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JournalScan_Galderma_FP.qxp 3/1/2012 3:45 PM Page 1 A S U P P L E M E N T T O Family Practice News® Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7:573-576.
Rosen T. Antibiotic resistance: An editorial review with recommendations. J Drugs Dermatol. 2011;10:724-733.
Baldwin HE. A community-based study of the effectiveness of doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads) on quality of life and satisfaction with treatment in participants with rosacea. Cutis. 2010;86(5 suppl):26-36. Fowler JF Jr. Combined effect of anti-inflammatory dose doxycycline (40-mg doxycycline, USP monohydrate controlled-release capsules) and metronidazole topical gel 1% in the treatment of rosacea. J Drugs Dermatol. 2007;6:641-645. JournalScan_Galderma_FP.qxp 3/1/2012 3:45 PM Page 2 tologic disorder that affectsthe central part of the face, is most prevalent in pale-skinnedindividuals of Celtic, Northern, or Faculty Disclosures
All relevant financial relationships with anycommercial interests and/or manufacturers must be disclosed at the beginning of each activity. The faculty of this educational the disease are a genetic predisposi-tion, increasing age, emotional Dr Berman has received funding for clinical
grants from, is an investigator for, and is aconsultant to, Galderma Laboratories, L.P.
er, UV radiation, and vasodilatingmedication. The disorder can pres- INTERNATIONAL MEDICAL NEWS GROUP, a Division of ELSEVIER MEDICAL INFORMATION, LLC. Neither the Editor of FAMILY PRACTICE EWS, the Editorial Advisory Board, nor the reporting staff reviewed or contributed to its contents. The ideas and opinions expressed in this supplement are those of the faculty and do not necessarily reflect the views of the Copyright 2012 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form, by any means, without prior written permission of the Publisher. Elsevier Inc. will not assume responsibility for damages, loss, or claims ofany kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein.
JournalScan_Galderma_FP.qxp 3/1/2012 3:45 PM Page 3 long-term antimicrobial agents. He points out that “wide- summarizes some of the recent studies that have investigat- spread antibiotic use for acne and rosacea has been implicated ed the use of subantimicrobial-dose modified-release oral in the conversion of normal cutaneous saprophytes into doxycycline. Our goal is to provide clinicians with a thera- drug-resistant pathogens.” As an example, the author cites peutic tool for rosacea that is both effective and potentially the fact that tetracycline-resistant Micrococcus luteus has been more tolerable than other treatment options.
implicated as a cause of bacterial endocarditis.
By way of contrast, a subantimicrobial-dose (40 mg) modified-release formulation that combined 30 mg of References
immediate-release and 10 mg of modified-release doxycy-
1. National Rosacea Society. What is rosacea? http://www.rosacea.org/index.php.
cline (Oracea®) has been proven effective in reduction of the total inflammatory lesions of rosacea.
2. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Del Rosso et al,2 for instance, found that 40 mg of modified-release doxycycline is just as efficacious as 100 mg 3. Walker C, Bradshaw M. The effect of oral doxycycline 100 mg once-daily for of doxycycline during a 16-week trial and was less likely to 14 days on the nasopharyngeal flora of healthy volunteers: A preliminary analysis.
produce adverse effects. Similarly, a community-based open Poster presented at: 26th Anniversary Fall Clinical Dermatology Conference;October 18-27, 2007; Las Vegas, NV.
label trial by Webster7 has found that at 12 weeks on 40 mg 4. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical of modified-release doxycycline, nearly 75% of the patients trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP were clear or near clear, based on the 5-point Investigator’s capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol.
2007;56:791-802.
Global Assessment scale. This same open-label trial also 5. Walker C, Webster G. The effect of anti-inflammatory dose doxycycline 40 mg demonstrated that a subantimicrobial dose of doxycycline once-daily for 9 months on bacterial flora: Subset analysis from a multicenter, improves patients’ quality of life, as measured by a rosacea- double-blind, randomized trial. Poster presented at: 26th Anniversary Fall ClinicalDermatology Conference; October 18-27, 2007; Las Vegas, NV.
