Tetracyclines in Acne and Rosacea

Tetracycline, minocycline and doxycycline comprise a powerful and effective group of anti-acne agents, termed the tetracyclines. These agents are believed to function by both suppressing growth of Propionibacterium acnes and by exerting a direct anti-inflammatory effect.1 More recently, sub-antimicrobial dose doxycycline has demonstrated superb efficacy as a first-line rosacea treatment. Thus, despite increased bacterial antibiotic resistance, therapeutic efficacy persists due to anti-inflammatory effects of tetracyclines.1 The first tetracycline antibiotic, chlortetracycline, was introduced in 1954.2,3 During the 1950s and 1960s, tetracyclines were the most commonly prescribed antibiotics in the United States due to their efficacy in treating infection.3 By 1976, 10% of the tetracycline hydrochloride produced for human use was prescribed for acne.4 Despite widespread popularity, a retrospective study of 4,922 patient visits from the National Ambulatory Medical Care Survey found a significant decrease in the use of tetracycline group antibiotics from 1990 to 2002.5 Furthermore, a 10-year surveillance study of 4,274 acne patients showed that tetracycline-resistant isolates rose from 12.5% of patients in 1990 to 29.9% of patients in 1998.6 Perhaps increased awareness of antibiotic-resistant Propionibacterium species has contributed to this prescription decline.5 Second-generation tetracyclines, including minocycline and doxycycline, are superior to tetracycline in regard to bioavailability, lipophilicity (better uptake into the pilosebaceous unit), tissue penetration, absorption in the gastrointestinal tract and antibacterial activity.7,8 More importantly, second-generation tetracyclines have longer half-lives (21.2 hours for doxycycline) than tetracycline, translating into less frequent dosing that may improve adherence.9,10 All tetracyclines, however, are associated with numerous side effects (Table 1).

General Characteristics of Tetracyclines

Mechanism of Action Tetracyclines have a basic chemical structure consisting of a tetracyclic naphthacene carboxamide ring system, with a dimethyl-amine group at carbon 4 in ring A that confers antibiotic activity.2 Doxycycline has a distinguishing hydroxyl side chain at carbon 5 in ring B, while minocycline has a dimethylamino group at carbon 7 in ring D.11 When used in acne treatment, tetracyclines principally treat inflammatory acne, characterized by deep papules and pustules. They also have a role in papulopustular rosacea (rosacea subtype 2) treatment.8 A combination of oral tetracyclines and topical metronidazole may be considered first-line treatment in flare-ups of moderate-to-severe rosacea.12,13 Furthermore, tetracyclines, even at levels below the minimum inhibitory concentration, are effective in rosacea due to their anti-inflammatory properties, which include direct and indirect suppression of chemical mediators that promote inflammation, connective tissue destruction and granuloma formation.3 The antimicrobial action of tetracyclines in acne occurs via P. acnes protein synthesis inhibition; subsequent down-regulation of P. acnes lipase is thought to play a role in acne resolution.2,14 Tetracyclines, by targeting problematic surface bacteria, inhibit production of bacterial products that stimulate inflammation.15 Direct anti-inflammatory actions of tetracyclines include: inhibition of bacterial lipases, inhibition of mitogen-induced lymphocytic proliferation, inhibition of phagocytosis, down-regulation of proinflammatory cytokines (ie,TNF-a, IL-1b, IL-6), production of anti-inflammatory cytokine (ie, IL-10) secretion, reduction in antibody production, inhibition of polymorphonuclear (PMN) neutrophil migration and chemotaxis (in vivo and in vitro),15,16 inhibition of NOS activity, inhibition of phospholipase A2, down-regulation of ROS production, reduction in arachidonic acid metabolites, inhibition of leukocyte-derived matrix-degrading metalloproteinases (MMPs), reduction of complement component C3 activation, modulation of a-MSH (minocycline only), and prevention of reactive oxygen species release.2,3,14,15,17 Additionally, tetracyclines have anti-angiogenic properties, which may be useful in rosacea treatment, as angiogenetic factors (linked to MMP activity) may contribute to the telangiectasia of rosacea.2,15

Specific Characteristics of Tetracycline

