and        71) vehicle control (n-70) and                           available gel by day 84 of the study.
           efficacy of tretinoin with     commercially available 0.025%
           polyolprepolymer-2             tretinoin gel (n-72).
           compared with
                                          Evaluations were performed at
           commercially available
                                          day 0, 7, 14, 28, 56 and 84.
           0.025% tretinoin gel in the
           treatment of acne.
22


Table 3b. Use of Benzoyl Peroxide

 Level of         Author(s)/Date/                  Study Population/               Method of
                                                                                                                     Results                      Conclusions
 Evidence          Study Design                       Intervention                Assessment
            Belknap, Cutis 1979; 23:        69 patients ages 15-30 with        Patients were          A significantly higher percentage of    The benzoyl peroxide
            856-9.42                        acne.                              evaluated by total     patients in the benzoyl peroxide        group showed
    I
                                                                               lesion counts.         group exhibited excellent overall       improvement earlier
            Randomized, controlled          Patients were randomly
                                                                                                      response compared to the retinoic       than the retinoic acid
            clinical trial to compare the   assigned to receive 0.05%          Overall evaluation
                                                                                                      acid group.                             group.
            effectiveness of topical        vitamin A acid cream or benzoyl    of clinical response
            benzoyl peroxide and            peroxide 5% gel treatments for 8   was done for each      Both treatment groups were effective    Statistically, there was
            tretinoin in the treatment of   weeks.                             patient.               in reducing lesions.                    no significant
            acne.                                                                                                                             difference between the
                                            Subjects were evaluated at
                                                                                                      There was significantly less peeling    two drugs after 8
                                            baseline and after 2, 4, and 8
                                                                                                      in the benzoyl peroxide compared to     weeks.
                                            weeks for the response to the
                                                                                                      the vitamin A acid group after 4
                                            treatments.                                                                                       This study should
                                                                                                      weeks.
                                                                                                                                              have used proper
                                                                                                                                              controls especially
                                                                                                                                              because the trial is
                                                                                                                                              comparing gel versus
                                                                                                                                              cream. Each treatment
                                                                                                                                              should have had its
                                                                                                                                              respective vehicle as a
                                                                                                                                              control.

            Schutte et al., Br J            65 patients ages 17-23 years       Patients were          The control preparation had no effect   This study indicates
            Dermatol 1982; 106: 91-         with acne.                         evaluated by lesion    on the number of papules or             that 5% benzoyl
    I
            4.48                                                               count before the       pustules.                               peroxide lotion does
                                            Patients were randomly
                                                                               start of therapy and                                           have a rapid effect in
            A multicenter, randomized,      assigned 5% benzoyl peroxide                              There was a significant reduction of
                                                                               after 5 days after                                             resolving inflamed
            double-blinded, placebo-        lotion or placebo/base.                                   lesions seen in the treatment group
                                                                               treatment.                                                     lesions.
            controlled study to                                                                       and there was significantly reduced
            determine the effect of a                                          Facial fluorescence    facial prophyrin fluorescence.          The mechanism of
            5% benzoyl peroxide lotion                                         by ultraviolet                                                 action of benzoyl
            in the treatment of acne                                           photography was                                                peroxide lotion should
            compared to its base.                                              done.                                                          be studied.
                                                                               The degree of                                                  Larger populations of
                                                                               redness and scaling                                            patients are required
                                                                               was recorded.                                                  in studies to prove
                                                                                                                                              safety and efficacy.
23


