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Antibiotics: How and Why
They Benefit Acne and
Rosacea Care
Scientific inquiries increasingly articulate the importance of systemic antibiotics as therapeutic
agents in the treatment of both conditions.
By Leon H. Kircik, MD
A
cne and rosacea are chronic inflammatory disorders long thought to be primarily infectious.
However, evidence in recent years indicates
that far more than microorganisms inflammation plays a key role in the pathogenesis of these
disorders.1 Coinciding with recent emphasis on
inflammation has been an increased reliance on
antibiotic agents, which we now know to confer
anti-inflammatory effects. In the last 10 years, prescriptions for oral antibiotics by both dermatologists
and non-dermatologists have continued to rise. The
most commonly prescribed antibiotics in dermatology are the tetracyclines, of which second-generation molecules doxycycline and minocycline are
most prominent. While antibiotics can be used in a
variety of dermatologic conditions, doxycycline and
minocycline are likely used as much or more for
their anti-inflammatory properties as for their
antimicrobial effects.
As researchers strive to learn more about the specific role of inflammation in the etiology of acne
and rosacea, clinicians should be aware of new
developments and prepare to adapt to changing
therapeutic conditions. Ahead, I will provide an
update of research on antibiotics in acne and
rosacea care with a particular focus on the antiinflammatory effects of antibiotics. I will also discuss novel formulations that may be particularly
beneficial for patients.
Therapeutic Challenges and Resistance Concerns
Compared to tetracycline, doxycycline and minocycline provide important benefits, including less frequent dosing and improved safety.2 However, certain potential side effects of this class, including GI
concerns, staining of developing teeth in children,
candidiasis, and photosensitivity, are still a
concern.2,3,4 Probably one of the major disadvantages
of the use of minocycline is the potential for
blue/grey staining of the skin, sclera, teeth, and
nails.5 Increasingly, there has been more attention
paid to the risk for development of autoantibodies,
including antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), and antiphospholipid antibodies, associated with minocycline,
with or without associated clinical symptoms.4
Take-Home Tips. Despite concerns of resistance and adverse
effects, antibiotics have proven most useful for the anti-inflammatory
effects associated with their use. Given the equivalent efficacy of
doxycycline and minocycline, selection of an agent often depends on
the specific patient and the prescriber’s assessment of the relative
risks for development of therapy-associated adverse events. As
advancements in formulation are undoubtedly paving the way for more
efficacious antibiotic agents to play an increased role in acne and
rosacea therapy, clinicians’ abilities to understand and manage these
conditions will continue to evolve. ●
November 2011 |
Practical Dermatology | 43
Antibiotics
While serious side effects associated with secondgeneration tetracyclines are rare, they warrant consideration. All tetracyclines —but especially minocycline—may be associated with benign intracranial
hypertension with dizziness, lethargy, headaches,
nausea and vomiting associated with photophobia,
diplopia, and papilledema. Staining of the teeth can
occur with these agents, and they are not recommended in children under the age of eight years.
Although the rates of adverse events were perceived to be similar between doxycycline and
minocycline, a review of the published data shows a
disadvantage for minocycline.2 In data from clinical
trials published from 1966 to 2003, rates of reported
adverse events ranged from 0 to 61 percent for
doxycycline and 11.7 to 83.3 percent for minocycline. The majority of AEs associated with doxycycline were related to GI complaints, while minocycline had primarily CNS or GI complaints.
Similarly, evaluation of FDA MedWatch reports
from 1998 to 2003 found a rate of adverse events of
13 per million new prescriptions for doxycycline
and 72 per million new prescriptions for minocycline.2
Minocycline is associated with potentially fatal
hypersensitivity syndrome or Drug Reaction with
Eosinophilia and Systemic Symptoms (DRESS).6 A
retrospective analysis of 15 ICU-admitted cases of
DRESS in France found that minocycline was
causative in three cases. All three of those patients
experienced renal failure, and two of those three
patients died. Based on their analysis of these cases
and other databases, the authors recommend that
minocycline be considered a “higher risk” medication.12 Although predictive and prognostic factors
are not well-defined, evidence from another recent
review of hypersensitivity reactions in African and
African-American patients suggests that the risk for
DRESS may be associated with prolonged exposure
to minocycline and subsequent accumulation of the
drug in plasma and skin.7
Antibiotic Resistance. In addition to treatmentassociated adverse events, use of topical and oral
antibiotics at standard doses (at or above minimal
inhibitory concentration) is associated with the risk
44 | Practical Dermatology
| November 2011
of antibiotic resistance. The problem of resistance
has been especially well documented in the management of acne and has been linked to resultant
treatment failure.8 However, resistance is not limited to Propionibacterium acnes (P acnes). Researchers
have identified resistant strains of Staphylococcus
epidermidis,9-11 among acne patients treated with oral
erythromycin. Another study of acne patients
showed that systemic antibiotic therapy was associated with Streptococcus pyogenes colonization and
resistance in the oropharynx. While only 20 percent
of S pyogenes cultures from individuals not treated
with antibiotics were resistant to at least one tetracycline, 85 percent of cultures from antibiotic-treated patients demonstrated resistance.12
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. Continuous use of low-dose
antibiotics contributes to development of resistance.13
Anti-Inflammatory Effects
Despite concerns of resistance and adverse effects,
antibiotics have proven most useful for the antiinflammatory effects associated with their use.