6. Rosen T. Antibiotic resistance: An editorial review with recommendations. To test the effects of modified-release oral doxycycline in J Drug Dermatol. 2011;10:724-733.
combination with a topical agent, Fowler9 administered 7. Webster GF. An open-label, community-based,12-week assessment of the40 mg of modified-release doxycycline capsules (Oracea®) effectiveness and safety of monotherapy with doxycycline 40 mg (30-mg once daily with topical metronidazole 1% (MetroGel®). The immediate-release and 10-mg delayed-release beads). Cutis. 2010;86(5 suppl):7-15.
combination was compared to placebo plus MetroGel in a 8. Baldwin HE. A community-based study of the effectiveness of doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads) on quality of life and double-blind fashion. Combining Oracea and MetroGel was satisfaction with treatment in participants with rosacea. Cutis. 2010;86(5 suppl): found to be more effective than was placebo plus MetroGel, and combination therapy resulted in faster and greater reduc- 9. Fowler JF Jr. Combined effect of anti-inflammatory dose doxycycline (40-mg doxycycline, USP monohydrate controlled-release capsules) and metronidazole tion of inflammatory lesions than did MetroGel monotherapy. topical gel 1% in the treatment of rosacea. J Drugs Dermatol. 2007;6:641-645. This Journal Scan supplement to FAMILY PRACTICE NEWS JournalScan_Galderma_FP.qxp 3/1/2012 3:45 PM Page 4 Comparing Antimicrobial and Anti-Inflammatory Doses of Oral Doxycycline in the Treatment of Rosacea Some of the strongest evidence supporting the value group complained of this AE; whereas, none in the of subantimicrobial-dose, modified-release doxycy- subantimicrobial-dose, modified-release formulation cline in the treatment of rosacea comes from a group mentioned it. Similarly, patients in the 100-mg randomized double-blind trial that compared 100 mg of group complained of diarrhea, esophageal pain, vomiting, oral doxycycline to a 40-mg formulation containing and abdominal pain; whereas, these GI reactions were not 30 mg of immediate-release doxycycline and 10 mg of reported by any patients in the subantimicrobial-dose, delayed-release doxycycline in the treatment of moderate The researchers reached several conclusions after analyz- Del Rosso and associates recruited 91 subjects in this multicenter, outpatient noninferiority study and adminis- •Antimicrobial and anti-inflammatory doses of doxycy- tered standard-dose doxycycline plus topical cline are equally effective when used as a once-daily metronidazole 1% to one group and the modified-release treatment for moderate to severe rosacea.
formulation plus topical metronidazole 1% to the other •Antimicrobial doses (100 mg) of doxycycline do not group over a 16-week period. The patient population com- have a more rapid onset of action than do doses of anti- prised 89 men and women more than 18 years of age who inflammatory (40-mg) modified-release doxycycline.
had been diagnosed with inflammatory papulopustular •Doses of 100 mg doxycycline are more likely to cause rosacea. All patients were classified as scoring between 2 AEs than are doses of anti-inflammatory (40 mg) mod- and 5 on the Investigator’s Global Assessment (IGA) scale.
The IGA scale starts at 0, representing completely clear Based on Del Rosso JQ, Schlessinger J, Werschler P. Comparison of skin, and extends to 5, representing very severe disease anti-inflammatory dose doxycycline versus doxycycline 100 mg in the with more than 25 papules and pustules, as well as the treatment of rosacea. J Drugs Dermatol. 2008;7:573-576.
presence of nodules, perilesional redness, and edema.
Patients were excluded from the trial if they were taking clinically significant concomitant medications, including vasodilatory drugs and corticosteroids. The primary thera- The Del Rosso trial confirms what other investigators peutic end point measured was an observed change in have observed, namely that 40 mg of modified-release papules, pustules, and nodules from baseline to week 16.
doxycycline is as effective as an antimicrobial Both treatment groups experienced a similar onset of ac- (100-mg) oral dose of the drug, but with fewer AEs.
