STUDY
`
`Effects of Subantimicrobial-Dose Doxycycline
`in the Treatment of Moderate Acne
`
`Robert Skidmore, MD; Rodney Kovach, MD; Clay Walker, PhD; John Thomas, PhD; Mark Bradshaw, PhD;
`James Leyden, MD; Christopher Powala, BS; Robert Ashley, MA
`
`Objective: To determine if treatment with subantimi-
`crobial-dose (SD) doxycycline hyclate (20-mg tablets
`taken twice daily) improved clinical outcome, had any
`detectable effect on skin flora, led to overgrowth or colo-
`nization of skin by opportunistic pathogens, or resulted
`in an increase in antibiotic resistance by the surface skin
`microflora in patients with moderate acne compared with
`placebo.
`
`Design: Multicenter, double-blind, randomized, placebo-
`controlled, parallel-group trial.
`
`Setting: Two university-based clinics.
`
`Subjects: Adults (N=51) with moderate facial acne.
`
`Interventions: Patients were randomized to receive SD
`doxycycline (Periostat; CollaGenex Pharmaceuticals Inc,
`Newtown, Pa) or placebo twice daily for 6 months.
`
`Main Efficacy Outcomes: Primary: changes from
`baseline in numbers of inflammatory, noninflamma-
`tory, and total lesions. Secondary: changes from base-
`line of individual counts of papules, pustules, and nod-
`
`ules and global assessments of clinical improvement by
`patient and physician.
`
`Results: Forty patients completed 6 months of treat-
`ment. At 6 months, the SD doxycycline group had a sig-
`nificantly greater percent reduction in the number of corn-
`edones (P<.Ofl, inflammatory and noninflammatory
`lesions combined (P<.01), and total inflammatory le-
`sions (P<.05) than did the placebo group. They also had
`significantly greater improvement according to the cli-
`nician’s global assessment (P=.03). There were no sig-
`nificant differences in microbial counts between groups
`and no evidence of change in antibiotic susceptibility or
`colonization by potential pathogens. The treatment was
`well tolerated.
`
`Conclusions: Twice-daily SD doxycycline treatment sig-
`nificantly reduced the number of inflammatory and non-
`inflammatory lesions in patients with moderate facial acne,
`was well tolerated, had no detectable antimicrobial effect
`on the skin flora, and did not result in any increase in
`the number or severity of resistant organisms.
`
`Arch Dermatol. 2003;139:459-464
`
`From the Department
`of Medicine, Division
`of Dermatology (Dr Skidmore)
`and the College of Dentistry
`(Dr Walker), University
`of Florida, Gainesville; School
`of Medicine, Dermatology
`Section (Dr Kovach) and
`Department of Pathology,
`Health Sciences Center
`(Dr Thomas), West Virginia
`University, Morgantown;
`Covance Inc, Princeton, NJ
`(Dr Bradshaw); School of
`Medicine, Department of
`Dermatology, University of
`Pennsylvania, Philadelphia
`(Dr Leyden); and CollaGcnex
`Pharmaceuticals Inc Newtown,
`Pa (Messrs Powala and Ashley).
`The financial disclosure
`statement for these authors
`appears at the end of this article.
`
`T ETRACYCLINES ARE indi-
`
`cated for use as adjunctive
`therapy in patients with se-
`vere acne; doxycycline and
`minocycline are the most
`commonly prescribed.’,’ Doxycycline treat-
`ment at doses of 100 to 200 mg/d has been
`shown to reduce the number and sever-
`ity of inflammatory lesions.’ ,’ However,
`these antimicrobial doses are often asso-
`ciated with the emergence of resistant bac-
`teria34 and adverse effects such as gram-
`negative folliculitis, vaginal candidiasis,
`gastrointestinal upset, and dose-related
`phototoxic effects , 35 sequelae that ad-
`versely influence the use of these doses in
`the treatment of acne.’
