IntroductionAcne vulgaris is a common skin disease,

seen primarily in adolescents and youngadults. Effective treatment is essential toprevent physical and psychological scarring;acne is frequently associated with profoundemotional aspects. Currently, broad-spec-trum antibiotics, primarily tetracycline or itsderivatives, are widely used in the treatmentof acne. Oral eythromycin, a macrolide an-tibiotic, was shown to be as effective as tetra-cycline in a double blind study (1). Howev-er, there is increasing evidence of develop-ment of erythromycin resistant strains of P.

acnes from both the topical and systemicuse of erythromycin (2). Because the treat-ment involves long-term therapy with theseantimicrobials, an agent with a long half-lifecould be very useful in increasing the com-plicance. Azithromycin is a 9-methyl deriva-tive of erythromycin with an average termi-nal half-life of 68 hours (3, 4). In compari-son with erythromycin, azithromycin is bet-ter absorbed and is more extensively distrib-uted into tissue (5). Its unique pharmacoki-netic properties include a high concentra-tion within cells (including phagocytes) (6).These attributes result in a much greater tis-sue or secretion drug concentration com-pared to the simultaneous serum concentra-tion. To evaluate the role of monthly dosesof azithromycin and compare it with that ofdaily doxycycline in the treatment of moder-ate to severe acne, we conducted this ran-domized comparative study.

Patients and MethodsSixty patients with moderate to severe acne

(grade 2–8) on the Burke and Cunliffe scale (7)were randomly assigned to two treatment

The Journal of DermatologyVol. 28: 1–4, 2001

Original articles

Azithromycin Monthly Pulse vs Daily Doxycycline in the Treatment of Acne Vulgaris

Davinder Parsad, Roma Pandhi, R. Nagpal and K.S. Negi*

Abstract

Acne vulgaris is a common skin disease seen primarily in adolescent and young adults.As the treatment involves long term therapy with antibiotics, an agent with a long half lifecan be very useful in increasing the compliance. To evaluate the role of a monthly dose ofazithromycin and compare it with daily doxycycline, we conducted this randomized com-parative study. Sixty patients with moderate to severe acne were randomly assigned to twotreatment groups, A & B. Patients in group A received 100 mg doxycycline daily in addi-tion to topical 0.05% tretinoin cream, whereas patients in group B were given 500 mgazithromycin once a day for four days per month along with 0.05% topical tretinoin for atotal of 12 weeks. Of the 60 patients, 22 in group A and 28 in group B were evaluated. Themonthly dose of azithromycin was found to be as effective as daily doxycycline on a pureprotocol basis and statistically significantly better than doxycycline by intention to treatanalysis.

Key words: acne; azithromycin; doxycycline; treatment

Received September 4, 2000; accepted for publica-tion November 17, 2000.

Department of Dermatology, Postgraduate Insti-tute of Medical Education and Resaerch, Chandigarhand Department of Dermatology, *Department ofSPM (Biostatistics), Himalayan Institute of MedicalSciences, Jolly Grant, Dehradun, India.

Reprint requests to: Dr. Davinder Parsad, M.D.,Department of Dermatology, Venereology & Leprol-ogy, Postgraduate Institute of Medical Education andResearch, Chandigarh, 160 012, India.

Parsad et al

groups, A and B. Exclusion criteria were as fol-lows: individuals of less than 16 years of age, in-dividuals with sensitivity to any drugs used in thisstudy, females who were pregnant, planning apregnancy, or nursing a child. Patients in groupA received 100 mg doxycycline in addition totopical 0.05% tretinoin cream. Patients in groupB were given azithromycin 500 mg once a dayfor four days per month for a total of 12 weeksalong with topical 0.05% tretinoin. Efficacy eval-uations were carried out at baseline and eachscheduled visit by counting each type of facial le-sion and evaluating the global severity according

to the Leeds technique (7). Global assessmentof the improvement was evaluated for the face,chest and back (when affected) at 12 weeks.Global assessment of improvement was evaluat-ed at week 12 in comparison with the baseline,using a 4 point scale: −1=worsened (exacerba-tion in the quantitative assessment of lesions);0=unchanged (acne showed no changes); 1=im-proved (improvement in quantitative assess-

2

0

10

20

30

40

50

60

70

80

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100

Group A

Group B

1st 4th 8th 12th

Follow-up（weeks）�

% r

educ

tion

in to

tal l

esio

n c

oun

t

Fig. 1. Percentage reduction in total lesioncount on a pure protocol basis

0

10

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50

60

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80

90

1001st 4th 8th 12th

Follow-up（weeks）�%

red

ucti

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tota

l les

ion

cou

nt

Group A

Group B

p＜0.001

Fig. 2. Percentage reduction in total lesioncount on using intention to treat analysis

Table 1. Baseline patient characteristics

Group BGroup A

3012/18

228

30.6±13.439.2±14.4 3.4± 0.9

3013/17

822

28.8±12.632.6±16.2 3.0± 0.8

EnrolledSex (Males/Females)DiscontinuedCompleted studyLesion count (mean+SD)*Inflammatory*Non inflammatorySeverity Grade

Table 2. Percentage reduction in severity grade in both the treatment groups

Group BGroup A% reductionMean±S.D.

