Although the problem of antibiotic resistance continues to generate concern among clinicians and public health officials, prescribing for oral tetracyclines among both dermatologists and non-dermatologists has increased over the last decade.34 Proposed strategies to reduce the risk of resistance are to limit the use of oral and topical antibiotics, to use these agents in combination with adjunctive antimicrobial agents, such as benzoyl peroxide, or to administer antibiotics at levels below the minimal inhibitory concentration or MIC. The MIC is the plasma concentration that must be achieved in order for an antibiotic agent to inhibit or kill bacteria. The MIC is specific to each antibiotic agent. Importantly, the sub-MIC dose is not simply a low dose; any antibiotic currently marketed as a “lowdose” formulation is indicated for the management of infectious etiologies and will when properly administered achieve plasma levels above the MIC. Continuous use of low-dose antibiotics contributes to development of resistance.35
Doxycycline is available on the market in a sub-MIC dose in the form of Oracea (Galderma). The novel formulation of Oracea features a unique combination of 30mg doxycycline monohydrate immediate-release beads and 10mg anhydrous doxycycline monohydrate delayed-release beads in a capsule administered once-daily. The unique formulation of both immediate and delayed release (DR) doxycycline enables plasma concentrations of doxycycline to peak well below the MIC for the drug. Therefore, the formulation confers no antimicrobial effect and is not shown to encourage the development of bacterial resistance, even with nine months of continuous use. Importantly, the unique formulation of Oracea has a pharmacokinetic profile that differs significantly from that of standard low-dose (50mg) doxycycline. Oracea confers anti-inflammatory effects, as demonstrated by the reduction in inflammatory lesions of rosacea. Oracea is the only FDA-approved oral agent approved for the management of inflammatory lesions of rosacea.
Background and Rationale
Rosacea is an inflammatory skin disease with a high prevalence, affecting an estimated 14 million Americans. The condition is associated with a significant impact on the individual’s quality of life (QoL), much of which can be linked to feelings of embarrassment or effects of the disease on self-esteem, emotions, and personal/ social and professional relationships. 58 Additionally, rosacea is associated with physical discomfort, due to sensations of stinging, burning, itching, etc. While the pathogenesis of rosacea is not entirely understood, current conceptions of the disease emphasize the significant influence of inflammatory mediators in driving the disease process and producing associated symptoms. Rosacea is an inflammatory rather than infectious disease; any infectious etiologies that had been considered in the past have all been disproven.
Histological evidence has confirmed the perivascular and perifollicular infiltration of inflammatory lymphocytes and neutrophils in the cutaneous lesions of rosacea.36
Recent evidence has further implicated neutrophils in the development and persistence of rosacea. For example, nitric oxide is thought to mediate the dilation of dermal capillaries in rosacea,37 while increased levels of matrix metalloproteases are also evident.38 Additionally, high levels of reactive oxygen species, also shown to activate matrix metalloproteases, have been associated with the disease. 37
The erythema that is characteristic of rosacea is directly mediated by inflammatory compounds, such as prostacyclin, prostaglandin-E2, nitric oxide (NO), or other vasoactive compounds. Dilation initiates a cycle of events that contribute to worsening of symptoms and persistence of the disease. With time, dilation leads to weakening of the capillary walls and accumulation of extravascular fluid, producing edema. Neutrophils and proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1 and IL-6), leak into the dermis creating inflammation in the surrounding dermis. In response to increased inflammation, additional neutrophils are recruited, including matrix metalloproteinases (MMPs), reactive oxygen species (ROS), nitric oxide (NO), and other degradative or proinflammatory compounds.37, 38 The course of rosacea is known to wax and wane, though the inciting factors remain unknown. With repeated episodes of neutrophilmediated tissue injury, progressive damage to skin structure occurs and may lead to the development of telangiectases.38