`Pioneering work in the 1980s with
`minocycline(cid:176) and other chemically modi-
`fied tetracyclines’ led to the discovery that
`these compounds could inhibit matrix me-
`
`talloproteinases (MMPs) and down-
`regulate connective tissue destruction in
`inflammatory diseases independent of their
`antimicrobial activity.’ More recent work
`has confirmed this therapeutic potential
`in studies of subantimicrobial-dose (SD)
`doxycycline (20 mg) administered twice
`daily for 2 weeks to 18 months in the treat-
`ment of chronic adult periodontitis. 81
`
`See also page 467
`
`Doxycycline was chosen for these stud-
`ies over the other tetracyclines because it
`is well absorbed, has a favorable safety pro-
`file, and is a more potent inhibitor of the
`collagenases associated with inflamma-
`tion.’ Adverse effects and the emergence
`of tetracycline-resistant organisms were
`not observed in the early studies,"(cid:176) and
`these initial investigations led to long-
`
`(REPRINTED) ARCH DERMATOI../VOL 139, APR 2003 (cid:9)
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`

`

`1.4 (cid:9)
`
`1.2 (cid:9)
`
`U 20 mg Twice Dailyj
`50 mg Daily
`
`Minimum Antimicrobial Level
`
`0 (cid:9)
`
`2 (cid:9)
`
`4 (cid:9)
`
`0 (cid:9)
`
`14 (cid:9)
`16 (cid:9)
`10 (cid:9)
`12 (cid:9)
`8 (cid:9)
`Hours After Administration
`Figure 1. Steady-state doxycycline plasma concentrations. Administration of
`20 mg of doxycycline hyclate twice daily to healthy adults resulted in
`concentrations well below the minimum antimicrobial level.
`
`18 (cid:9)
`
`20 (cid:9)
`
`22 (cid:9)
`
`24
`
`lagenase and MMP-8). 8 ’8 However, it is not known
`whether these anti-inflammatory properties of tetracy-
`clines are sufficient by themselves to manage the clini-
`cal signs and symptoms of acne. Therefore, we con-
`ducted a placebo-controlled clinical trial to evaluate the
`effectiveness of twice-daily SD doxycyclirie treatment in
`acne. This trial represents the first acne treatment study
`in which the anti-inflammatory effects of a tetracycline
`have been studied independent of its antimicrobial effect.
`
`The present study is a multicenter, double-blind, randomized,
`placebo-controlled, parallel-group trial conducted at the Uni-
`versity of Florida in Gainesville and the West Virginia Univer-
`sity School of Medicine in Morgantown. Patients qualified for
`the study if they were 18 years or older and had moderate fa-
`cial acne, defined by the total count of noninflammatory le-
`sions (6-200 comedones) and inflammatory lesions (10-75 pap-
`ules and pustules and <5 nodules).
`No topical acne treatments or systemic antibiotics were
`permitted during the 6 weeks preceding the trial period. Dur-
`ing the study, use of penicillin, other tetracycline antibiotics,
`or any acne treatment was not permitted, nor was use of sulfa
`drugs, erythromycin, cephalosporins, quinolones, or nonste-
`roidal anti-inflammatory drugs for more than 14 days. Pa-
`tients who had isotretinoin treatment must have discontinued
`use 6 months prior to the start of the study. Patients were not
`permitted to use a hormonal method of contraception 6 months
`before the start or during the course of the study.
`Medical history and patient and physician assessments of
`severity of acne were taken, numbers and types of acne lesions
`were noted, and microbiological samples, vital signs, and stan-
`dard clinical laboratory test results were evaluated for each pa-
`tient at the baseline visit. Patients were randomized to receive
`either a tablet containing 20 mg of cloxycychine hyclate or a
`matching placebo tablet and were instructed to take 1 tablet in
`the morning and 1 in the evening.
