Adolfo C. Fernandez-Obregon, MD

Abstract

Background Acne affects a large number of young adults, including women, who often present with facial as well as truncal involvement. Systemic antimicrobial agents currently used for the reduction of inflammatory papules and cysts require frequent administration and are sometimes associated with uncomfortable side-effects contributing to a decrease in compliance.

Methods Ninety-nine episodes of inflammatory acne in 79 patients treated with oral antimicrobial agents were studied retrospectively over a period of 46 weeks. Patients were treated with tetracycline, erythromycin, minocycline, and doxycycline, the most commonly prescribed oral antimicrobials used to treat acne. Individuals that were unable to tolerate this therapy or had failed conventional therapy were treated with the azalide antibiotic azithromycin (Zithromax), given in a single oral 250-mg dose three times a week. The other agents were administered daily in divided doses as is current practice. Patients were also on topical care.

Results The efficacy and reported side-effects were examined for all agents. Significant improvement was noted in 4 weeks. All agents were effective in reducing inflammatory lesions and improving acne. Azithromycin produced a slightly higher percentage of patients with a greater than 80% reduction in their inflammatory acne lesions (85.7%) vs. an average of 77.1% for all other agents. All differences observed were not statistically significant.

Conclusions The results show that azithromycin is a safe and effective alternative in the treatment of inflammatory acne with few side-effects and good compliance, and suggest the need for further investigation with a clinical trial that will compare the long-term efficacy and tolerability.

Acne affects a large proportion of young adults, especially women, and remains to this day a major cause of visits to the physician’s office.1 In spite of efforts to regard it as a minor ailment, acne patients call for attention. Effective treatment is essential to prevent facial deformity and to deter psychologic and physical scarring.2 Systemic antimicrobial therapy, generally required to reduce inflammatory papules and cysts, often leads to uncomfortable side-effects, including gastrointestinal symptoms, headaches, and vulvo-vaginal candidiasis. For more than 30 years, oral broad-spectrum antibiotics, such as tetracyclines and macrolides, have been used for the treatment of inflammatory acne without an officially approved indication.3’4 Because the short half-life of commonly prescribed antimicrobials necessitates administration several times a day, an agent has been sought whose prolonged mode of action would permit less frequent dosage and thus improve compliance. Such women, and remains to this day a major cause of visits to the physician’s office.1 In spite of efforts to regard it as a minor ailment, acne patients call for attention. Effective treatment is essential to prevent facial deformity and to deter psychologic and physical scarring.2 Systemic antimicrobial therapy, generally required to reduce inflammatory papules and cysts, often leads to uncomfortable side-effects, including gastrointestinal symptoms, headaches, and vulvo-vaginal candidiasis. For more than 30 years, oral broad-spectrum antibiotics, such as tetracyclines and macrolides, have been used for the treatment of inflammatory acne without an officially approved indication.3’4 Because the short half-life of commonly prescribed antimicrobials necessitates administration several times a day, an agent has been sought whose prolonged mode of action would permit less frequent dosage and thus improve compliance. Such an agent, in addition, should be safe, cost-effective, well tolerated, and, naturally, effective in the treatment of acne.

Macrolide antimicrobials (like erythromycin) have a wide spectrum of activity against a number of important microbial pathogens and are well absorbed orally.5 Azithromycin, the first azalide antibiotic, is a 9-methyl derivative of erythromycin that effectively inhibits significant intracellular pathogens as well as Gram-positive and Gram-negative aerobic and anaerobic bacteria.5,6 The drug has been used successfully in the treatment of upper and lower respiratory and soft-tissue infections, as in nonspecific urethritis and cervicitis secondary to Chlamydia trachomatis,5,6 in urethritis and cervicitis due to Neisseria gonorrhoeae, chancroid in males due to Haemophilus ducreyi, and as prophylaxis for Mycobacterium avium complex disease in people with human immunodeficiency virus (HIV) infection. Azithromycin shows affinity for inflammatory tissue, and demonstrates activity against

 

 

many anaerobic species, including Propionibacterium acnes, which is inhibited in vitro at minimum inhibitory concentrations for 90% of isolates of 0.15 |g/mL or less.⁵ Unlike other systemic antimicrobials, azithromycin has a singular pharmacokinetic profile that enables it to move rapidly from blood to tissues, where it remains for pro­longed periods at levels that are higher than the minimum inhibitory concentration for many common pathogens.⁶ The drug has an average terminal half-life of 68 h.⁷ Its ability to penetrate into eukaryotic and prokaryotic cells may be responsible for its expanded spectrum of activity.⁶ Also, unlike other macrolides, it produces fewer gastrointes­tinal side-effects.⁷ Because of azithromycin’s in vitro activ­ity, unique penetration in tissues, long terminal half-life, and safety profile, its use in treating inflammatory acne deserves evaluation. Successful use of azithromycin for the treatment of acne has been reported previously.⁸

Methods

Ninety-nine episodes of inflammatory acne in 79 patients (22 males and 57 females; aged 13-48 years) were treated with a variety of antimicrobials (see Table 1).