Tetracycline Characteristics and Concerns Tetracycline is a first-line agent for inflammatory acne due to its efficacy and price.18 Dosing typically starts at 500 mg bid, and is maintained until marked improvement is observed; a 50% reduction may be observed in just 6 weeks.18 At that point, a maintenance dose of 500 mg daily can be prescribed.18 In addition to its use in acne, tetracycline is also widely used as a treatment for rosacea, typically at 500 mg to 1,000 mg daily.17 Regardless of treatment, tetracycline appears in surface film material collected from the foreheads of acne patients 4 to 8 days after oral administration.19 Long-term oral tetracycline resulted in significantly reduced surface free fatty acids, presumably due to inhibition of extracellular or bacterial lipases.20 However, tetracycline may not decrease surface bacterial flora, and there is an absence of correlation between drug dosage and cutaneous bacterial counts.16,20 Emergence of resistant strains may be to blame. In fact, patients with high surface levels of tetracycline-resistant strains of P. acnes may be associated with therapeutic failure.21 Of 19 patients with an MIC < 5mg/ml for tetracycline, 17 showed clinical improvement and two remained unchanged; 32 of 43 patients with MIC ≥ 5mg/ml were clinically unchanged or worse, while 11 showed clinical improvement.21 Unfortunately, prolonged usage of tetracycline has indeed resulted in selection of resistant strains. These bacteria have typically acquired genes encoding efflux pumps that eject antibiotics from cells and enzymes that inactivate antibiotics.3 More than one in 10 acne patients carry tetracycline-resistant propionibacteria.22 Additionally, low-dose oral tetracycline (250 mg per day to 500 mg per day for 2 weeks, then 250 mg per day) selects for not only tetracycline-resistant E. coli, but also multiple drug-resistant E. coli in the gastrointestinal tract.23 Tetracycline absorption is optimized if pills are taken with water at least 30 minutes before food intake.24 However, if the capsule adheres to the esophagus, tetracycline release may result in a burning sensation lasting 3 or 4 days.4 Other gastrointestinal side effects include esophagitis, esophageal ulceration, diarrhea, vomiting and dyspepsia.18 Furthermore, tetracycline absorption is affected by concurrent consumption of dairy products, food or heavy metals (ie, iron).18,25 Candidal vaginitis has been reported in 5% to 10% of patients, and may occur secondarily to medication-induced changes in the mucocutaneous bacterial flora of the vagina.18 Tetracycline may also cause adverse cutaneous reactions, such as Stevens-Johnson syndrome, although these are typically rare and nonfatal.4 Hypersensitivity reactions and a serum sickness-like reaction have also been reported.18 Benign intracranial hypertension, characterized by dizziness, lethargy, headache, nausea, vomiting, photophobia, diplopia, and papilledema, has been reported; it typically resolves after drug discontinuation.18,26 Additionally, current and past users of tetracycline may have a significantly higher risk of developing hepatotoxicity (ie, acute and subacute liver necrosis, hepatic coma and toxic hepatitis).27 Doxycycline Characteristics and Concerns Doxycycline was first introduced in 1966, and has long been used in acne and rosacea. It has demonstrated excellent penetration into the pilosebaceous unit in acne treatment.18 Initial dose for acne is usually 100 mg bid, with a subsequent maintenance dose of 100 mg daily.18 Reduced risk of gastrointestinal irritation and vertigo make doxycycline an attractive treatment option.7 Additionally, it can be taken with meals as its absorption is not affected by food. A new controlled-release 40 mg doxycycline monohydrate capsule (Oracea) was FDA-approved for papulopustular rosacea; the formulation includes 30 mg of immediate-release and 10 mg of delayed-release doxycycline beads.3,28 This dose has been termed “anti-inflammatory” and “sub-antimicrobial,” as it results in serum levels below the antibacterial minimum inhibitory concentration while still possessing potent anti-inflammatory characteristics.9,29 It needs to be taken only once daily, which may increase adherence.10,29 Unlike doxycycline hyclate, which dissolves at a pH of 2 to 3, doxycycline monohydrate dissolves at a pH of 5 to 6, producing even less GI upset and no esophageal irritation.7,17 Doxycycline combats rosacea by protecting capillary wall integrity, reducing sensitivity to vasodilatory stimuli, preventing capillary leakage, improving connective tissue integrity (by matrix-degrading metalloproteinase and collagenase inhibition), reducing inflammatory cell