`Patients returned to the clinic for evaluation 2, 4, and 6
`months after the baseline visit. At each of these visits, num-
`bers and types of lesions were evaluated, and patient and phy-
`sician assessments were recorded. Vital signs and adverse events
`were also evaluated at each visit, and drug compliance was re-
`viewed. Clinical laboratory and microbiological samples were
`obtained at the 6-month visit. Telephone calls were made to
`each patient at i-month intervals between visits to assess drug
`compliance and the patient’s general well-being.
`
`EFFICACY AND SAFETY EVALUATIONS
`
`The primary efficacy parameters were percent change from base-
`line in the Counts of inflammatory lesions (papules, pustules,
`and nodules), noninflammatory lesions (open and closed corn-
`edones), and total lesions (inflammatory plus noninflammatory).
`The secondary efficacy parameters were the change from base-
`line of individual counts of papules, pustules, and nodules; cli-
`nician global assessment score; and patient self-assessment score.
`The assessment scale used by physician and patient alike at base-
`line was as follows: 1, clear or almost clear skin (>90%); 2,
`moderately clear skin (>80% but <90%); 3, fairly clear skin
`(>70% but <80%); 4, acne covered about 50% of the face; 5,
`fairly severe acne (>70% but <80% coverage); 6, moderately
`severe acne (>80% but <90% coverage); 7, severe acne, with
`almost total coverage (>90%). At the follow-up visits, the fol-
`lowing assessment scale was used: 1, clear (100%); 2, almost
`clear (90% to <100%); 3, marked improvement (75% to <90%);
`4, moderate improvement (50% to <75%); 5, fair improve-
`
`term, randomized, placebo-controlled, multicenter,
`double-blind clinical trials, which led to the approval, in
`1998, of twice-daily SD doxycycline administration (Perio-
`stat; CollaGenex Pharmaceuticals Inc, Newtown, Pa) as
`an adjunct in the treatment of chronic adult periodon-
`titis." The postulated mechanism of action of SD doxy-
`cycline is down-regulation of the inflammatory host re-
`sponse characteristic of adult periodontitis through
`inhibition of multiple proteinases and cytokines, includ-
`ing MMP-8, MMP-13, MMP-9, interleukin (IL) 13, and
`tumor necrosis factor a (TNF-a).
`8
`We chose the twice-daily SD doxycycline hyclate be-
`cause it provided the maximum dose that achieved plasma
`concentrations consistently well below those required for
`an antimicrobial effect, t2 resulting in mean maximum and
`average steady-state plasma concentrations of 0.79 pg/mL
`and 0.48 pg/mL, respectively, after 1.5 hours (Figure 1), "
`thereby avoiding the emergence of resistant organisms,
`yet retaining efficacy in treating periodontitis. This pos-
`tulate has been confirmed in extensive studies of the oral,
`gastrointestinal, genitourinary, and skin microflora treated
`with SD doxycychine administered twice daily for 6 to 18
`months; findings in these studies showed no reductions
`in the microflora, no development of resistant organ-
`isms, and no cross-resistance to 6 commercially avail-
`able antimicrobial agents.’ t ’3
`It is believed that elevated host collagenolytic ac-
`tivity, induced by infection of the periodontal pocket with
`various periopathogenic bacteria, is responsible for the
`rapid destruction of host connective tissue and bone that
`leads to the clinical signs and symptoms of periodonti-
`tis. 1415 Similarly, in inflammatory acne, the resident or-
`ganism Propionibacteriusn acnes proliferates in an abnor-
`mal environment (the microcomedo) and causes
`inflammation by metabolizing sebum, recruiting infil-
`trating neutrophils, and inducing the production of a va-
`riety of proinflammatory cytokines.