Another recently identified contributor to the disease process are cathelicidins, a family of antimicrobial peptides. Cathelicidins are directly antimicrobial, and they initiate additional host immune responses.38 Cathelicidins at increased levels have been shown to promote tissue responses that resemble the histopathologic features of rosacea, including increased leukocyte infiltration and angiogenesis.39 When cathelicidin peptides were injected into the skin of mice, a dose-related inflammatory response, including erythema, vascularization, and neutrophil infiltration was observed.39
Benefits of Anti-inflammatory
The use of oral antibiotics to treat rosacea dates to at least the1960s.39 It has been proposed that tetracyclines were first used in rosacea on the assumption that an infectious etiology caused the disease. However, an article published in 1966 acknowledged that the mechanism of action of tetracycline in rosacea was unknown but was not thought to be associated with antiinfective properties.40 Over the ensuing four decades, doxycycline and other tetracyclines have been shown to produce a number of anti-inflammatory effects that may contribute to their beneficial effects in patients with rosacea. The tetracyclines, generally classified as antibiotics, have a range of therapeutic effects that are independent of antimicrobial mechanisms. In fact, tetracyclines have current or theoretical applications in periodontitis, arthritis, osteoporosis, and cancer.41-43
Doxycycline and other tetracyclines
have been shown to reduce
the production of interleukin-1
beta (IL-1β) and tumor necrosis
factor alpha (TNF-α)
Appreciation of the anti-inflammatory effects of tetracyclines may be attributed to research with chemically-modified tetracycline (CMT) analogues. There are at least 10 CMTs, modified so that the dimethylamino group from carbon- 4 position (the side-chain required for antimicrobial activity) is removed. These analogues provide no antimicrobial effect, but they inhibit synthesis of collagenase and other matrix metalloproteinases and down regulate cytokines in animal models.42-44 The anti-inflammatory effects of the tetracyclines are thought to produce their efficacy in rosacea therapy.51
The Novel Formulation of
Based on the evidence that CMTs confer anti-inflammatory benefits even when no antibiotic effect is possible, researchers investigated subantimicrobial dose doxycycline (SDD), now commonly called antiinflammatory dose doxycycline, for the management of periodontal disease, which was shown to involve an increase in matrix metalloproteinases. A 20mg dose of doxycycline hyclate is below the minimum inhibitory concentration; there is no antibiotic action.49 Twice-daily Periostat (20mg doxycycline hyclate, CollaGenex) received FDA approval in 1998 for treatment of adult periodontitis and has been widely used for that indication. Long-term use (up to 18 months) produced no changes in antimicrobial susceptibility in patients during the treatment period or up to six months post-treatment. 50
As the evidence shows, “subantimicrobial” does not mean “subtherapeutic.” 3 The efficacy of subantimicrobial dose doxycycline in reducing the inflammation of periodontitis without simultaneously providing an antibacterial effect prompted interest in the potential for SDD to treat rosacea. The ability to reduce inflammatory lesions and target the inflammatory component of the disease without the side effects of standard dose antibiotics or risk of resistance would be clearly beneficial.51
Oracea (doxycycline capsules 40mg, Galderma), is the first and only oral therapy approved for rosacea. The once-daily 40mg doxycycline anhydrous capsule, formulated with a mixture of immediate-release and delayedrelease beads is designed to provide an anti-inflammatory dose of doxycycline.
This unique 40mg capsule is not formulated in the same manner as Periostat. Periostat is prescribed for BID dosing, delivering a total 40mg dose in a day.
Randomized controlled clinical trials demonstrate the efficacy of Oracea for treatment of the inflammatory lesions of rosacea and demonstrate a favorable adverse event profile, similar to placebo (most common AEs associated with treatment are nausea, gastrointestinal upset, nasopharyngitis/ pain and nasal congestion/ sinusitis). Although it has not been definitely established, it is believed that Oracea, by delivering a constant dose of sub-antimicrobial dose doxycycline, provides only the anti-inflammatory effects of doxycycline. A review of the study data follows.
Two parallel, 16-week, randomized, double-blind, placebo-controlled phase 3 clinical trials were conducted to evaluate the efficacy and safety of Oracea for the treatment of moderate-to-severe rosacea (Fig. 4). Study 1 enrolled 251 patients. Study 2 enrolled 286 patients. Study 2 included a posttherapy assessment of efficacy and safety parameters four weeks after discontinuation of study medication.