Guidelines from the Global Alliance to Improve
Outcomes in Acne Therapy highlight findings the
inflammatory component of acne. It has now been
shown that immune changes and inflammatory
responses precede comedogenesis.14 Recent in vivo
research into the pathophysiology of acne and
associated scarring found a marked increase in
inflammatory cytokine gene transcripts in active
acne lesions, including TNF-α and IL-1β.15 These
pro-inflammatory cytokines amplify NF-κβ signaling pathways. These reports suggest that acne is a
disease mediated not only by bacteria but also by
inflammatory processes.
Antibiotics
Table 1. Antibiotic Formulations to Consider
Doryx. A unique formulation of doxycycline (Doryx, Warner Chilcott) may provide benefits in terms of treatment tolerability and
reduced incidence of adverse events. Doryx has been linked to a decrease in GI side effects.31,32 Available in 50mg, 75mg, and 150mg
QD dosage strengths, Doryx capsules can be cut or crushed without diminishing their therapeutic efficacy or the GI tolerability of
doxycycline.
Doryx features a unique delivery system of delayed-release, enteric-coated pellets of doxycycline hyclate. The pressed powder tablet
dissolves in the stomach, releasing the enteric-coated pellets. The pH-sensitive enteric coating remains intact in the acidic environment of the stomach. When the pellets reach the more alkaline small intestine, the enteric coating dissolves, and the active drug is
released and absorbed. This unique design minimizes exposure of the stomach to doxycycline.
Once-daily dosing of medication is also associated with improved therapeutic adherence.33,34 To further assure tolerability, doxycycline
may be taken with food, which is not shown to reduce absorption of the drug. Because the individual doxycycline pellets are entericcoated, crushing the capsule does not interfere with the release of active drug. Therefore, capsules may be crushed and the contents
sprinkled on food to facilitate dosing, which may also be cost-efficient.
Oracea. Oracea (doxycycline capsules 40mg, Galderma), the once-daily 40mg doxycycline anhydrous capsule, formulated with a mixture of immediate-release and delayed-release beads is designed to provide an anti-inflammatory dose of doxycycline. 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).35
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. Data show
that sub-antimicrobial dose doxycycline does not induce resistance in organisms after treatment for up to nine months. In trials, the
percent change in doxycycline resistance was equivalent in SDD-treated patients and controls.36
In addition, the low dose of doxycycline in Oracea coupled with its delayed release is thought to account for its favorable tolerability
profile.
Solodyn. Efforts to reduce the incidence of acute vestibular adverse events (AVAEs) associated with minocycline have resulted in a
novel, once-daily extended release oral formulation for the management of acne vulgaris. In trials, the rate of AVAEs associated with
extended-release (ER) minocycline hydrochloride (Solodyn, Medicis) 1mg/kg was similar to the rate seen among placebo controls.
The low rate of AVAEs is thought to result from a combination of the low dose and its extended release.
Individual and pooled analysis of data from phase II and III trials of ER minocycline 1mg/kg confirm its safety and efficacy.37 The
studies were prospective, multicenter, randomized, double-blinded, and placebo-controlled, involving a total of 1,038 subjects with
moderate to severe acne. Treatment was associated with statistically significant reduction in inflammatory lesions and improvement in
the Evaluator’s Global Assessment scores. The percentage of subjects reporting AVAEs was about 10 percent in those receiving ERminocycline 1-mg/kg and in those receiving placebo. Based on the data, researchers concluded that the once-daily ER formulation
delivers consistent levels of drug.
Studies of the bioavailability of the formulation show that the extended-release (ER) minocycline hydrochloride tablet formulation
demonstrates delayed time of maximum concentration (tmax, 3.5-4 hours) compared with a nonmodified-release minocycline (tmax,
2.25-3 hours), and a lower maximum concentration of drug (cmax) in the blood (90 percent) compared with nonmodified-release
“formulations.38
November 2011 |
Practical Dermatology | 45
Antibiotics
Table 2. Tips for Responsible Antibiotic Use and
Improved Adherence in Acne
• Choose a formulation for tolerability and to match patient needs/
preferences.