`It has been postulated that the effect of doxycy-
`dine and other tetracyclines on acne maybe due not only
`to an antimicrobial effect but also to the drug’s ability to
`inhibit P acnes(cid:151)derived lipase (thus reducing free fatty
`acid levels in the follicle) 16,17 and down-regulate IL- 13
`and TNF-a (which potentiate the inflammatory path-
`way and lead to further recruitment of cellular compo-
`nents, such as polymorphonuclear leukocyte(cid:151)derived col-
`
`(REPRINTED) ARCH DERMATOL! VOL 139, APR 2003
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`
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`
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`(cid:9)
`

`

`Table 1. Target Microorganisms, Media, Incubation Conditions, and Confirmatory Tests
`for the Recovery and Enumeration of Microorganisms From the Surface of the Skin
`
`Target Microorganisms
`Total anaerobic organisms
`Total facultative organisms
`Total doxycycline-resistant
`organisms (anaerobic)
`Total doxycycline-resistant
`organisms (facultative)
`Prop/on/bacterium acnes
`Enterics
`Staphylococcus species
`Streptococcus species
`
`Medium
`Trypticase soy blood agar
`Trypticase soy blood agar
`Trypticase soy blood
`agar/doxycycline
`Trypticase soy blood
`agar/doxycycline
`Trypticase soy blood agar
`IviacConkey agar
`Mannitol salt agar
`Mitis-Salivarius agar
`
`Gram-positive rods
`
`Trypticase soy blood agar
`
`Incubation Conditions
`Anaerobic, 37(cid:176)C, 5-7 d
`10% carbon dioxide, 37(cid:176)C, 3-5 d
`Anaerobic, 37(cid:176)C, 5-7 d
`
`10(cid:176)Io carbon dioxide, 37(cid:176)C, 3-5 d
`
`Anaerobic, 37(cid:176)C, 5-7 d
`Aerobic, 37(cid:176)C, 2-3 d
`Aerobic, 37(cid:176)C, 2-3 d
`Aerobic, 37(cid:176)C, 2-3 d
`
`Anaerobic, 37(cid:176)C, 5-7 d, and 10%
`carbon dioxide, 37(cid:176)C, 3-5 d
`
`Confirmatory Tests
`
`None
`None
`None
`
`None
`
`Colonial and cellular morphology
`Colonial and cellular morphology
`Colonial and cellular morphology
`Colonial and cellular
`morphology, hemolysis
`Colonial and cellular
`morphology, gram stain
`
`rnent (25% to <50%); 6, no change; 7, worse. Safety was as-
`sessed by comparing adverse events recorded during the course
`of the study and comparing clinical laboratory values at base-
`line and at the end of the study.
`
`MICROBIOLOGICAL EVALUATIONS
`AND SAMPLE COLLECTION
`
`The microbiological objectives of the study were to determine
`whether twice-daily SD doxycycline therapy (1) had any de-
`tectable antimicrobial effect on the normal skin flora; (2) led
`to overgrowth or colonization of the skin by opportunistic patho-
`gens; or (3) resulted in an increase in antibiotic resistance in
`the predominant skin microflora. Microbial samples of the sur -
`face of the skin were collected from a 2-cm 2 area in the center
`of the brow at baseline and after 6 months of treatment. The
`sample was collected by placing a 2-cm’ template over the gla-
`bella and gently rubbing a sterile cotton swab over the area.
`The swab was placed in a tube containing 1.0 mL of pre-
`reduced, anaerobically sterilized Ringer solution and immedi-
`ately transported to the laboratory for processing.
`
`SAMPLE PROCESSING
`
`The sample was plated on nonselective media to determine the
`total number of anaerobic and facultative bacteria. The micro-
`bial media used are listed in Table 1, along with incubation
`conditions and confirmatory tests for the target microorgan-
`isms. Total anaerobic counts and total facultative counts were
`determined from the plate dilutions that gave rise to 30 to 300
`colony-forming units. For all other media, colony counts were
`taken from plates with 30 to 300 colony-forming units. If there
`were fewer than 30 colonies on the most diluted plate, the ac-
`tual number of colonies was counted.