recruitment, reducing ROS and NO production and release, and down-regulating cytokines (IL-1 and TNF-a) which produce erythema and inflammation.9,26,30 Doxycycline may have the best side effect profile of all the tetracyclines. FDA data estimated adverse event rates of 13 per million compared to 72 per million for minocycline.31 A large review of case reports and clinical trials examining the safety of doxycycline found GI effects (ie, heartburn, nausea, vomiting, diarrhea and gastritis) and photosensitivity to be the most common adverse events.31 Between 1966 and 2003, case reports describe esophageal erosion as the main side effect for doxycycline doses ranging from 100 mg/day to 100 mg bid.31 Thus, doxycycline should be taken in the morning with a full glass of water and separate from food intake.32 Although doxycycline may be the most photosensitizing of the tetracyclines, this side effect is rare (< 1% patients) and dose-dependent.7,17 Phototoxic reactions are most common with immense sun exposure (UV A) and since sunscreen use may not prevent photosensitivity reactions, it may be wise to avoid doxycycline in the summer, especially in those with fair skin.18,33 Additionally, doxycycline may interfere with low-dose oral contraceptive efficacy and has been associated with an increased incidence of uterine polyps in female rats receiving megadoses (200 mg/kg/d) of doxycycline for 2 years.9,26 Murine experiments have also suggested an adverse effect on fertility and reproductive performance.26 Subantimicrobial dose doxycycline is associated with fewer side effects; photosensitivity and candidal vaginitis have not yet been described.9,26 A large safety analysis of Oracea in 537 rosacea patients followed over 16 weeks determined the most common adverse events (in order of decreasing frequency) to be: nasopharyngitis, diarrhea, headache, upper respiratory infection, hypertension, sinusitis and increased aspartate aminotransferase levels.26,30 Of note, certain drugs including PPIs, antacids, carbamazepine, phenytoin and rifampin may result in decreased Oracea concentrations.32 Minocycline Characteristics and Concerns First introduced in 1972, minocycline is widely believed to be the most effective tetracycline-agent.18 It produces more rapid and sustained lesion reduction and a greater decrease in P. acnes counts than other tetracycline-agents.18 Additionally, it is more lipid soluble and penetrates the sebaceous follicle better than other tetracyclines.34 This results in the build-up of high concentrations within the sebaceous follicles after oral administration.18,35 Its suppression of ROS (H2O2, O2 . -, OH.) is superior to that of tetracycline and many other antibiotics used in acne, including erythromycin and cephalexin.36 The initial does is usually 50 mg bid to 100 mg bid, with a maintenance dose of 50 mg to 100 mg daily.18 Minocycline has a long half-life of 15 to 25 hours.37 Absorption of minocycline is greatest when taken 30 minutes before a meal because drug absorption is reduced 10% to 15% with concurrent food intake.37 Minocycline demonstrated superior efficacy against propionibacteria than did tetracycline and doxycycline. In fact, 46 tetracycline-resistant propionibacteria strains were usually cross-resistant to doxycycline, but entirely sensitive to minocycline 100 mg bid. MIC of minocycline was far less than tetracycline and doxycycline, and despite being widely prescribed, bacterial resistance to minocycline is rare.18,25 Unlike other tetracyclines, minocycline is not photosensitizing and far less likely to produce pseudotumor cerebri.7 Concerns About Minocycline Though an incredibly effective drug, minocycline is frequently criticized for rare, but possible, side effects. Minocycline metabolism may result in a reactive metabolite — possibly, an electrophilic iminoquinone derivative.11 A systematic review of minocycline safety (using FDA and clinical trials data) found CNS and GI effects to be the most commonly associated adverse events.31 Perhaps the most disquieting adverse event generated by minocycline is drug-induced lupus, which occurs between 2 and 6 years after starting therapy.11 Patients present with malaise, accompanied by symmetrical polyarthritis or polyarthralgia in the small joints of the hand and wrist.11 Women are more likely to develop this disorder, and elevated serum hepatic transaminase levels occur frequently.11 In a retrospective study of 97,694 acne patients, minocycline use was associated with more than a threefold increased risk of developing