24.2± 4.2 33.4± 7.6 56.4±14.1 77.6±14.1

18.2± 3.6 31.4± 6.8 53.2±12.2 75.5±12.2

Week 1Week 4Week 8Week 12

ITT Analysis

23.2± 5.1 31.6± 7.9 53.6±14.8 75.6±13.2

17.6± 4.2 22.4± 6.8 41.7±13.2 60.2±13.8

Week 1Week 4Week 8Week 12

Azithromycin in Acne

ment of lesions); 2=clear (no lesions). Variablesof the two groups such as sex, age, duration ofdisease and the entry-level total scores were com-pared. Discrete variables were analyzed by Fish-ers Exact Test supplemented by categorical lin-ear models. The studen’s t test was used to ana-lyze the differences in means. Chi-square testwith or without Yates correction was applied. In-tention to treat analysis was also used. Intentionto treat includes all randomized patients in thegroups to which they were randomly assigned,regardless of the treatment they actually re-ceived, and regardless of subsequent withdrawalfrom the treatment on division from the proto-col. There are two reasons why one might usethis approach first; intention to treat preservesthe effect of ramdomization. Second, intentionto treat often provides an assessment of the prac-tical impact of a treatment.

ResultsOf 60 patients, 22 in group A and 28 in

group B could be evaluated (Table 1).Three patients in group A discontinuedtreatment because of intolerable side effectsof doxycycline and five patients discontin-ued for non-medical reasons (protocol vio-lation, loss to follow up etc.). Two patientsin group B discontinued because of reasonsunrelated to the study. All the patients en-rolled in the study were retained for the in-tention to treat analysis (ITT). There was nosignificant difference at baseline in diseaseseverity parameters between the two groups.

Two patients in group A complained of se-vere nausea and one developed photosensi-tivity with doxycycline and withdrew fromthe study. Two patients developed vaginitisand five complained of mild to moderategastrointestinal discomfort. Monthly dosesof azithromycin were well tolerated exceptfor patients who complained of mild andtransient gastrointestinal discomfort. Threepatients in group A and four patients ingroup B complained of mild irritation fromthe topical tretinoin application.

Efficacy results—lesion counts: Figure 1 shows the efficacy results of both

the treatments in term of percentage reduc-

tion in inflammatory as well as non-inflam-matory lesion counts. Both treatmentgroups showed reductions in lesions fromthe baseline at each evaluation time. Therewere no significant differences in the lesioncounts between the two treatment groupson a pure protocol basis. The ITT showed ahighly statistically significant decrease in le-sions in group B patients (Azithromycin)(Fig. 2).

Efficacy results—severity grade: The efficacy was also determined from

the global severity grade and is shown inTable 2. There were no significant differ-ences in the baseline severity grade. Thescores of both groups decreased from base-line to week 12 with no statistically signifi-cant differences. However, ITT showed ahighly statistically significant decrease inseverity score in the azithromycin group.

Efficacy results—global assessment of improve-ment:

Eighteen patients in group A and 23 pa-tients in group B were rated as improved;the Chi-square test and ITT indicated statis-tically significant improvement in theazithromycin group.

DiscussionThe unique pharmacokinetics of azithro-

mycin makers it a highly suitable agent forthe treatment of acne. It appears that tissuefibroblasts act as a natural reservoir for thedrug in vivo and that transfer of the drug tophagocytes is easily accomplished. Thesephagocytic cells could act as a vector for de-livering azithromycin to the site of infection.Azithromycin shows activity against manyanaerobic species, including Propionobacteri-um acnes, which is inhibited in vitro at a min-imum inhibitory concentration of 0.15µg/ml or even less for 90% of isolates.Whether its action is medicated through an-timicrobial activity or through some anti-in-flammatory activities is not yet clear. A de-crease in free fatty acid formation has beenreported with erythromycin. No pharmaco-kinetic drug-drug interactions have beenobserved in trials studying the concomitant

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Parsad et al

use of azithromycin and other medications(8, 9). Azithromycin at a dose of 250 mgthree times a week was shown to be safe andeffective in the treatment of acne in an opentrial by Fernandez-Obergon (10, 11). Simi-larly, Gruber et al. (12) compared azithro-mycin 500 mg for 4 days every 10 days withminocycline. They concluded that azithro-mycin is at least as clinically effective andwell tolerated as minocycline in the treat-ment of facial comedonic and papulopustu-lar acne. In our study a monthly dose ofazithromycin was found to be as effective asdaily doxycycline on a pure protocol basisand statistically significantly better thandoxycycline by ITT analysis.

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