`The sample was also plated on the same nonselective me-
`dium containing 4 pg/mL of doxycycline for the isolation of
`doxycycline-resistant bacteria. The number of anaerobic bac-
`teria and the number of facultative bacteria resistant to at least
`4 pg of doxycycline were determined and expressed as a per-
`centage of the total for each organism. These isolates were iden-
`tified by genus and species if possible and then tested for sus-
`ceptibility to 6 antibiotics (doxycycline, minocycline,
`tetracycline, erythromycin, clindamycin, and vancornycin) by
`agar dilution. The results were reported as the minimal inhibi-
`tory concentration (MIC) required to inhibit visible growth on
`the agar medium. An MIC to inhibit 50% of the colony’s growth
`and one to inhibit 90% were calculated for all bacterial organ-
`isms for each group at each sample period.
`
`STATISTICAL ANALYSIS
`
`Individual changes from baseline lesion counts were found to
`be nonnormal]y distributed; therefore, nonparametric analy-
`ses of variance were performed on rank-transformed changes
`from baseline counts. The ranked percent change from base-
`line count was also analyzed for the 3 primary lesion param-
`eters: total inflammatory lesions, total comedones (noninflam-
`matomy), and total lesions (inflammatory plus noninflammatory).
`This was considered the preferred analysis for these param-
`eters because it adjusted for the high individual variation ob-
`served at baseline.
`Clinical global assessment and patient self-assessment
`scores, which were based on ordinal scales, were analyzed non-
`parametrically. The proportions of patients who experienced
`one or more adverse event in each body system were com-
`pared between study groups using 2-tailed Fisher exact tests.
`Clinical laboratory data were analyzed using x2 statistics ap-
`plied to shift tables.
`Microbiological data were analyzed using the unpaired
`test. If the data did not follow a normal distribution, the non-
`parametric Mann-Whitney test was used to avoid the bias of
`outliers. Differences within groups were evaluated using a paired
`test or a rank sum test.
`
`PATIENTS
`
`A total of 51 adults with moderate facial acne were
`enrolled in the study; 26 were randomly assigned to
`receive 20 mg of doxycycline hyclate twice daily and 25
`to receive placebo. Patients were approximately equally
`divided between the sexes, with 25 men and 26 women;
`however, men accounted for 68% (n=17) of the pla-
`cebo group and 31% (n=8) of the doxycycline group.
`Most of the patients (35/51; 69%) were white, with the
`remaining patients of Asian, African, and Hispanic
`ancestry. The mean age was 23 years, with a range from
`18 to 37 years. Forty patients completed the 6 months
`of treatment, 21 in the doxycycline group and 19 in the
`placebo group. Of the 11 patients who discontinued
`treatment, 5 were lost to follow-up, 4 used concomitant
`medications prohibited by the protocol, and 2 had
`adverse events (1 bleeding ulcer and 1 recurring yeast
`infection).
`
`(REPRINTED) ARCH DERMATOLI VOL 139, APR 2003
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`

`Table 2. Summary Lesion Counts at 6 Months*
`
`P
`Valuet
`
`.04
`
`<.01
`
`51.00 (8.08)
`45.58 (4.59)
`-5.42 (7.84)
`-10.6
`
`Parameter
`
`Baseline
`Month 6
`Change from baseline
`Change from baseline, %
`
`Baseline
`Month 6
`Change from baseline
`Change from baseline, %
`
`Doxycycline Group Placebo Group
`(n = 19)
`In = 21)
`Total Inflammatory Lesions
`27.37 (4.54)
`31.38 (4.32)
`19.11 (2.89)
`1567 (2.75)
`-8.26 (4.07)
`-15.71 (3.87)
`-30.2
`-50.1
`Total Comedones
`54.95 (7.69)
`25.48 (4.37)
`-29.48 (7.46)
`-53.6
`Total Lesions
`86.33 (10.54)
`41.14 (5.86)
`-45.19(9.93)
`-52.3
`
`Baseline
`Month 6
`Change from baseline
`Change from baseline, %
`
`78.37 (11.08)
`64.68 (6.16)
`-13.68 (10.44) <.01
`-17,5
`
`(SE) number of lesions.