• Prescribe oral antibiotics for an appropriate course.
Do not prolong therapy unnecessarily.
• If using conventional systemic antibiotics, prescribe concomitant
topical benzoyl peroxide to reduce resistance risk.
• Recognize and capitalize on the multiple actions of antibiotics.
• Educate patients regarding the multiple actions of antibiotic
agents and your rationale for prescribing them.
• Educate patients about the basis for combination approaches
in acne/rosacea treatment.
• Emphasize adherence to optimize systemic therapy efficacy and
reduce the risk of resistance.
The fact that tetracycline antibiotics confer both
antimicrobial and anti-inflammatory effects
accounts for their utility in acne management.
Both minocycline and doxycycline are lipophilic
agents that demonstrate better tissue permeability
than tetracycline, adding to their therapeutic benefit.16
Minocycline and doxycyline appear to offer similar efficacy in the management of acne. A systematic review of clinical trials from 1962 to 2006
failed to identify a significant difference in reduction of inflammatory or non-inflammatory lesions
between patients treated with doxycycline and
those treated with minocycline.17 In a head-to-head
study in which 64 patients were randomized to
receive either doxycycline or minocycline 50mg
twice daily for four weeks and then once daily for
the next eight weeks,18 the two agents had equivalent efficacy. In another comparative trial, this one
involving 34 patients randomized to treatment
with doxycycline 50mg once daily or minocycline
50mg twice daily, the agents again had similar efficacy.19
Given their equivalent efficacy, selection of an
agent often depends on the specific patient and the
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| November 2011
prescriber’s assessment of the relative risks for
development of therapy-associated adverse events.
For patients with moderate to severe inflammatory
acne, initiation of appropriate systemic therapy
should not be delayed. Treatment aimed at reducing
inflammation can reduce the risk of scarring and
post-inflamamtory hyperpigmention.20
Oral antibiotics have also been used effectively in
the treatment of rosacea since the 1960s.21
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.22-24
Doxycycline and other tetracyclines have been
shown to reduce the production of interleukin-1
beta (IL-1β) (p <0.05) and tumor necrosis factor
alpha (TNF-α)25 and may reduce neutrophil chemotaxis.26 Tetracyclines also reduce the activity of
phospholipase A2, a family of inflammatory
enzymes.27 Doxycycline reduces the generation of
neutrophil-derived toxic reactive oxygen species,
including superoxide anion, hydrogen peroxide, and
the hydroxyl ion.28 In vitro studies show that doxycycline can reduce the production of nitric oxide by
epithelial cells at concentrations as low as 3µg/ml.29
Doxycycline has also been shown to reduce angiogenesis in animal models.
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.22-25
Conclusion
While the pathogeneses of acne and roscea are not
Antibiotics
fully understood, scientific inquiries increasingly
articulate the importance of systemic antibiotics as
therapeutic agents in the treatment of both conditions.2-5 In addition, new data indicate that the widespread use of oral antibiotics is associated with a
significant decrease in total annual prescription
spending.30 As advancements in formulation are
undoubtedly paving the way for more efficacious
antibiotic agents to play an increased role in acne
and rosacea therapy (Table 1), clinicians’ abilities to
understand and manage these conditions will con✔
tinue to evolve. ■ ❑
Dr. Kircik has served as a researcher, consultant, or
speaker for Allergan, Coria, Dermik, Galderma,
Stiefel/GSK, Intendis, Medicis, Obagi,
OrthoDermatologics, and Triax.
Leon Kircik, MD, FAAD is Director of Derm
Research, PLLC and Physicians Skin Care, PLLC.
He is Clinical Associate Professor of Dermatology
at Mount Sinai Medical Center and Indiana
University School of Medicine.
14. Do TT, Zarkhin S, Orringer JS, Nemeth S, Hamilton T, Sachs D, Voorhees JJ, Kang S.
Computer-assisted alignment and tracking of acne lesions indicate that most inflammatory
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15. Kang S, et al. Inflammation and Extracellular Matrix Degradation Mediated by Activated
Transcription Factors Nuclear Factor- B and Activator Protein-1 in Inflammatory Acne Lesions
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17. Simonart T, Dramaix M, De Maertelaer V. Efficacy of tetracyclines in the treatment of acne
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18. Olafsson JH, Gudgeirsson J, et al. Doxycycline versus minocycline in the treatment of
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22. Golub LM, Ramamurthy NS, Llavaneras A, et al. A chemically modified nonantimicrobial
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