Patients selected to receive azithromycin were derived from a population of private practice outpatients, and had shown poor results with previous regimens. This was due to either poor compliance or having experienced undesirable side-effects with other antimicrobials (head­aches, vertigo, nausea, diarrhea, or candidal vaginitis). In some cases, an associated medical condition, such as dermatitis, favored the use of a macrolide. Efficacy was described clinically, and thus was not uniformly quantit- ated. Although no grading scale was used to measure the severity of acne, every patient treated had inflammatory acne with a minimum of 12 lesions (papule, pustule, or cyst). Some patients were rotated through different oral agents (always only one agent at a time). Excluded from the study were patients who failed to return for follow-up to determine efficacy and verify adherence to the specified treatment. Compliance to the regimen was examined at every patient encounter. If a dose of a specific agent needed to be reduced due to side-effects, the observations were reported, and the lower dose was utilized for the purpose of estimating efficacy. Most patients were also on topical care. Patients were encouraged to stay on their initial topical treatment whenever possible. An initial topical agent was used in 81 episodes. Combinations were used in 31 episodes. In 18 episodes, no topical agents were used. By far the most commonly used topical agent was tretinoin gel (59 episodes). As there was relative uniformity in the topical agent used, results observed could be more readily associated with the oral antimicrobial under review.

Results

Ninety-nine episodes of inflammatory acne in 79 patients (22 males and 57 females; aged 13-48 years) were treated with azithromycin, cefuroxime, doxycycline, erythromycin, minocycline, and tetracycline (Table 2). The difference in the numbers of males and females reflected the available clinic population. Thirty-one episodes were treated with more than one oral agent because of failure of the initial therapy. Each patient took an average of 16 antibiotic doses per week (with the exception of those patients on azithromycin, who took only three). No adjunctive topical therapy was used in 18 episodes because of a lack of tolerability. Other topical agents used included erythromy- cin, clindamycin, benzoyl peroxide, and sodium sulface- tamide.

Efficacy, defined as the percentage reduction in lesions and by the duration of treatment before a reduction in lesions was achieved, was approximately the same for all oral agents used, with an average of 77.1% reduction in the inflammatory lesions (see Table 2). Azithromycin taken three times a week was as effective as other agents requiring frequent daily doses. The use of azithromycin produced a higher percentage of patients with a greater than 80% reduction in their inflammatory acne lesions (85.7%) as shown in Table 3. Table 4 shows the average duration of treatment with the antibiotics used in this study. The differences observed were not statistically significant. The average treatment period for all patients was 9.75 weeks. Figures 1-4 show the results of treatment in four patients.

 

Table 5 lists the reported side-effects. Only one case of vaginitis (5.5%) was reported with the use of azithromycin, which may be due to the concomitant use of an additional antibiotic prescribed by another physician. Four cases of gastrointestinal discomfort (14.3%) experienced by patients on azithromycin were mild and transient from the patient’s own description. They were self-limited with a tendency to disappear with ongoing use. In contrast, the tetracycline group showed a 20% rate of vaginitis. Erythromycin showed a 25% incidence of gastrointestinal side-effects, while doxycycline-treated patients exhibited a 20% incid­ence. Finally, minocycline showed a 17% incidence of central nervous system side-effects (headache and lightheadedness).

Discussion

In the patients described here, azithromycin was safe and effective, with minimal side-effects and a reduced likelihood of the uncomfortable reactions often associated with oral antimicrobial therapy in women. No pharmacokinetic drug-drug interactions have been observed in trials studying the concomitant use of azithromycin and other medications, including terfenadine and theophylline.^9-12 The unique pharmacokinetics of azithromycin make it a highly suitable agent for the treatment of acne. Significant intracellular concentrations of azithromycin find their way to body sites where inflammatory cells are present, allowing the delivery of the effective agent at the focal point at which it is needed. This explains the long tissue half-life and the prolonged activity of azithromycin. Whether its action is mediated through antimicrobial activity or through some anti-inflammatory action is left to speculation, as in the case of the other antimicrobials used in the treatment of acne. In this study, patients treated with azithromycin, by virtue of their selection, constituted a group of acne sufferers with an expected resistance to conventional agents, as many had already failed standard treatment or experienced undesirable side-effects from previous therapy. By virtue of the study design, it was impossible to standardize the topical agent used. It was also impossible to determine if the distribution of the agents used had a direct effect on the outcome observed. Most patients, however, received tretinoin gel topically, and no single antimicrobial per­formed significantly better than the others. It was not expected that azithromycin would perform as well as it did in this limited study. Within 3-4 weeks of starting antimicrobial treatment, substantial improvement was noted in facial acne. The azithromycin group did at least as well as patients on other antimicrobials, although several azithromycin patients had previously done poorly on other, more established agents.

Compliance in the azithromycin group was not a prob­lem, and, not surprisingly, better than that with the other antimicrobials. One patient experienced vaginitis, which may have been due to an additional oral antibiotic pre­scribed by another physician and taken concurrently. In other patients, mild gastric distress, which developed shortly after azithromycin therapy was begun, was self- limited and unnoticeable after 3 weeks of treatment. Women taking azithromycin generally experienced signi­ficantly less likelihood of developing vulvovaginal vaginitis than for most of the other agents studied. All patients found azithromycin easy to take, and all but one found it effective in controlling their acne. This study looked at a relatively small number of patients in some of the groups. The results observed are not statistically significant and cannot be conclusive due to the design, small number of patients, and other variables that could not be controlled blindly. A large double-blind clinical trial is needed to compare effectively the strength of this new agent in the treatment of acne.

In this substantially young adult population with inflammatory acne, regardless of anatomic location, con­ventional antimicrobial therapy reduced inflammatory lesions by nearly 80%. In contrast, use of the new macrolide azithromycin led to a slightly higher than 80% improve­ment with good compliance, although this difference was not statistically significant. Side-effects, which were mild to moderate in nature, were seen in a total of 24% (24 out of 99 episodes) of patients taking all medications. Controlled clinical trials to assess long-term effectiveness and tolerability are needed.

Acknowledgment

Supported in part by an unrestricted educational grant from Pfizer, Inc.