Level of         Author(s)/Date/                 Study Population/              Method of
                                                                                                                 Results                        Conclusions
Evidence          Study Design                      Intervention               Assessment
           Smith et al., Cutis 1980;      59 patients (mean age 20 years,   Patients were          Benzoyl peroxide treated group had      This study showed
           25:90-2.50                     range 18-30) with at least 10     evaluated for          an excellent response compared to       that 20% benzoyl
   I
                                          inflammatory lesions and 3 or     efficacy by counting   the placebo group.                      peroxide is effective in
           A multicenter, randomized,
                                          fewer nodulocystic lesions were   all lesions on the                                             reducing the lesions of
           double-blinded, controlled                                                              Redness and peeling were observed
                                          selected for the study.           face.                                                          acne.
           study to evaluate the effect                                                            in both groups but more in the active
           of 20% benzoyl peroxide        The patients were randomized to   Erythema and           treated group.                          There was some
           lotion in the treatment of     receive 20% benzoyl peroxide      peeling were also                                              improvement in the
           acne.                          lotion or placebo lotion base     assessed.                                                      placebo group also.
                                          twice daily for 12 weeks:
                                                                                                                                           Study with a larger
                                          Benzoyl peroxide 20% lotion                                                                      number of population
                                          (n=29);                                                                                          is required to prove
                                                                                                                                           safety and efficacy.
                                          Placebo control lotion (n=30).
                                          Subjects were evaluated at
                                          baseline and every 2 weeks.
24


Table 3c. Use of Topical Antibiotics

 Level of         Author(s)/Date/                 Study Population/                 Method of
                                                                                                                     Results                        Conclusions
 Evidence          Study Design                      Intervention                  Assessment
            Bernstein and Shalita, J       348 patients (age range 13-30        Efficacy was           There was a significant reduction in    Topical erythromycin is
            Am Acad Dermatol 1980;         years) with inflammatory acne        assessed by total      papulopustule count in the treatment    effective in the
    I
            2: 318-21.52                   were randomized to receive 2%        lesion count and       group compared to the placebo           treatment of
                                           erythromycin solution (n=178) or     papulopustule          group.                                  papulopustular acne.
            Randomized, placebo-
                                           placebo control (n=170) twice        count.
            controlled trial to evaluate                                                               Comedones and cysts and total            Vehicle base
                                           daily for 8 weeks.
            the effectiveness of topical                                        Physician global       lesions were not significantly different preparation contained
            2% erythromycin compared       Patients were evaluated at           severity rating was    after 8 weeks in both groups.            alcohol and
            to its vehicle in the          baseline and after 2, 4, 8 and 12    assessed at                                                     polyethylene which are
                                                                                                       Fewer adverse effects were noted in
            treatment of acne.             weeks.                               baseline and after                                              local irritants.
                                                                                                       the active preparation compared to
                                                                                2, 4, and 8 weeks of
                                                                                                       the placebo group.
                                                                                treatment.

            Jones and Crumley, Arch        175 subjects (ages 12 years and      Efficacy was           The total count of inflammatory         Topical 2%
            Dermatol 1981; 117: 551-       over) with inflammatory acne         assessed by total      pustules was significantly reduced      erythromycin
    I
            3.53                           were randomized to receive 2%        lesion count and       after therapy in the 2% erythromycin    demonstrated
                                           erythromycin (n-90) solution or      inflammatory           group.                                  significantly better
            Randomized, double-
                                           placebo control (n-85) twice daily   papulopustule                                                  results than the blank
            blinded, placebo-controlled                                                                After 12 weeks, there was a 56%
                                           for 12 weeks.                        count.                                                         vehicle.
            trial to evaluate the                                                                      papule reduction in the treated group
            effectiveness of topical 2%                                                                compared to 33% in the blank            Study confirms the
            erythromycin compared to                                                                   vehicle group.                          effectiveness of topical
            its vehicle in the treatment                                                                                                       erythromycin in the
                                                                                                       62% of subjects in the topical 2%
            of acne.                                                                                                                           treatment of acne.
                                                                                                       erythromycin group had good to
                                                                                                       excellent response compared to 27%      Adverse effects were
                                                                                                       in the blank vehicle.                   similar in both groups.
25