drug-induced lupus erythematosus, with a further risk increase in those using it for 6 months or more.1 Nevertheless, this complication is exceedingly rare; the number needed to harm is 11, 364.1 Another group found an 8.5-fold increase of lupus-like syndrome in young women using minocycline for acne compared with non-users or past users; the effect was most pronounced in patients who had received a longer duration of therapy.38 Minocycline has been associated with vertigo, which is more common in women. Vestibular effects may occur more frequently in the generic formulation compared to the brand (Dynacin) formulation.39 This may be explained by differences in dissolution rate, drug release, and rate of rise in serum level.39 Dizziness, lightheadedness and ataxia are also a result of vestibular toxicity; like vertigo, these are reversible upon cessation of the drug.18,31 Interestingly, the incidence of CNS effects overall may be higher in women.31 Pigmentation, possibly due to oxidative intermediates, is a well known side effect of minocycline. Blue-gray pigmentation may manifest in the skin (eg, legs, feet, face), sclera and conjunctiva, thyroid gland,40 cardiac valvular tissue, bone, acne scars, or gums (typically 3 to 6 months after starting therapy).7 Pigmentation, which is due to deposition of black metabolites of the drug,24 may present locally (at a site of previous inflammation) or diffusely; much larger doses are typically necessary for diffuse staining.17,41 Nail discoloration has been reported after only 8 weeks of therapy.42 Staining of teeth, typically after 5 years of continuous treatment, may also occur.7 Yellow-orange staining of abdominal and thoracic lymph nodes was reported.40 A hypersensitivity syndrome (HSR), characterized by fever, lymphadenopathy, eosinophilia, lymphocytosis and rash may occur between 3 weeks and 2 months after starting therapy.7,11 Internal organ involvement is not uncommon in this syndrome; hepatitis, lymphadenopathy, hematologic abnormalities, renal abnormalities and pulmonary abnormalities have all been described.11 In addition, an eosinophilic pneumonitis in which patients develop dyspnea, hypoxia, cough and fever, along with radiologic evidence of pulmonary infiltrates, may develop although resolution may occur a few weeks after stopping minocycline.24 Serum sickness-like reactions have also been reported, developing on average 16 days after starting therapy.14,43 Long-term treatment has been associated with hepatitis, thyroiditis, polyarteritis nodosa and arthritis.14 Hepatitis may occur in the first weeks of treatment (as an acute hypersensitivity reaction, with eosinophilia and cutaneous involvement) or after > 12 months (as a less severe autoimmune hepatitis), particularly in young women.14,44,45 A British study examining medical records from more than 60,000 acne patients in the General Practice Research Database found the attributable risk of liver dysfunction in acne patients exposed to minocycline to be 5.74 cases per 100,000 exposed person months (EPM). Furthermore, the risk appeared greatest in the first month of use, although most cases were mild, resolving without further sequelae. This large study suggested a minimally increased risk in liver dysfunction associated with minocycline.44 A study of 700 patients taking minocycline 100 mg to 200 mg daily for an average of 10.5 months demonstrated various side effects in 95 patients, including (in order of decreasing frequency) gastrointestinal symptoms, vestibular dysfunction, headache and visual disturbance, memory disturbance and poor concentration, cutaneous symptoms (urticaria, photosensitive rash, pruritus), vaginal candidiasis or pityriasis versicolor, and pigmentation.41 Only pigmentation was significantly increased in patients taking higher doses of minocycline; all patients with pigmentation had a taken cumulative dose of more than 70 g.41 Baseline liver function tests (particularly hepatic transaminase levels) and an antinuclear antibody test may be useful prior to initiating therapy.43 However, some authors suggest that patients receiving long-term therapy should undergo these tests only if symptoms present.11 One study found benzoyl peroxide 5% gel twice daily to be as effective as minocycline 100 mg daily in mild-to-moderate acne, but at 1/12th the cost.46 In the UK NHS, the cost of a 6-month supply of minocycline is greater than that of doxycycline or tetracycline; in fact, for a 6-month supply, minocycline is more than twice the cost of doxycycline (£96 vs. £34).