`*Unless otherwise indicated, data are mean
`tPvalue from ranked percentage change from baseline.
`
`EFFICACY
`
`There were no significant differences between the 2 study
`groups in any efficacy parameter at baseline. The mean
`change (reduction) in total inflammatory lesions from
`baseline to the end of treatment (6 months) was 50% in
`the doxycycline group and 30% in the placebo group
`(P=.04) (Table 2; Figure 2). There was a consistent
`reduction in lesion count in the doxycycline group over
`the course of the study, with clinically relevant mean re-
`ductions of 24% and 36% at 2 and 4 months, respec-
`tively, compared with an inconsistent clinical response
`in the placebo group, which had a mean increase of 9%
`at 2 months and a reduction of 29% at 4 months.
`The mean reduction in the number of coonedones
`from baseline to the end of treatment was 54% in the doxy-
`cycline group compared with 11% in the placebo group
`(P<.01). There were clinically relevant mean reduc-
`tions of 25% and 32% in the doxycycline group at 2 and
`4 months, respectively, compared with a mean increase
`of 2% at 2 months and a mean reduction of 24% at 4
`months in the placebo group.
`In the number of all lesions combined, the mean re-
`duction from baseline to the end of treatment was 52%
`in the doxycycline group and 18% on the placebo group
`(P<.01). There were clinically significant mean reduc-
`tions of 25% and 33% in the doxycycline group at 2 and
`4 months, respectively, compared with a mean increase
`of 4% at 2 months and a mean reduction of 26% at 4
`months in the placebo group.
`At baseline, the clinician’s global assessment and pa-
`tient self-assessment scores for both study groups showed
`that acne covered approximately 50% of the face on av-
`erage. The clinician’s global assessment scores improved
`in both groups over time, with mean scores in the doxy-
`cycline group of 5.5, 5.0, and 4.4 at 2, 4, and 6 months,
`respectively, compared with 5.8, 5.4, and 5.1 in the pla-
`cebo group. A score of 4 indicated moderate improve-
`ment (50% to <75%) and 5 indicated fair improvement
`
`P=.04
`
`Inflammatory
`Lesions
`
`P<.01
`
`Camedones
`
`-52.3/c
`
`P<.01
`
`Camedones and
`Inflammatory Lesions
`
`Fm DocycIine Hyclate, 20 mg Twice Oaily
`
`Placebo
`
`]
`
`Figure 2. Mean percent decrease from baseline to 6 months in the total
`number of comedones, inflammatory lesions, and all lesions combined.
`
`(25% to <50%). At 6 months, the scores in the doxycy -
`dine group were significantly better than in the placebo
`group (P=.03). The pattern of improvement was similar
`with the patient self-assessments, with mean scores in the
`doxycycline group of 5.4,4.9, and 4.8 at 2,4, and 6 months,
`respectively, compared with 5.5, 5. 1, and 5.3 in the pla-
`cebo group. The differences in these scores between the
`study groups were not statistically significant but consis-
`tently trended toward improvement in the treatment group.
`
`MICROBIOLOGICAL FINDINGS
`
`There were no statistically significant differences be-
`tween or within the groups from baseline to 6 months
`in microbial colony counts, indicating that there was no
`change in the composition of the normal skin flora
`(Figure 3). Antibiotic susceptibility testing showed no
`differences between or within the study groups in the
`MICs obtained for doxycycline. There were no strong
`correlations between resistance to doxycycline and re-
`sistance to any of the 5 other antibiotics tested. The stron-
`gest correlation was between erythromycin and clinda-
`mycin resistance (r=0.5 to <0.70). This was expected
`because most bacteria that are resistant to clindamycin
`are also resistant to erythromycin. Moderate correla-
`tions (r=0.5) were detected between doxycycline and both
`tetracycline and minocycline in some instances. Again,
`this was expected because many bacteria with resis-
`tance to one tetracycline are frequently resistant to the
`others and also because of the carriage of tetracycline-
`9 There
`resistant genes coding for ribosomal protection.’
