Eric S. Schweiger MD – Articles

Abstract: Acne vulgaris is an extremely common disorder affecting adolescents and adults throughout their lifetimes. The pathogenesis of acne is multifactorial and is thought to involve excessive sebum, follicular hyperkeratinization, bacterial colonization, and inflammation. Many therapeutic options exist for treating acne, including topical benzoyl peroxide, topical and oral antibiotics, topical and oral retinoids, and oral contraceptives. Systemic antibodies also have anti-inflammatory and immunomodulatory properties. This article reviews the English language literature on the efficacy of various systemic antibiotics for treating acne vulgaris, including second-line and less historically used medicines. We discuss the tetracyclines, including subantimicrobial dose doxycycline, macrolides (notably azithromycin), trimethoprim-sulfamethoxazole, cephalosporins, and fluroquinolones as treatment options for acne vulgaris.

INTRODUCTION

Acne vulgaris is an extremely common disorder affecting up to 95% of the adolescent population, and virtually everyone at some point in life. It can lead to significant psychological distress and long-lasting scaring. Acne vulgaris comprises lesions of varying morphology, from comedones, papules, and pustules to nodules and cysts. The pathogcnesis of acne is multifactorial. Excessive sebum production, sebaceous follicles with abnormal epithelial hyperkeratinization, the presence of microbial organisms, notably the anaerobic diphtheroid Propionibacterium acnes (P. acnes), and inflammation are the key factors involved. Many different therapeutic options exist for treating acne, including topical benzoyl peroxide, topical and oral antibiotics, topical and oral rerinoids, and oral contraceptives.

Since the late 1950s, oral antibiotics have been a mainstay in the treatment of acne. Systemic antibiotics are frequently used in patients with 1) moderate to severe inflammatory acne, 2) acne resistant to topical medications, 3) acne with the potential to cause pigmentary changes or permanent scarring, and 4) truncal acne. The mechanism of action of oral antibiotics involves exerting an antibacterial effect by reducing the follicular colonization of P. acnes; in addition, systemic antibiotics also have various anti-inflammatory and immuno-modulatory properties. At in vivo concentrations too low to affect P. acnes proliferation, systemic antibiotics have been shown to inhibit its lipase production. This minimizes the sebum content of free fatty acids, which are both proinflammatory and comedogenic. For years, the first-line antibiotlcs have consisted of tetracycline and its derivatives, along with erythromycin. However, P. acnes resistance to erythromycin has been well-established, and its resistance to other antibiotics is gradually increasing, resulting in therapeutic failures with these classic agents. Because widespread and long-term use of antibiotics has led to the emergence of resistant bacteria, dermatologists are now increasingly forced to seek alternate treatment strategies. These include prescribing less commonly used antimicrobials, reducing the dosage or duration protocols of the commonly used antimicrobials, or resorting to different therapeutic modalities altogether (eg, phototherapy, lasers, chemical peels). This article reviews the literature on the efficacy of various systemic antibiotics for the treatment of acne vulgaris, focusing on second-line and less historically used medications (Table I). In order to appropriately select an oral antibiotic, multiple factors, such as efficacy, compliance, tolerability, cost-effectiveness, and the potential for development of bacterial resistance, should be considered.

Tetracyclines

Since tetracycline (tetracycline hydrochloride and oxytetracycline) first became available in 1953, followed by doxycycline in 1967 and minocycline in 1972, the tetracyclines have become the most commonly prescribed first-line systemic antibiotic for the treatment of acne. (Lymecycline, a second-generation tetracycline introduced in 1963, is used outside of the US for acne and will not be discussed further here.) Tetracyclines are antimicrobials that exert a bacteriostatic effect by interfering with protein synthesis on the 30S ribosomal subunit. Additionally, these agents exert anti-inflammatory properties by inhibiting chemotaxis, decreasing the formation of reactive oxygen species, inhibiting proteolytic matrix metalloproteinases, and downregulating proinf1ammatory cytokines. They also alter sebum excretion by inhibiting phospholipase A2 metabolism of arachidonic acid and P. acnes-derived lipase, resulting in a decreased accumulation of follicular free fatty acids that serve as potent chemokines for neutrophil recrultment. Tetracycline, administered in doses of 5OO mg twice daily followed by 500 mg daily, can be an inexpensive, effective, and generally safe treatment. Because the absorption of tetracycline is affected by food, dairy products, antacids, vitamins, and iron, taking it on an empty stomach is recommended. Adverse effects most commonly include gastrointestinal distress manifested as diarrhea, vomiting, dyspepsia, and, rarely, esophagitis and esophageal ulceration. Vaginal candidiasis, acneiform and fixed drug eruptions, benign intracranial hypertension, photosensitivity, and, rarely, severe cutaneous reactions such as Stevens-Johnson syndrome can also occur. Cross-reactivity is more frequent with doxycycline than with minocycline, as the former is more chemically similar. Tetracyclines should be avoided by pregnant women as they cause discoloration and enamel hypoplasia of deciduous teeth, and in children younger than 8 due to staining of the developing permanent teeth.