Tetracyclines in Acne

Tetracycline in Acne In an early study of 51 patients, those treated with tetracycline 250 mg bid for 3 months demonstrated a significant improvement in acne appearance compared to those taking placebo (75% vs. 33%).47 Both clinical and photographic assessments were made before, during, and after treatment.47 However, a 2-month double blind cross-over study comparing tetracycline 250 mg bid to placebo pills in acne found no objective difference between groups, though participants believed tetracycline was more effective.48 In patients with recalcitrant, nodulocystic and conglobate acne, doses of 1.5 to 3.0 g/d (increased from standard doses of 250 to 1,000 mg/d) may be beneficial, though this has not been studied extensively in clinical trials.49 An early study demonstrated no significant difference between topical tetracycline treatment (6 mg daily) and oral tetracycline treatment (500 mg daily) for 3 months.50 However, a topical tetracycline preparation is not available in the United States. Other studies have shown that tetracycline is more effective with concomitant topical therapy in acne treatment.51 Concurrent treatment of oral doxycycline with topical adapalene has yielded significantly greater reductions relative to doxycycline alone for median percent change from baseline in total, inflammatory and noninflammatory lesion counts.52 In addition, azelaic acid (20%) combined with minocycline has shown a more rapid lesion count reduction during the first 3 months (compared with isotretinoin) along with a better side effect profile.53 Data for the combination of oral tetracyclines with topical benzoyl peroxide or retinoids also suggests synergistic effects.14 Doxycycline in Acne An early study of 62 patients found doxycycline hyclate 100 mg/d to be significantly more effective in reducing inflammatory lesions than placebo (34% vs. 22% obtained a good or excellent response).54 In a 12-week study of 34 patients, doxycycline 50 mg daily was found to be as effective in reducing lesions as minocycline 50 mg bid.55 A similar study of 16 patients demonstrated equivalent lesion reduction in groups taking minocycline 100 mg/d or doxycycline 100 mg/d; side effects were minimal and comparable between groups.56 Subantimicrobial-dose doxycycline has also been found to be beneficial in acne. In fact, 20 mg bid has produced significant inflammatory and non-inflammatory lesion reduction after 6 months in those with moderate acne.9,26 A 6-month study of 40 acne patients demonstrated significant reduction in comedones, inflammatory lesions, and total lesions (> 50% reduction) in a group receiving doxycycline hyclate 20 mg bid compared with a placebo group.57 There were no significant differences in microbial counts and no evidence of change in antibiotic susceptibility or colonization by potential pathogens between groups.57 The therapeutic effect of subantimicrobial-dose doxycycline in acne may be due to reduction in neutrophil chemotaxis and inhibitory effect on proinflammatory cytokines (IL-6, IL-1b, and TNF-a) and MMP-9.2,57 Minocycline in Acne A 6-month study of 49 patients with mild-to-moderate acne found minocycline to be superior (though not statistically significant) to tetracycline in lesion resolution. The patients in the minocycline group attained and maintained improvement more quickly (63 days vs. 76 days) and in greater numbers (23/25 vs. 18/24) than those in the tetracycline group.58 Another study echoed these results, demonstrating a superior clinical response in those taking minocycline 50 mg bid than those taking tetracycline 250 mg bid. Furthermore, adverse events were lower in the minocycline group than in the tetracycline group (10% vs. 22%).54 Starting at higher doses may prove beneficial in minocycline acne therapy. Minocycline 100 mg daily for 4 weeks followed by 50 mg daily for 8 weeks proved to be better in reducing acne lesions than minocycline 50 mg daily for 12 weeks. Adverse events did not differ between groups in this study of 86 patients.34 Subminimal inhibitory concentrations (1/10 MIC or sub-MIC) of minocycline suppressed production of neutrophil chemotactic factors, an indicator of inflammatory capacity in five biotypes of P. acnes.59 Furthermore, sub-MIC of erythromycin, tetracycline and clindamycin suppressed only 2 of 5 biotypes.59 A 6-month study of 25 acne patients found that minocycline 50 mg bid produced a 10-fold greater reduction in P. acnes numbers compared to