`were no differences between the correlation coefficients
`for cross-resistance in the doxycycline 6-month samples
`and either the placebo 6-month samples or the doxycy-
`dine baseline samples.
`
`SAFETY
`
`Doxycycline and placebo were equally well tolerated.
`Treatment-emergent adverse events were reported for 12
`patients (46%) in the doxycycline group and 8 patients
`(32%) in the placebo group. The most frequently re-
`ported adverse events were influenza in 3 patients in the
`
`(REPRINTED) ARCH DERMATOL/VOL 139, APR 2003
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`
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`

`

`Figure 3. Mean number of target organisms at baseline (BL) and after 6 months of treatment with placebo or 20 mg 01 doxycycline flyclate twice daily.
`
`doxycycline group, headache in 3 patients in the pla-
`cebo group, and rash in 2 patients in the doxycycline
`group. No other adverse event was reported for more than
`1 patient in either treatment group. Most of the adverse
`events were mild or moderate. Prior to the data being un-
`blinded, events considered possibly related to the study
`medication were heartburn and vaginal yeast infection
`in the doxycycline group and headache, heartburn, and
`stomach upset in the placebo group.
`Two patients, both in the doxycycline group,
`dropped out of the study because of adverse events. One
`patient experienced 2 episodes of gastrointestinal bleed-
`ing and was diagnosed with a gastric ulcer during the
`study; these events were not considered to be related to
`the doxycycline administration. Another patient, who had
`a history of recurrent vaginitis, reported an episode of
`vaginitis during treatment. Although independent con-
`firmation of yeast vaginitis was not obtained, the vagi-
`nitis was considered related to treatment because of the
`temporal relationship to administration of the study drug.
`There were no notable changes in vital signs, which
`were assessed at each study visit. Laboratory evaluations
`after 6 months of treatment showed clinically significant
`changes for 3 patients: low hemoglobin and hematocrit
`values and a low red blood cell count in 1 woman treated
`with doxycycline; and elevated liver function findings (ala-
`nine arninotransferase, aspartate aminotransferase, and lac-
`tate dehydrogenase) in 2 patients given placebo.
`
`Early studies demonstrating the effectiveness of treat-
`ment with SD doxycycline (Periostat) adminstered twice
`
`daily as an adjunct in the treatment of chronic adult pen-
`odontitis paved the way for further research on this dos-
`20 This regimen is now well ac-
`ing regimen for acne .
`cepted and consistent with recommendations from the
`Food and Drug Administration and the Centers for Dis-
`ease Control and Prevention that subtherapeutic anti-
`microbial doses, such as 50 mg of doxycycline adminis-
`tered once daily, should be avoided because they increase
`the likelihood that resistant microorganisms will emerge.
`The pharmacokinetic profile of SD doxycycline admin-
`istered twice daily shows that plasma concentrations re-
`main well below antimicrobial levels. In addition, long-
`term doxycycline therapy at this dosage resulted in fewer
`adverse events such as gastrointestinal upset, vaginitis,
`and phototoxic effects than have been reported with higher
`doxycycline doses.