Doxycycline is a broad-spectrum antibiotic synthetically derived from tetracycline and is available as several different forms: doxycycline monohydrate, doxycycline hydrochlotide hemierhanolate hemihydrate, doxycycline hyclate, and doxycycline calcium (Table 2). It is more lipophilic Than tetracycline and has demonstrated excellent penetration into rhe pilosebaceous unit. lts side effect profile parallels that of tetracycline, with the exception that doxycycline is more likely to cause phororoxic reactions. For patients with gastrointestinal complaints, capsules of doxycycline in the form of enteric-coated pellets (Doryx®) may be a viable alternative. Doryx was shown to result in fewer gastrointestinal side effects when compared to capsules containing the powdered form.

With the worldwide emergence of P. acnes strains resistant to tetracyclines, recent studies have demonstrated therapeutic efficacy with doxycycline administered at doses below necessary for its antimicrobial properties. Subantimicrobial-dose doxycycline (SDD) hyclate 20 mg twice daily (Periosta®) was approved by the US FDA in 1998 for chronic adult periodontitis, and in 2006 for the treatment of rosacea in the form of 40 mg once daily (Oracea®). In 2003, Skidmore et al published the first acne trial examining the antiinflammatory properties of a tetracycline dcrivative independent of its antimicrobial effect. In this randomized, double-blind, controlled trial, participants with moderate facial acne were treated with either doxycycline hyclate 20 mg twice daily (n=2 I) or placebo (n=19) for 6 months. Skin samples were collected pre- and post-treatment to evaluate whether SDD therapy altered normal skin flora, had an antimicrobial effect. or resulted in antibiotic resistance. At 6 months, the doxycycline group had significantly greater improvement according to the clinician’s global assessment. Comedonal and inflammatory lesions were reduced by 53.2% and 50.1%, respectively, compared to 10.6% and 30.2% lesion reductions in the placebo group. SDD had no effect on the composition of skin microflora, and did not result in organisms resistant to doxycycline or cross-resistant to other antimicrobials. Both SDD and placebo were equally well-tolerated.

This was followed by a smaller study in which 12 patients wcre first given doxycycline hyclate 100 mg daily for 8 weeks. This produced a 50% reduction of lesions in all that remained enrolled (n=11). Six of these patients were subsequently given doxycycline hyclate 20 mg BID while the rest received placebo. The former group maintained improvement, while the latter did not. Although there have becn few studies on SDD thus far, it appears to be an effective treatment for clinically improving acne vulgaris while having an undetectable antimicrobial effect, potentially minimizing the emergence of resistant organisms and colonization of the skin with opportunistic pathogens. Unfortunately, there are no studies comparing the clinical efficacy of subantimicrobial doses to conventional doses of doxycycline for acne treatment.