Subjects with moderate-tosevere rosacea (defined as the presence of 10 to 40 papules and pustules and two or fewer nodules) and a score greater than 2 on an Investigator's Global Assessment of rosacea severity (rated on a scale from 0 (no signs or symptoms present) to 4 (severe disease)) were also required to have telangiectasia with moderateto- severe erythema at baseline. All patients were randomized to receive Oracea capsules or placebo once daily every morning for 16 weeks. In Study 2, patients were instructed to use no rosacea or acne therapies until the 20-week assessment.
Of note, in dose-ranging studies, 30mg immediate release plus 10mg delayed release doxycycle provided a similar reduction in inflammatory lesions regardless of the subject's body mass or the associated dose in mg/kg. (Fig. 5)
Importantly, anti-inflammatory dose doxycycline is distinct from low-dose doxycycline because of its specific formulation of 40mg active drug. In vitro plasma concentration data demonstrate the unique pharmacokinetic profile of the sub-antimicrobial dose formulation. In the study, which involved 32 healthy adult subjects randomized to receive standard doxycycline 50mg QD or Oracea once-daily (16 subjects per arm), the plasma concentration of doxycycline remained well below the antimicrobial threshold over 24 hours in the anti-inflammatory dose group, while the 50mg dose group exceeded the antimicrobial threshold over a period of several hours. Mean subject weight was 75kg. Plasma concentration measurement was conducted on day 7 of use.
Of note, the plasma concentrations in the anti-inflammatory dose group remained more consistent over time, fluctuating no more than 300 units from baseline to peak. The plasma concentration approached 400ng/mL at one hour and at 75 minutes it neared its peak at roughly half the 1000ng/mL threshold for antimicrobial effect. The concentration remained in the 500ng/mL range through hour 4, then gradually declined to 200ng/mL at hour 12.
By contrast, the standard dose group showed an 800-unit fluctuation from drug administration to plasma concentration peak. The peak, at 1200ng/mL was well above the antimicoribal threshold. At about 105 minutes, the plasma concentration reached 1000ng/mL and remained at or above this level through hour 6. (Fig. 6)
Data show that sub-antimicrobial dose doxycycline does not induce resistance in organisms after treatment for up to 9 months. In trials, the percent change in doxycycline resistance was equivalent in SDD-treated patients and controls.53 These data contrast with those for standard dose doxycycline, which is associated with the development of bacterial resistance with just two weeks of continuous therapy. A 14 day, prospective, placebocontrolled, randomized, doubleblind study of 29 healthy male and female subjects sought to determine the effect of a typical 2-week course of oral doxycycline on the proportion of resident nasopharyngeal flora expressing resistance to doxycycline and on the minimal inhibitory concentrations (MICs) of resistant flora. Subjects aged 21-60 years (mean 39 years, median 35 years; 11 men, 18 women) received oral doxycycline 100mg once-daily for 14 days. Analyzable data obtained from 26 subjects (14 in the doxycycline group and 12 in the placebo group) showed a significant increase in the percentage of culturable nasopharyngeal flora expressing resistance to doxycycline 4μg/mL. The greatest increase occurred within the first seven days of doxycycline administration with a minor increase seen between days 7 and 14. On Day 28, two weeks after cessation of antibiotic administration, resistance remained high.54
There is evidence to support the combination of SDD with topical therapy, with the oral agent enhancing the efficacy or the topical treatment. A double-blind, randomized, placebo-controlled study involving 40 patients with rosacea with eight to 30 total inflammatory lesions compared SDD plus topical metronidazole lotion 0.75% to placebo plus topical metronidazole lotion 0.75%. The results document clinically significant differences in Clinician’s Global Severity Scores between individuals in the SDD/topical metronidazole group and those in the placebo/topical metronidazole group by week four of treatment. These differences became statistically significant by week 12, at which time the topical agent was withdrawn and patients continued either oral therapy or placebo treatment. SDD-treated patients maintained changes through monotherapy.
Conclusion: Vehicle Benefits
The unique formulation of 30mg immediate-release and 10mg delayed-release doxycycline in an anhydrous capsule produces a predictable and relatively stable plasma concentration of doxycycline that remains well below the antimicrobial threshold. The ability of Oracea to provide improvement in the inflammatory lesions of rosacea is directly linked to this novel design; Standard doxycycline in a similar dose quickly achieves plasma concentrations above the antimicrobial threshold. The low dose of doxycycline in Oracea coupled with its delayed release is thought to account for its favorable tolerability profile.