`The present study shows that SD doxycycline ad-
`ministered twice daily for 6 months in patients with mod-
`erate inflammatory acne resulted in a greater than 50%
`reduction in the number of total lesions (inflammatory
`plus noninflammatory) and a similar reduction in the
`number of cornedones and inflammatory lesions mea-
`sured independently. Treatment with SD doxycycline
`twice daily had no effect on P ctcnes or other microflora
`of the skin, and there was no change in the composition
`of the normal skin flora. The treatment did not result in
`the emergence of organisms resistant to doxycycline or
`cross-resistance to commercially available antimicro-
`bial agents, including vancomycin. There was no in-
`crease in the proportion of flora resistant to doxycy -
`dine, nor was there an increase in MIC values for bacteria
`resistant to 4 pg/mL of doxycycline. There was no evi-
`dence of development of cross-resistance between doxy-
`
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`cycline and related or unrelated antibiotics. Although the
`present study only evaluated the microflora of the skin,
`previous studies of the microllora of the oral cavity
`and the gastrointestinal and genitourinary tracts using
`twice-daily administrations of 20 mg of doxycycline and
`matching placebo over 6 to 18 months demonstrated no
`differences between groups in the quantity and types
`of flora recovered at any time point, no evidence for
`the development of tetracycline-resistant organisms, and
`no evidence of the development of cross-resistance to
`6 commercially available antimicrobial agents.
`1113
`In studies of periodontitis, SD doxycycline adminis-
`tered twice daily has been shown to significantly inhibit
`polymorphonuclear leukocyte-derived collagenase
`(MMP-8) and the generation of inflammatory cytokines,
`thereby preventing the tissue destruction induced by the
`inflammatory response to the periodontal infection. Simi-
`larly, doxycycline’s effect on inflammatory acne lesions may
`be due to its inhibition of IL-6, IL-1 P, and TNF-a, inflam-
`matory cytokines up-regulated in response to P acnes. In
`turn, this inhibits the inflammatory pathway that leads
`to further recruitment of cellular components, such as
`neutrophils and their proteolytic enzymes, for example,
`MMP-8. 2122 Furthermore, by down-regulating P acnes
`lipase, doxycycline can reduce the virulence of this or-
`ganism, reducing the levels of free fatty acids that act as a
`7
`potent chemokine for neutrophil recruitment.
`The observation in the present study that SD doxy-
`cycline administered twice daily reduced comedone
`counts by greater than 50% was not anticipated. Com-
`edonal acne is believed to result from the up-regulation
`of kertainocyte proliferation and sloughing, which re-
`sults in the blockage of the sebaceous gland by keratin
`and cellular debris. It is postulated that these changes are
`mediated through the up-regulation of IL-1, and it is pos-
`sible that this activity is also suppressed by SD doxycy-
`dine administered twice daily .13
`In conclusion, this is the first placebo-controlled
`trial of SD doxycycline treatment administered twice
`daily for acne and the first to show that the nonantimi-
`crobial properties of doxycycline are effective and suffi-
`cient in controlling and improving the clinical signs
`and symptoms of acne without any effect on the skin
`flora. Twice-daily treatment with SD doxycycline for
`adults with moderate facial acne for 6 months signifi-
`cantly reduced the number of acne lesions, was well tol-
`erated, had no detectable antimicrobial effect on the
`cultivable skin flora, and did not result in the emer-
`gence of resistant organisms.
`
`Accepted for publication October 8, 2002.
`This study’s research received financial support from.
`CollaGenex Pharmaceuticals Inc.
`Drs Skidmore, Walker, Thomas, and Leyden are 011 the
`Scientific Advisory Board of ColiaGenex and have received
`consulting fees for their work in this capacity. Dr Brad-
`shaw has received consulting fees from CollaGenex. Messrs
`Powala and Ashley are employees of CollaGenex.
`
`This study was presented in part by Dr Skidmore as a
`poster, titled "Effects of Su ban tinticrobaal-Dose Doxycy-
`dine Hyclate in the Treatment of Moderate Acne," at the
`summer meeting of the American Academy of Dermatol-
`ogy, New York, NY, August 1-4, 2002.
`Corresponding author and reprints: Robert Skidmore,
`MD, Division of Dermatology, Department of Medicine, 1601
`SWArcher Rd, UF-VA Educational Building, No. 125, Gaines-
`ville, FL 32608 (e-mail: sizithnra@medicine.ujl.edu).
`
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