Level of        Author(s)/Date/                Study Population/                 Method of
                                                                                                                  Results                       Conclusions
Evidence         Study Design                     Intervention                  Assessment
           Lesher et al., J Am Acad     225 subjects (range 14-30 years)     Facial inflammatory   Erythromycin group had 46% mean       This study showed that
           Dermatol 1985; 12: 526-      with at least 10 inflammatory        lesions were          lesion count reductions compared to   2% erythromycin
   I
           31.55                        lesions, 10 non-inflammatory         counted and overall   19% in the placebo group after 12     ointment was
                                        lesions, and no more than 3          severity grade was    weeks of treatment.                   significantly more
           Multicenter, double-blinded,
                                        nodulocystic lesions were            assessed using                                              effective than its
           controlled clinical trial to                                                            Topical 2% erythromycin group had a
                                        randomized to receive topical        Cook’s et al. 7                                             placebo control in
           assess the effectiveness of                                                             40% reduction in mean acne severity
                                        2% erythromycin ointment             grading scale for                                           decreasing
           topical 2% erythromycin in                                                              grade compared to 23% reduction for
                                        (n=112) or placebo vehicle           acne severity 0-8                                           inflammatory acne
           the treatment of acne.                                                                  the vehicle group.
                                        control (n=113) twice daily for 12   scale.                                                      lesions.
                                        weeks.                                                     No significant differences were noted
                                                                                                   between groups for side effects.
                                        Subjects were evaluated at
                                        baseline and after 2, 4, 8, 10,
                                        and 12 weeks of treatment.

           Pochi et al., Cutis 1988;    187 patients (range 13-48 years)     Facial lesions were   2% erythromycin gel proved to be        2% erythromycin gel
           41: 132-6.56                 with mild to moderate acne were      counted at each       significantly more effective than the   was effective and well
   I
                                        randomized to receive topical        visit and a grade     placebo in the reduction of the         tolerated in the
           Multicenter, double-blinded,
                                        2% erythromycin gel (n=93)           was based on          number of inflammatory and non-         treatment of acne.
           controlled clinical trial to
                                        compared to placebo vehicle          percentage of         inflammatory lesions.
           assess the effectiveness of                                                                                                     A strong placebo effect
                                        control (n=94) twice daily for 8     overall
           topical 2% erythromycin gel                                                             After 8 weeks, 60% of the treated       was noted.
                                        weeks.                               improvement.
           compared to its vehicle in                                                              group had a good to excellent
           the treatment of acne.       Patients were evaluated at           Adverse effects       response compared to 36% of the
                                        baseline, 4 and 8 weeks after        were evaluated on     vehicle group.
                                        treatment.                           mild-to-severe
                                                                                                   Side effects were generally mild and
                                                                             scale.
                                                                                                   transient, with no significant
                                                                                                   differences noted between the
                                                                                                   groups.

           Dobson and Bellknap, J       253 patients were randomized to      Total lesion count    The reduction in the number of          This study
           Am Acad Dermatol 1980;       receive either topical 1.5%          was used for          inflammatory lesions, papules, and      demonstrated a
   I
           3: 478-82.57                 erythromycin solution (n=127) or     evaluation of the     pustules was significantly greater in   statistically significant
                                        placebo vehicle control (n=126)      treatment.            the erythromycin treated group.         benefit in the patients
           Multicenter, double-blinded,
                                        twice daily for 12 weeks.                                                                          with acne receiving
           controlled clinical trial to                                      Global physician      The global evaluation of the clinical
                                                                                                                                           1.5% erythromycin
           assess the effectiveness of Patients were evaluated at            evaluation was also   response correlated well with the
                                                                                                                                           solution compared to
           topical 1.5% erythromycin    baseline and at 2, 4, 8, 10 and      performed after 2,    reduction in the lesion counts.
                                                                                                                                           its vehicle.
           solution compared to its     12 weeks of treatment.               4, 8, 10 and 12
           vehicle in the treatment of                                       weeks of treatment.                                           No serious or
           acne.                                                                                                                           irreversible adverse
                                                                                                                                           effects were seen.
26