Minocycline is another second generation tetracycline commonly used to treat acne. While minocycline has been proven to be as effective as tetracycline and doxycycline for the quantitative reduction of inflammatory lesions, it is considered by many to produce a more rapid and sustained clinical improvement. Of the 3 agents, minocycline is the most lipophilic, allowing greater penetration into sebaceous follicles. Furthermore, resistance of P. acnes to minocycline is considerably less than with tetracycline and doxycycline, which frequently have cross-resistance with each other. Thereforc, minocycline has been prescribed by many practitioners, despite frequently being more expensive than doxycycline. Minocycline can be taken with or without food and is often administered at initial doses of 50 to 100 mg twice daily followcd by 50 to 100 mg daily. In addition to the adverse effects noted with the othcr tetracyclines, minocycline has been known to cause bluish-gray skin pigmentation, reversiblc vestibular toxicity, and various autoimmune phenomena. Minocycline-induced lupus, autoimmune hepatitis, serum sickness, vasculitis, and pneumonitis have been reported, with recent safety concerns raised following the deaths of several patients on this medication. Therefore, baseline and periodic liver function tests and an antinuclear antibody test are recommended.

A recent systematic review of 27 randomized controlled trials examining thc efficacy of minocycline with active or placebo control found that although minocycline was shown to be an effective treatment for acne vulgaris, only 2 studies found it to be superior to other tetracyclines. The authors commented that these 2 trials were conducted under open-label conditions with questionable methodology. Interestingly, no study found minocycline to be beneficial in acne refractory to other medications. The authors concluded that given its high cost, lack of superior efficacy, and safety concerns, minocycline should not routinely be used as a first-line agent.

Solodyn® (Medicis, Scottsdale, AZ), an extended-release formulation of minocycline HCL for once-daily dosing, became the first FDA-approved oral antibiotic for acne vulgaris in May 2006. According to a review in the ovember 2006 Medical Letter on Drugs and Therapeutics, limitcd clinical data is available to compare efficacy of this fonnulation versus immcdiate-release minocycline. The 2 forms of the drug are not bioequivalent, as the l35-mg dose of the cxtcnded release formula takes one hour longer to reach maximum serum concentration and has a lower peak serum concentration than the same dose of immediate-release minocycline. Furthermore, the area under the 24-hour time-concentration curve is sma1ler. These pharmacokinetic characteristics are thought to lowcr the total serum and central nervous system exposure to minocycline and thus the common acute vestibular adverse events while maintaining efficacy. In a pooled analysis of 1,038 patients with moderate to severe facial acne in phase 11 and III studies, weight-based extended-reIease minocycline was significantly better than placebo at 12 weeks. Acute vestibular adverse events occurred in approximately 10% of the patients in the 1 mg/kg drug group and in the placebo group. Dose escalation to 2 and 3 mg/kg worsened the adverse side effects while adding no acne benefit. No direct comparisons of efficacy with immediate release minocycline have been published.

Macrolides

Macrolide antibiotics have also demonstrated efficacy in the treatment of acne. They have a wide spectrum of activity, are well-absorbed orally, and are lipid soluble, thus penetrating well into skin structures and body fluids. They inhibit protein synthesis by binding to the 23S rRNA molecule in the subunit of bacterial ribosomes. One advantage of the macrolides over the tetracyclines is their safety in pregnancy. Erythromycin, commonly used for years in the treatment of acne, has been shown to be as efficacious as the tetracyclines in several studies. However, because P. acnes resistance to erythromycin is growing, other macrolides and antibiotic classes are supplanting its use.

Azithromycin is a 9-methyl derivative of erythromycin that inhibits atypical intracellular pathogens such as Chlamydia and Mycobacterium species in addition to Gram-positive and Gram-negative aerobic and anaerobic bacteria including P. acnes. Unlike other oral antibiotics, the phannacokinetic profile of azithromycin is characrerized by rapid uptake from blood to tissues, at concentrations more than 10 times that of erythromycin. With a terminal half-life of approximately 68 hours, it remains for a prolonged period in intracellular compartments at levels higher than the minimum inhibitory concentration for many pathogens. Compared to trythromycin, mithromycin has also been shown to cause fewer gastrointestinal symptoms. With the potential for improved compliance due to a higher tolerability profile and longer half-life, along with proven defectiveness in several clinical trials, azithromycin is a suitable option for the treatment of acne. The first case series of 3 patients using azithromycin to treat acne vulgaris was published in 1997, and reported that Zithromycin 250 mg 3 times per week improved acne significantly at 4 weeks and maintained the improvement at 12 wceks. Gruber et al compared azithromycin 500 mg daily for 4 consecutive days repeated every 10 days versus daily minocycline, and concluded that azithromycin is as effective and as well-tolerated as minocycline. Another investigator treated 20 patients with both oral azithromycin and topical tretinoin 0.01% ge1. He reported a 75% improvement in acne when azithromycin was dosed 500 mg on day I, followed by 250 mg for 4 days on the first and fifteenth of each month for 3 months. This regimen was well-tolerated. A retrospective analysis of 21 patients treated with azithromycin 250 mg every Monday, Wednesday, and Friday for an average of 11 weeks compared patients treated with tetracycline, doxycycline, minocycline, and erythromycin. The azithromycin group had the greatest percentage of patients (85.7%) with a significant amount of lesion reduction. (>80%). It also had the least incidence of adverse effects. Because this was a retrospective report, many of these patients were using various topical medications concomitantly.