tetracycline 500 mg bid. Minocycline also produced a significant and sustained staphylococcal reduction (unlike tetracycline), and a much lower increase in multiply resistant staphylococci than tetracycline.60 Another study of 15 patients demonstrated a greater P. acnes reduction in the foreheads and cheeks of those taking minocycline 200 mg/d than in those taking tetracycline 1000 mg/d. Furthermore, 3 weeks after stopping therapy, P. acnes counts (and free fatty acid levels) were still substantially suppressed in the minocycline group, while they were back to pretreatment levels in the tetracycline group. Both groups experienced greater than 50% inflammatory lesion reduction, but 3 weeks after therapy discontinuation, this reduction was only maintained in the minocycline group.35 However, there is evidence that topical medications may be equally or more effective than oral minocycline. An 18 week study of 649 patients found topical benzoyl peroxide and topical benzoyl peroxide/erythromycin combinations (2 types) similar in efficacy to oral minocycline (60% vs. 66% vs. 63% vs. 54%), but without the issue of proprionibacterial antibiotic resistance.46 Extended-Release Minocycline in Acne A new extended-release (ER) minocycline hydrochloride formulation was recently developed to reduce side effects while still providing effective acne treatment. ER minocycline utilizes a modified-release technology that results in low sustained drug levels in the blood.37 ER minocycline was shown to deliver a lower maximum concentration of drug (Cmax) and a delayed time of maximum concentration (Tmax) compared with conventional (immediate-release) minocycline; this may lower the amount and rate of drug crossing the blood-brain barrier into the CNS, thus diminishing the incidence of vestibular adverse events.37 Dosing is weight-based, designed to gradually deliver approximately 1 mg/kg of drug daily to the patient.61 ER minocycline 1 mg/kg was significantly more effective than placebo in reducing inflammatory lesion counts in pooled data from 1,038 subjects enrolled in one Phase II and two Phase III trials (all trials were 12 weeks duration).37 During the 12-week period, inflammatory and total lesion counts continued to decrease. In the Phase III trials, evaluator’s global severity assessment (EGSA) was significantly higher in the treatment group. Headache, nausea, fatigue and dizziness were the most commonly reported adverse events. However, pooled analysis of the trials indicated similar incidences of adverse events (including adverse vestibular events) between treatment groups and placebo groups.37

Tetracyclines in Rosacea

Tetracycline in Rosacea In an early study, tetracycline 250 mg bid produced marked improvement in 87% of patients with papulo-pustular rosacea. Both erythema and ‘pustulation’ improved significantly, although relapses and recurrences are not uncommon once treatment has stopped.8,62 Antimicrobial Dose Doxycycline in Rosacea Doxycycline 50 mg/day or 100 mg/day can rapidly (1 to 2 months) clear inflammatory rosacea without use of topical medications.7 This has important implications, as topical medications may be associated with decreased adherence.63 Doxycycline 100 mg daily for 12 weeks resulted in significant improvement for those with ocular rosacea (eg, ocular erythema and telangiectasia, Meibomian gland dysfunction, and short tear break-up time), which may occur in as many as 85% of patients with rosacea.64 Anti-Inflammatory/Subantimicrobial Dose Doxycycline in Rosacea Oracea once daily produced significant inflammatory lesion reduction in rosacea.28 Two Phase III clinical trials involving 537 patients with moderate-to-severe rosacea demonstrated a significant reduction in total inflammatory lesions (ie, papules, pustules, nodules) at 16 weeks, compared to placebo (61% and 46% lesion reduction vs. 29% and 20% lesion reduction, respectively).26,30 Oracea demonstrated a rapid onset of action, producing significant lesion reduction in the first 3 weeks of treatment. Superiority to placebo was also demonstrated in investigator’s global assessment (IGA) scores. In both studies, inflammatory lesion reduction did not plateau within the 16 week time frame; reduction in erythema (based on Clinician’s Erythema Assessment) in the treatment groups was demonstrated at 16 weeks, but was not significant.30 Another clinical trial of 134 patients confirmed these earlier results; 13.1% of the study group patients achieved a score