Level of         Author(s)/Date/                  Study Population/                 Method of
                                                                                                                      Results                      Conclusions
Evidence          Study Design                       Intervention                  Assessment
           Mills et al., Acta Derm         208 patients were randomized to      Acne severity was      The prevalence of erythromycin         Resistance
           Venereol 2002; 82: 260-         receive either topical 2%            evaluated by total     coagulase-negative staph on the        development was
   I          58
           5.                              erythromycin gel or placebo          lesion count and the   face was high at 87% at baseline. At   confined to the
                                           vehicle control twice daily for 12   use of photographs.    the end of 12 weeks of erythromycin,   macrolide class of
           Randomized, single-             weeks.                                                      coagulase-negative staph increased     antibiotics.
           blinded, controlled clinical                                         Bacteriologic
                                                                                                       to 98% in the erythromycin-treated
           trial to assess the             Patients were evaluated at           samples were also                                             No anti-acne efficacy
                                                                                                       group.
           effectiveness of topical        baseline and after 2, 4, 8, 10 and   assessed at                                                   was observed.
           2% erythromycin gel             12 weeks of treatment.               baseline and at 4,     Nearly all bacteria were highly
                                                                                                                                              This suggests that
                                                                                12, 16 and 24          resistant (MIC > 128ug/ml).
           compared to its vehicle in      To study the regression of any                                                                     topical treatment with
                                                                                weeks of treatment.
           the treatment of acne and       bacteriologic changes at 12                                                                        erythromycin may
           to determine the bacterial      weeks, the patients on active                                                                      result in higher
           resistance associated with      treatment were switched over to                                                                    carriage rates and
           its use.                        placebo. The patients on                                                                           dissemination of
                                           placebo continued their placebo                                                                    erythromycin-resistant
                                           treatments.                                                                                        S. aureus from nares.

           Leyden et al., J Am Acad        102 patients (14 to 34 years)        Acne severity was      Both medications significantly         Topical antibiotics
           Dermatol 1987; 16: 822-         were randomized to receive           evaluated by total     reduced the number of papules and      have advantages over
   I
           7.62                            either topical 2% erythromycin       facial lesion count.   open and closed comedones.             systemic therapy
                                           gel or 1% clindamycin phosphate                                                                    because of direct local
           Multicenter, randomized                                              Global physician       There was no significant difference of
                                           solution twice daily for 12 weeks.                                                                 application on the
           parallel-group clinical trial                                        evaluation was also    lesion count detected between the
                                                                                                                                              affected areas of the
           to assess the effectiveness     Patients were evaluated at           performed.             treatment groups after 8 and 12
                                                                                                                                              skin and a resultant
           of topical 2% erythromycin      baseline and at 4, 8, and 12                                weeks of treatment.
                                                                                                                                              decrease in systemic
           in the treatment of acne.       weeks of treatment.
                                                                                                       At the end of 12 weeks, about 50%      side effects.
                                                                                                       of patients had a good to excellent
                                                                                                       response.
                                                                                                       Side effects included peeling,
                                                                                                       erythema, burning, and itching.
27


Level of        Author(s)/Date/                  Study Population/                Method of
                                                                                                                   Results                     Conclusions
Evidence         Study Design                       Intervention                 Assessment
           Becker et al., Arch            413 patients (14-29 years) with     Acne severity was      86% of patients in the clindamycin   Both clindamycin
           Dermatol 1981; 117: 482-       acne were randomized to             evaluated by           hydrochloride group, 77% of the      phosphate and
   I
           5.65                           receive either 1% clindamycin       counting pustules,     clindamycin phosphate group, and     clindamycin
                                          phosphate solution (n=123), 1%      papules, and           56% of the placebo group reported    hydrochloride
           Multicenter, double-blinded,
                                          clindamycin hydrochloride           nodules over the       improvement.                         treatment had
           controlled clinical trial to
                                          solution (n=120) or placebo         entire face.                                                significant reduction in
           evaluate the effectiveness                                                                Side effects included peeling,
                                          vehicle control (n=112) twice                                                                   lesion count when
           of topical clindamycin                                             Mean change in         erythema, burning, and itching.
                                          daily for 8 weeks.                                                                              compared to baseline
           hydrochloride and                                                  lesion count in each
                                                                                                                                          and placebo group.
           clindamycin phosphate          Patients were evaluated at          group was reported.
           compared to placebo in the     baseline and after 2, 4, 6, and 8
           treatment of acne.             weeks of treatment.
28