In an open-label study published in 2004, patients were standardized with azithromycin 500 mg 3 times weekly, with 83% showing at least 60% improvement in only 4 weeks and the majority achieving 80% clearance in 12 weeks. The authors noted excellent compliance in their patients, with 11% of patients reporting mild gastrointestinal distress. Kus et al compared azithromycin (administered 3 times weekly, then twice weekly, and finally once a week in 4-week intervals) to doxycycline taken twice daily for 4 weeks followed by once daily for 8 weeks. They measured efficacy with multiple parameters and discovered no significant difference in efficacy or tolerability with either antibiotic. Azithromycin has also been shown to be as effective as doxycycline when administered for 4 consecutive days each month as a monthly “pulse” dose, minimizing the need for frequent administration. The largest randomized, investigator-blinded trial with azithromycin to date compared it to tetracycline. The 100 patients evaluated in the azithromycin arm received 500 mg daily for 3 consecutive days per week in the first month, then on 2 consecutive days per week in the second month, and then once weekly in the third month. The 94 patienrs evaluated in the tetracycline group received 1,000 mg daily for 1 month and then 500 mg daily for the following 2 months. The patients on azithromycin fared slightly, but not significantly better than the tetracycline arm: 84.7% improvement versus 79.7% improvement.

From these trials, azirhromycin appears at least as efficacious and well-tolerated as doxycycline and minocycline, and because azithromycin is effective at doses given 1 to 3 times weekly, compliance may be superior (Table 4). This may be a better option for adolescents with poorer compliance and those intolerant or unable to take tetracyclines for various reasons. However, further studies are needed to bener establish an optimal dosing schedule.

Trimethoprim +/- Sulfamethoxazole

In cases of treatment failure with macrolide and tetracycline antibiotics, trimethoprim with or without sulfamethoxazole has been shown to be effective. Trimerhoprimsulfamethoxazolc (TMP-SMX) is FDA-indicated to treat infections such as bronchitis, acute otitis media, urinary tract infections, traveler’s diarrhea, and also the prevention and treatment of Pneumocystis jiroveci (formerly carinii) pneumonia. Off-label uses have included acne, perioral dermatitis, and rosacea. However, use in these conditions has been limited secondary to fear of serious adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and blood dyscrasias. The perception of a high incidence of these side effects is likely incorrect. While several case reports do document serious adverse events with TMP-SMX, in practice these events are infrequently the most common adverse effect being a maculopapular rash. Overall, both trimethoprim and TMP-SMX have been considered relatively safe and successful third-line agents in refractory cases of acne vulgaris by many authorities.

In many instances, patients may fail to respond to conventional antibiotics due to microbial resistance, but it has also been postulated that a high. sebum excretion rate results in reduced drug concentrations in the pilosebaceous until leading to therapeutic failure. A reduced clinical response in the presence of a high sebum excretion rate has been associated with oxytetracycline, erythromycin, and minocycline, but not trimethoprim. Therefore, trimethoprim may be helpful in such a situation. In 1999, a large retrospective analysis of 611 patients who had failed to respond to 2 adequate courses of oral antibiotics found that trimethoprim 300 mg BID for 8 months was effective for two thirds of the patients. Multiple smaller trials have compared either TMP-SMX or rrimethoprim alone to oxytetracycline and concluded that the former 2 are at least as effective and well-tolerated. The standard dose of TMP-SMX is one or two 480 mg tablets daily, and for
trimethoprim, 100 mg 3 times daily or 300 mg twice daily.