tion at week 4 when compared to baseline, with no In that respect, it is useful to compare doxycycline to statistically significant difference in therapeutic response aspirin. In high doses, aspirin has an analgesic effect, (P=0.61). At week 16, the investigators observed that both but along with that therapeutic effect comes the risk groups experienced significant improvements in inflam- of GI bleeding and other adverse reactions. However, matory lesion counts with no significant differences at a much lower dose, namely 81 mg, aspirin has anti- between the two groups (P=0.83). There were, however, coagulant effects and a lower risk of GI complications. noticeable differences in adverse effects (AEs): 26 patients in So, too, does subantimicrobial-dose 40 mg doxycy- the antimicrobial-dose (doxycycline 100-mg) group experi- cline benefit patients with inflammatory lesions of enced one or more of the 10 most frequent AEs, including rosacea with lower reported side effects in clinical stud- nausea, headache, influenza, nasopharyngitis, urticaria, diar- ies. In one study, for instance, there were five times the rhea, esophageal pain, vomiting, abdominal pain, and upper number of GI AEs in patients on the 100-mg antimi- abdominal pain. In the anti-inflammatory–dose (doxycy- crobial oral dose. In addition, photosensitivity and cline 40-mg) group, only six patients experienced any of fungal overgrowth can occur with the antimicrobial these reactions. As the authors point out, “Both the num- doses of doxycycline, but, in controlled clinical trials, ber of AEs and the number of subjects with AEs were there were no reports of vaginal candidiasis or photosen- sitivity with the subantimicrobial, anti-inflammatory Most of the AEs were gastrointestinal (GI) in nature, with nausea topping the list. Eight patients in the 100-mg JournalScan_Galderma_FP.qxp 3/1/2012 3:45 PM Page 5 Impact of Antibiotic Resistance on Dermatologic Practice Antibiotic resistance has become a major concern With these concerns in mind, Rosen concludes that to both health professionals and the general pub- “systemic use of antibiotics in the treatment of rosacea lic in recent years. That has not always been the might be minimized or completely avoided, by prescrib- case. When penicillin became commercially available in ing an FDA-approved subantimicobial dose (SD) of the 1940s, many looked on it as a “wonder drug,” and, in doxycycline (40 mg controlled released doxycycline once fact, it had a profound effect on Streptococcus pneumoniae, daily). Using this anti-inflammatory dose of antibiotics the leading cause of infectious disease and death world- may avoid the side effects associated with the long-term wide at the time. Unfortunately, within a relatively short use of tetracyclines…and reduce the potential for devel- time, bacteria found “creative” ways to resist the drug’s effects, and now many clinicians worry that they may In addition to avoiding unnecessary long-term antibi- soon run out of therapeutic agents to treat infections that otic therapy, other important measures that can help were once considered relatively minor inconveniences in reduce the risk of antibiotic resistance include strict ad- herence to an infection-control protocol, includingthorough hand washing and topical antiseptics; avoiding Mechanism of Action
broad-spectrum antimicrobials, when possible; and pa- Rosen points out that some bacterial species are inher- tient education that encourages patients to take the full ently resistant to certain classes of antibiotic agents, whereas others acquire resistance through a variety ofmechanisms. For example, as an antibiotic destroys the vast Based on Rosen T. Antibiotic resistance: An editorial review with recommendations. J Drugs Dermatol. 2011;10:724-733.
majority of organisms in a given host, there is less compe-tition for available nutrients and water, which givessurviving organisms an opportunity to thrive. Some resistant organisms also have the ability to pass on their genetic material to their neighbors, thereby spread- In the vast majority of patients with rosacea, the dis- ing resistance to a much larger community of microbes.
ease is the result of an inflammatory process, not an Such genetic exchange usually takes two pathways. During infectious process. It is, therefore, important to avoid vertical evolution, microbes develop advantageous chromoso- the use of antimicrobial dosing of doxycycline in cases mal mutations that they pass on to their progeny. During like this for at least two reasons: (1) these higher dos- horizontal evolution, one species passes on new genetic mate- es are associated with more side effects, including rial to unrelated species or groups. During the process of gastrointestinal distress, photosensitivity, and vertigo, transduction, for instance, genetic material is transferred and (2) equally important, at higher doses, the drug can from one bacterial species to another via viruses called bac- contribute to antibiotic resistance. By way of contrast, a teriophages, a phenomenon that specifically contributes to modified-release 40-mg doxycycline formulation has S. aureus resistance to antibiotics.