Table 3d. Use of Other Topical Agents

 Level of         Author(s)/Date/                   Study Population/                Method of
                                                                                                                        Results                        Conclusions
 Evidence          Study Design                        Intervention                 Assessment
            Zouboulis et al., Br J           209 patients (aged 14-26 years)  Acne severity was           At week 12 there was significantly      A single daily topical
            Dermatol 2000; 143: 498-         were randomized to receive       evaluated by                greater reduction of inflamed lesions   application of 1%
    I
            505.70                           either CTG once (n=104) or CLN   counting open and           from baseline to week 12 in the CTG     clindamycin/0.025%
                                             (n=105) twice daily for 12 weeks.closed comedones,           group compared to the CLN group.        tretinoin gel formulation
            Multicenter, randomized,
                                                                              pustules, papules,                                                  was superior to 1%
            single-blinded, controlled       Patients were evaluated at                                   50% reduction in total lesion count
                                                                              and nodules. Acne                                                   clindamycin lotion
            clinical trial to compare the    baseline and after 2, 4, and 8                               was observed by day 60 in 77% of
                                                                              severity grade by                                                   applied twice daily for
            efficacy and safety of 1%        weeks of treatment to assess the                             patients on CTG compared with 56%
                                                                              Cook et al. 7 was                                                   the reduction of acne.
            clindamycin/0.025%               efficacy of both treatments.                                 receiving CLN.
                                                                              also used.
            tretinoin gel formulation                                                                                                             CTG had a rapid effect
                                                                                                          Both treatments were well tolerated.
            (CTG) to 1% clindamycin                                                                                                               on the onset of
            lotion (CLN) for the                                                                                                                  improvement
            treatment of acne.                                                                                                                    compared to CLN.


            Chalker et al., J Am Acad        165 subjects (age 15-30 years)      Patients were            There was no statistically significant The combination of 3%
            Dermatol 1983; 9: 933-6.72       with grade 3 acne on the Cook et    evaluated at each        difference between the groups for the erythromycin/
    I
                                             al. scale7 were randomized to       visit by lesion count.   first 8 weeks.                         5% benzoyl peroxide
            Randomized, double-
                                             receive one of the following                                                                        gel was more effective
            blinded, placebo-controlled                                          Grading method of        At week 10, the active groups were
                                             topicals twice daily for 10 wks.                                                                    than the individual
            clinical trial to determine if                                       Cook et al.7 was         statistically different.
                                                                                                                                                 constituents or
            topical erythromycin and         3% erythromycin/5% benzoyl          also used.
                                                                                                          Mean comedonal and pustule counts placebo.
            benzoyl peroxide were            peroxide gel (n=44);
                                                                                                          were reduced in all active treatment
            effective in the treatment of    5% benzoyl peroxide gel (n=44);                                                                     The most dramatic
                                                                                                          groups.
            acne. This study also            3% erythromycin gel (n=45);                                                                         effect was on
            compared the combination         placebo gel base, vehicle control                            Combination therapy consistently       combined inflammatory
            to its vehicle base.             (n=44).                                                      improved papule and inflammatory       lesions (papules and
                                                                                                          lesion counts.                         pustules).
                                             All patients were evaluated at
                                             baseline and every 2 weeks for                               Adverse effects were not reported.
                                             10 weeks.
29