Fluoroquinolones

Evolved from the quinolones, the fluoroquinolone antibiotics were first introduced in the 1980s, with their indications and use increasing rapidly ever since. Fluoroquinolones are a class of broad-spectrum antibiotics with an excellent safety and tolerability profile that prevent bacterial DNA synthesis through inhibition of the enzymes DNA gyrase and topoisomerase IV They are FDA-approved for use in uncomplicated and complicated skin and skin structure infections including abscesses, cellulitis, furuncles, impetigo, pyoderma, and wound infections due to various pathogens, along with a host of other infections. With bactericidal and bacteriostatic activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria, the fluoroquinolones have been extensively used. Although I% topical nadifloxacin (not available in the US) has been studied for the treatment of acne vulgaris,
oral fluoroquinolones until recently had not. In 2002, an open-label study of 35 patients treated with levofloxacin 100 mg 3 times daily for 4 weeks demonstrated 71.4% of the patients had marked improvement or complete clearance of their acne lesions based on the physician’s global improvement rating. Levofloxacin achieved a marked reduction in papules (58.1%), pustules (76.8%), and both lesions (62.9%) at 4 weeks with no reported adverse effects. The levofloxacin concentration in comedones of 21 out of the 35 patients was measured at 2 weeks, with intralesional concentrations well above the minimal inhibitory concentration for P. acnes. As this is the first documented trial studying an oral floroquinolone for acne, more clinical trials with controls are needed to determine adequate effectiveness, dosing, and duration of therapy. As the authors highlight, it is important to note that because fluoroquinolnnes have a vital role in treating significant medical infections, their use in acne should be limited and reserved for refractory cases.

Cephalosporins

Cephalosporins are bactericidal and act by disrupting the synthesis of the peptidoglycan layer of the bacterial cell wall. While first-generation cephalosporins are predominantly active against Gram-positive bacteria, successive generations have increased activity against Gram-negative organisms. However, penicillins and cephalosporins have a very limited ability to penetrate microcomedones due to their hydrophilicity, and are therefore thought to be of little use in the treatment of acne. No controlled studies have evaluated the efficacy of cephalosporin antibiotics for acne, but several anecdotal case reports, in which they were administered for a different reason, note simultaneous resolution of the patient’s acne. Two women with moderate facial acne, who had previously failed a 2-month course of tetracycline along with topical treatments, had total dearing of their acne when
administered a cephalosporin. One of these women was treated with cefadroxil 500 mg twice daily for 10 days, while the other took cefaclor 500 mg 3 times daily for the same duration. Within 4 to 7 days, both patients experienced dramatic clearing of their lesions. It is important to consider the possible presence of a superimposed Gram-negative folliculitis as a factor in producing such a substantial response. Routine or long-term use of this class of antibiotics requires further data on efficacy, safety, and the potential development of resistance. But at times dramatic results may be attainable
with short courses, so failure or intolerance of other antibiotics and acute flare-ups may be valid reasons to consider the use of a cephalosporin on a limired basis.

Conclusion

While standard tetracyclines have long been the mainstay for first·line oral antibiotic thempy in acne, it is important to be aware of other new potential options that are available within this class. These include subantimicrobial-dose doxycyclines, which have becn shown to be efficacious but do not contribute to increased antibiotic resistance. Within the macrolide class, erythromycin seems to be falling out of favor secondary to increasing antibiotic-resistant bacteria. Azithromycin appears to be a viable option within this class with several studies indicating efficacy similar to the tetracyclines but more convenient dosing and increased tolerability. Minocycline and trimethoprim-sulfamethoxazole remain good options for second·line treatment in cases of refractory acne, but physicians must be aware of their associated adverse events and closely monitor patients treated with them. Finally, fluoroquinolones and perhaps the cephalosporins may be additional options for refractory acne; however, further research must be conducted before these medications are used routinely.

Disclosure

Dr. Aires is a consultant for Amgen, Bioform Medical, Centocor, Connetics Corp, and Galderma. He is a speaker for Novartis, Stiefel Laboratories Inc, and Warner-Chilcott.

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