been given to patients with rosacea for up to 9 monthswith no evidence of antibiotic resistance and no re- Implications for Dermatologists
ported abnormalities in intestinal flora. Given the In 2009 alone, dermatologists wrote about 9.5 million availability of a subantimicrobial, anti-inflammatory prescriptions for oral antibiotics, with tetracycline deriva- oral therapy, a shift in the rosacea treatment regimen tives topping the list (68.6%). In fact, doxycycline, must be considered. With equivalent efficacy to an- tetracycline HCl, and minocycline are the three oral an- tibiotic doses of doxycycline, but with lower reported tibiotics most frequently given to patients with acne side effects and no evidence of resistance concerns, vulgaris and rosacea. But as Rosen points out, the need for subantimicrobial-dose doxycycline may warrant place- relatively high doses of these agents for rosacea is probably ment as the preferred first treatment option for unjustified because the disease is likely the result of in- patients with papulopustular rosacea.
flammatory mediators rather than infectious agents.
JournalScan_Galderma_FP.qxp 3/1/2012 3:45 PM Page 6 The Effects of Modified-Release Doxycycline on Quality of Life In order to evaluate the effects of a 40-mg subantimi- Table. Changes in mean RosaQoL scores after 12 weeks of crobial formulation of doxycycline (30-mg treatment with subantimicrobial formulation of immediate-release and 10-mg delayed-release beads; doxycycline monotherapy or add-on therapy Oracea®) in everyday clinical practice, investigators con- ducted an open-label phase IV trial among adults with mild to severe papulopustular rosacea with moderate to se- vere perilesional redness. The Oracea for Rosacea: A Community-Based Assessment (ORCA) study enlisted *P<0.0001 versus baselineRosacea-specific quality of life questions 5pt. scale: 1=never; 5=all the time 1,421 patients from 271 community-based investigationalsites and evaluated the benefits—both physical and psy-chological—and the side effects profile of the medicationover a 12-week period.
The researchers used the 5-point Investigator’s Global The ORCA study looked at the real-world use of oral Assessment (IGA) score as their primary end point, which doxycycline, as opposed to controlled randomized tri- consists of clear, near clear, mild, moderate, and severe rat- als in which the use of the drug is closely monitored ings. In addition to measuring physiologic parameters, and subjects are often paid for their involvement; both investigators also looked at the effects of the medication on factors encourage better-than-average compliance quality of life (QoL) and patient satisfaction. A 21-question with therapy. With that in mind, it is important to rosacea-specific survey called RosaQoL was given to pa- see how modified-release doxycycline monotherapy tients at the beginning of the trial and at week 12, or at the would work in community practice, where no one is standing over patients counting pills and watching Baldwin summarizes the effects of the 40-mg subantimi- crobial doxycycline formulation as monotherapy and as We know that rosacea has a significant negative im- add-on therapy on QoL and patient satisfaction; 966 pa- pact on patients’ well-being. In surveys by the National tients completed the trial without deviating significantly Rosacea Society, more than 76% of the patients with from the treatment regimen, including 826 patients on rosacea said that their condition had lowered their self- monotherapy and 140 who received 40-mg subantimicro- confidence and self-esteem, and 41% reported that it bial doxycycline as an add-on to topical medication. had caused them to avoid public contact or cancel social When patients initially enrolled in the study, QoL scores engagements.1 Among patients with rosacea with se- averaged 3.3 (Table). By the time they finished, the scores
vere symptoms, 88% said that the disorder had had dropped to 2.8, indicating a statistically significant adversely affected their professional interactions, and improvement (P<0.0001). Similarly, by the time the trial 51% said that they had even missed work because of was completed, about 80% of the patients in both groups their condition. As the summary above mentions, pa- said they were very satisfied or satisfied with doxycycline.
tients taking doxycycline as monotherapy or taking the And most patients also said they were very likely or likely drug in combination with topical medication reported that their quality of life improved, suggesting that theoral medication may benefit patients’ self-image and Based on Baldwin HE. A community-based study of the effectiveness of their overall emotional state. This is the first study to doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-releasebeads) on quality of life and satisfaction with treatment in participants with report that oral therapy with 40 mg of modified-release rosacea. Cutis. 2010;86(5 suppl):26-36. doxycycline for 3 months can significantly improve thispsychological parameter, regardless of whether patientsare taking it with topicals.
Reference
1. National Rosacea Society. What is rosacea?
http://www.rosacea.org/index.php. Accessed January 24, 2012.