of 0 (clear) on the IGA scale vs. 1.5% of the placebo group. Furthermore, in a 4-month trial of 67 patients, Oracea was as effective as doxycycline 100 mg/d in reducing inflammatory lesion count and erythema. Doxycycline 100 mg/d did not work more rapidly, and was associated with more adverse GI events than Oracea (26% vs. 5%).65 Data from these trials demonstrated that higher mg/kg doses do not result in increased clinical efficacy.28 Thus, conventional doses of 50 to 200 mg/d will not provide additional benefit in rosacea, as compared to 40 mg/d, but do increase risks — side effects and potential for resistance.65 Additionally, long-term exposure (18 months with an additional 9 months post-treatment surveillance) of anti-inflammatory dose doxycycline did not result in tetracycline resistance, shift in microbial flora or opportunistic overgrowth.9,28 There is some evidence that topical metronidazole, in conjunction with anti-inflammatory dose doxycycline, may be more effective than just topical metronidazole in rosacea treatment. A 16-week-long study of 40 rosacea patients demonstrated significant inflammatory lesion reduction in as early as 4 weeks in those taking doxycycline hyclate 20 mg bid and metronidazole 0.75% topical lotion; furthermore, this combination was superior in lesion reduction to monotherapy with metronidazole 0.75% topical lotion. Another 16-week-long study of 64 rosacea patients found Oracea 40 mg daily and metronidazole 1.0% topical gel to produce a significantly superior reduction in inflammatory lesion count than metronidazole 1.0% gel and placebo.67 Significant inflammatory lesion reduction was observed in as early as 4 weeks in the combination group, and persisted throughout the study; safety profiles were similar between the combination group and the metronidazole/placebo group.67 Both studies involved discontinuation of topical metronidazole at 12 weeks to observe the efficacy of doxycycline maintenance therapy; in both studies, from weeks 12 to 16, anti-inflammatory dose doxycycline maintained the excellent results of the combined therapy. Which Tetracycline-Agent to Choose A recent systematic review of clinical trials from 1962 to 2006 set out to assess the relative efficacy and optimal dosage of tetracyclines for inflammatory acne treatment.33 The findings were surprising: there was no evidence of superiority of one tetracycline over another in reducing lesion counts, there was no significant difference between tetracyclines in the improvement of inflammatory and noninflammatory lesions, and antibiotic dosage (in the range of investigated dosages) had no impact on efficacy in inflammatory and noninflammatory lesions. Six of seven randomized trials comparing tetracyclines found no difference in lesion count reduction.33 Furthermore, when non-comparative tetracycline trials were compared, lesion count reduction was similar between agents.33 Within the range of studied dosages (tetracycline: 375 mg/d to1000 mg/d; minocycline: 50 mg/d to 100 mg/d; doxycycline: 40mg/d to 200 mg/d), low doses were as efficient as high doses, which lends further credence to the anti-inflammatory properties of tetracyclines.33 Despite proven efficacy, an uncertain safety profile and lack of proven efficacy over other tetracyclines does not justify use of minocycline as a first-line acne therapy.33 Many have echoed this sentiment, citing lack of superior efficacy, increased costs, and questionable safety of minocycline compared to other tetracyclines.45,68 Conclusion Taken together, tetracyclines have served as effective acne and rosacea therapies for more than four decades. It appears that their anti-inflammatory properties are more important than their antimicrobial properties in these disorders. They assuredly have a place as first-line agents in inflammatory acne and may be effective monotherapeutic agents in rosacea. The development and efficacy of Oracea has demonstrated that these agents still have much to offer. Mr. Alikhan is a medical student at the University of California Davis School of Medicine, Sacramento, California. Ms. Kurek is a medical student at the University of California Davis School of Medicine, Sacramento, California. Dr. Feldman is with the Center for Dermatology Research, Departments of Dermatology, Pathology and Public Health Sciences at Wake Forest University School of Medicine, Winston-Salem, North Carolina. Disclosure: The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P.