Level of         Author(s)/Date/                   Study Population/                 Method of
                                                                                                                      Results                         Conclusions
Evidence          Study Design                        Intervention                  Assessment
           Tschen et al., Cutis 2001;       287 patients (ages13-30 years)       Total improvement     All study groups demonstrated             There was greater
           67: 165-9.73                     with moderately severe acne          in lesion counts      significant improvement from              efficacy obtained with
   I
                                            were randomly selected to            from baseline was     baseline.                                 the combination
           Randomized, double-
                                            receive one of the following         monitored.                                                      therapy and it was as
           blinded, parallel-group                                                                     The number of lesions was reduced
                                            topicals twice daily for 10 weeks:                                                                   safe as the other
           clinical trial to evaluate the                                        Patients’ global      to a greater extent in patients treated
                                                                                                                                                 treatments.
           effectiveness of benzoyl         (1) 5% benzoyl peroxide/1%           evaluations were      with the combination of 5% benzoyl
           peroxide and clindamycin         clindamycin phosphate gel            measured at week      peroxide/1% clindamycin phosphate
           separately and in                (n=95);                              10.                   gel compared to the other
           combination.                     (2) 5% benzoyl peroxide gel                                treatments.
                                            (n=95);
                                                                                                       Some patients reported adverse
                                            (3) 1% clindamycin phosphate
                                                                                                       effects.
                                            gel (n=49);
                                            (4) placebo control (n=48).
                                            Safety and efficacy was
                                            evaluated at baseline and at 2,
                                            4, 6, 8, and 10 weeks of
                                            treatment.

           Lookingbill et al., J Am         334 subjects (ages 13-30 years)      The study evaluated   All three active treatments were          Topical clindamycin/
           Acad Dermatol 1997; 37:          were randomly assigned to            lesion counts,        significantly superior to the placebo     benzoyl peroxide
   I
           590-5.75                         receive one of the following         assessed global       in global improvement and in              combination gel is well-
                                            topicals once daily:                 responses and         reducing both inflammatory and non-       tolerated and superior
           Multicenter, randomized,
                                                                                 irritant effects.     inflammatory lesions.                     to the other treatments.
           double-blinded, placebo          1% clindamycin phosphate/5%
           controlled clinical trial to     benzoyl peroxide gel;                                      The combination gel was significantly     This has an advantage
           determine the safety and         1% clindamycin phosphate gel;                              superior to the two individual agents.    over the combination of
           efficacy of combination          5% benzoyl peroxide gel;                                                                             erythromycin/benzoyl
           clindamycin/benzoyl              placebo vehicle gel control.                                                                         peroxide gel because it
           peroxide when compared                                                                                                                is not required to be
                                            Safety and efficacy evaluations
           with clindamycin, benzoyl                                                                                                             refrigerated.
                                            were performed at baseline and
           peroxide or placebo
                                            at 2, 5, 8 and 11 weeks.
           separately.
30


Level of         Author(s)/Date/                 Study Population/                Method of
                                                                                                                  Results                      Conclusions
Evidence          Study Design                      Intervention                 Assessment
           Hjorth and Graupe, Acta        First study had subjects with       Total lesion count   Both studies demonstrated significant   20% azelaic acid
           Derm Venereol Suppl            moderate to severe acne.            was monitored at     clinically relevant reduction in the    cream is an effective
   I
           (Stockh) 1989; 143: 45-                                            monthly intervals.   initial number of lesions during        treatment for
                                          Patients were randomized to
           8.79                                                                                    therapy.                                inflammatory acne and
                                          receive one of the following
                                                                                                                                           is well tolerated.
           Multicenter, randomized,       topicals twice daily:                                    No significant difference in either
           double-blinded, placebo-                                                                treatment was observed after 5
                                          20% azelaic acid cream (n-164);
           controlled clinical trial to                                                            months.
                                          placebo capsules (n-126).
           compare the 20% azelaic
           acid cream with its base       Second study had patients
           and compare it to oral         receiving oral tetracycline
           tetracycline treatment.        1-g/day for the first month,
                                          0.75-g/day for the second month
                                          and 0.5-g/day for the third month
                                          (n-169); and cream base (n-
                                          135).
                                          Patients with moderate acne
                                          were treated for 5 months and
                                          patients with severe acne were
                                          treated for 6 months.
31