JournalScan_Galderma_FP.qxp 3/1/2012 3:45 PM Page 7 Combining Anti-Inflammatory–Dose Doxycycline With Topical Metronidazole To determine what benefits might incur from com- Table. Mean Change in Inflammatory Lesion Count bining subantimicrobial, modified-release oraldoxycycline with topical metronidazole 1%, Fowler enlisted 72 patients in a 16-week double-blind randomized trial. The design consisted of two groups: one that received anti-inflammatory–dose doxycycline (30 mg of immediate- release and 10 mg of delayed-release doxycycline) plus metronidazole gel (group 1) and one receiving placebo plus a Group 1—40 mg modified-release doxycycline plus metronidazole 1%.
metronidazole gel (group 2). At week 12, the topical gel b Group 2—metronidazole 1% plus placebo. was discontinued, at which point group 1 continued on c Patients in groups 1 and 2 stopped taking metronidazole.
anti-inflammatory–dose doxycycline and group 2 contin-ued on placebo alone.
avoids long-term use of topical or systemic antimicrobials.” The Fowler study’s primary end point was the mean Finally, the study confirmed that the adverse effects pro- change in inflammatory lesion count, which included file of subantimicrobial-dose, modified-release doxycycline papules, pustules, and nodules. On average, patients had be- plus metronidazole gel was similar to that seen in patients tween eight and 40 lesions entering the study, two or fewer nodules, an Investigator’s Global Assessment (IGA) score of2 or higher, moderate to severe erythema, and telangiectasia.
Based on Fowler JF Jr. Combined effect of anti-inflammatory dosedoxycycline (40-mg doxycycline, USP monohydrate controlled-release IGA score was rated on a scale from 0 to 5, with 0 repre- capsules) and metronidazole topical gel 1% in the treatment of rosacea.
senting skin that was completely clear of inflammatory J Drugs Dermatol. 2007;6:641-645. lesions and 5 representing a very serious state in which pa-tients had more than 25 papules and pustules, the presence of nodules, accompanied by perilesional redness and edema.
Combination therapy using both oral doxycycline and Among the 64 patients who completed the trial, the re- topical metronidazole for rosacea is routinely used duction in inflammatory lesions was significantly better in among dermatologists. However, one unresolved issue is those on the combination of anti-inflammatory–dose doxy- which agent is doing the “heavy lifting” in a situation cycline and metronidazole than in those on placebo plus like this. Fowler has addressed that issue by comparing the topical gel. The difference in therapeutic response was anti-inflammatory–dose doxycycline plus topical seen as early as 4 weeks into the experiment, at which point metronidazole to placebo plus topical metronidazole.
the doxycycline plus metronidazole gel group’s change in Although he found that patients in both groups bene- lesions was -9.69, compared to only -2.86 in the placebo fited, the reduction in inflammatory lesions was 3 to plus topical gel group (P=0.0008) (Table). By week 12,
4 times greater when the oral medication was taken just before discontinuing the topical gel, the respective with the topical gel. In fact, the improvement among scores were -13.86 vs -8.47 (P=0.002). As expected, the patients on the combination at week 4 was slightly bet- placebo group’s improvement declined by week 16.
ter than what was achieved by the topical gel alone at IGA scores improved in patients taking both week 12. That suggests that the “heavy lifting” was, in anti-inflammatory–dose doxycycline and metronidazole at fact, done by the oral medication. That suggestion is each clinic visit, but the difference between this group and further supported by the results that Fowler observed the group taking placebo and the topical gel only became between weeks 12 and 16, when the topical gel was dis- statistically significant at weeks 12 and 16. By week 12, continued in both groups. By week 16, patients on the the mean percent change in IGA scores for group 1 was modified-release oral doxycycline monotherapy main- -66.4%, compared to -48.2% in the group 2 (P=0.008).
tained the benefits obtained by week 12, despite the fact It is significant to note that between weeks 12 and 16, pa- that they were no longer on the topical gel. Beginning tients who were taking doxycycline without the topical gel with the anti-inflammatory dose, doxycycline appears to “maintained the results of the combined therapy with re- result in faster and greater reduction of inflammatory le- gard to inflammatory lesions and IGA scores,” prompting sions. This also suggests that overall patient outcomes the author to conclude that maintenance therapy consisting of low-dose doxycycline monotherapy “is an option that JournalScan_Galderma_FP.qxp 3/1/2012 3:45 PM Page 8

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