IV.   The efficacy and safety of systemic antibacterial agents in the treatment of adult acne
      and acne vulgaris in adolescents to adults

Oral antibiotic therapy has been used for the treatment of moderate and severe acne for many years.
Systemic antibiotics have been shown to be effective as monotherapy and also in combination with
other therapies. Many clinical trials have shown the effectiveness of antibiotics like tetracyclines,
erythromycin, doxycycline, minocycline, trimethoprim with or without sulfamethoxazole and
azithromycin. These systemic antibiotics suppress P. acnes growth, and because of this, there is a
decrease in the production of inflammatory factors. The prevalent and long-term use of antibiotics has
led to the emergence of resistance to P. acnes. To minimize the development of bacterial resistance,
antibiotics should be used for a short period of time and combination therapy should be used.
32


Table 4a. Use of Tetracyclines

 Level of        Author(s)/Date/                Study Population/                Method of
 Evidence         Study Design                     Intervention                 Assessment                       Results                       Conclusion
            Smith et al., South Med       135 subjects (age 18-35 years)     All subjects were     Oral and systemic groups both had      This study confirms
            J 1976; 69: 695-7.90          with acne grade 2 and over,        evaluated with        achieved statistically significant     that tetracycline in
    I
                                          according to Cooke et al., 7       visual grading and    improvement after 4, 7, 10, and 12     oral dose of
            Randomized, double-
                                          were randomized to receive         photographs to        weeks of treatment compared to         0.5-gm/day is
            blinded study to evaluate
                                          one of the following:              assure critical       placebo.                               effective treatment for
            (1) patients treated with
                                                                             evaluation.                                                  acne after 4 weeks of
            topical and oral placebo;     (1) topical placebo and                                  The topical treatment was effective,
                                                                                                                                          therapy.
            (2) patients receiving        systemic placebo treatment;                              but somewhat less than the oral
            topical placebo and                                                                    tetracycline, but significantly better
            systemic tetracycline         (2) topical placebo/systemic                             than the placebo after seven weeks
            0.5-gm/day;                   tetracycline 0.5-gm/day;                                 of treatment.
            (3) patients treated with a   (3) new topical tetracycline and                         Slight yellowish discoloration was
            new topical tetracycline      oral placebo.                                            observed in 25% of subjects.
            preparation and an oral
            placebo.                      New topical tetracycline
                                          consists of tetracycline
                                          hydrochloride 0.22% with 4-
                                          epi-tetracycline 0.28% and n-
                                          decylmethyl sulfoxide in
                                          ethanol/water; this was applied
                                          twice daily.

            Gratton et al., J Am          305 patients (age range 18-35      Severity was          Both oral tetracycline and topical     Both oral tetracycline
            Acad Dermatol 1982; 7:        years) with moderate to severe     defined by papule,    clindamycin significantly reduced      and topical
    I
            50-3.91                       acne were randomized to            pustule and           the papule and pustule counts          clindamycin are
                                          receive one of the following       nodulocystic lesion   compared to placebo.                   effective in the
            A multicenter,
                                          three groups twice daily for 8     count.                                                       treatment of moderate
            randomized, double-                                                                    The most frequent side effect
                                          weeks:                                                                                          to severe acne.
            blinded, placebo-                                                Efficacy was          reported in the patients was
            controlled study to           (1) 250 mg oral tetracycline       evaluated with        diarrhea.
            compare oral tetracycline,    hydrochloride (n=103);             lesion count and
            topical clindamycin and                                          physicians’ overall
                                          (2) 1% topical clindamycin
            placebo for treatment of                                         evaluation of
                                          phosphate solution (n=97);
            acne.                                                            therapy.
                                          (3) placebo (n=97).
                                          Subjects were evaluated at
                                          baseline and after 2, 4, 6, and
                                          8 weeks.
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