Derms slow to embrace subantimicrobial dose concept

National report - Dermatologists might slash the development of resistance to antibiotics by embracing lower, subantimicrobial doses for acne cases that require only anti-inflammatory activity, experts say. However, they add, getting the majority of dermatologists to accept this message likely will prove challenging.

Dermatologists have long used antibiotics to reduce inflammation in acne, says Sandra Johnson, M.D., a dermatologist in private practice in Fort Smith, Ark. In fact, she says, “Maybe 60 percent to 70 percent of the general dermatology practice’s use of antibiotics is not for antibiotic purposes, but for inflammatory purposes in conditions such as acne and rosacea. So I would bet that we could improve the resistance problem by using lower anti-inflammatory doses” in acne cases that are predominantly inflammatory.

Neal D. Bhatia, M.D., says that based on dermatologists’ acceptance of extended-release minocycline for acne, dermatologists might reduce their overall antibiotic use by 30 percent if they embraced the low-dose approach in appropriate acne cases. He is a dermatologist in private practice in Long Beach, Calif., and an associate professor of dermatology at Harbor-UCLA Medical Center, Los Angeles.

Typical doxycycline doses for antimicrobial activity in acne are 100 mg to 200 mg daily. Doxycycline 20 mg BID, however - approved for periodontitis in 2006 - also has shown utility and safety in treating inflammatory acne. Additionally, extended-release minocycline (in doses starting at 45 mg daily) gained approval for inflammatory acne in 2006.

But dermatologists have not widely accepted the subantimicrobial dose (SD) concept, Dr. Johnson says, because most were not trained to do so.

“In training, we were taught to use antibacterial doses of antibiotics to treat inflammatory conditions such as acne. But now we have more data, especially regarding doxycycline,” she says.

She says that her “aha” moment came with the first small study of low-dose doxycycline in acne (Skidmore R, Kovach R, Walker C, et al. Arch Dermatol. 2003;139(4):459-464). After six months of treatment, inflammatory lesion counts in patients randomized to receive doxycycline 20 mg twice daily fell 50 percent, versus 30 percent for placebo-treated patients (p=0.04), with no significant changes in normal skin flora.

In another study, investigators gave 11 subjects eight weeks of doxycycline 100 mg daily. Those whose inflammatory lesion counts fell 50 percent then got either eight weeks of SD doxycycline or placebo. The six subjects who got SD doxycycline maintained their improvements through the trial's conclusion, while the placebo group did not (Parish LC, Parish JL, Routh HB, Witkowski JA. Acta Dermatovenerol Croat. 2005;13(3):156-159).

“This study is intriguing,” says Hilary Baldwin, M.D., “because it shows you can start with a full-dose antibiotic, get your bang for your buck, and then back off to the low dose and maintain clinical improvements, while having less concerns about development of resistance.” Dr. Baldwin is associate professor and vice chair of dermatology at the State University of New York Downstate Medical Center, Brooklyn, N.Y.

Dosing versus chronicity

In larger patients or for more severe cases, Dr. Bhatia says, “Dosing and duration are paradoxical.” Minimizing the duration of therapy demands dosing patients properly for their weight, he says. “It also requires making sure that their topical program is optimized. That’s where we lose out a lot. Without a proper topical program, patients are wasting their time with oral antibiotics. A good topical program will penetrate better to the comedones, as well as the papular component.”

Drs. Bhatia and Johnson agree that for those concerned with antibiotic resistance, dose levels ultimately matter less than treatment duration.

“But you could argue that if you use a low, non-antibiotic dose, then you can use it for as long as you wish” without stoking antibiotic resistance, Dr. Baldwin says. As such, “There’s no need to discontinue Oracea (doxycycline, Galderma) rapidly, because we have nine-month data showing that no antibiotic resistance occurs during that time (Preshaw PM, Novak MJ, Mellonig J, et al. J Periodontol. 2008;79(3):440-452).”

However, says Dr. Bhatia, another study shows that resistance can develop within two to four weeks (Walker C, Bradshaw M. Poster presented at: Fall Clinical Dermatology Meeting; Oct. 18-21, 2007; Las Vegas).

“This should affect our prescribing decisions,” he says.

Other factors to consider in prescribing oral antibiotics include acne patterns.

“For example,” Dr. Bhatia says, “if there’s secondary folliculitis, or a diffuse presentation of acne, it’s different than rosacea, which has no bacterial target - the anti-inflammatory dose won’t help.” In such cases, he recommends adding topical treatments and tapering oral antibiotics as soon as possible.

‘Too many refills’

Occasionally, Dr. Bhatia says, a patient needs six months on standard-dose oral antibiotics. For patients who don’t, “That’s where people tend to get too many refills. Some of that also comes from dermatologists maybe waiting too long between visits to taper patients down.” When this happens, “We’re seeing a little more resistance developing.”

To avoid this, Dr. Bhatia sees patients monthly (insurance permitting), usually starting the tapering process during the second month.

Other key considerations for Dr. Bhatia include the risk of scarring.

“If there’s a secondary infection, he adds, “That’s going to lead to longer treatment. Also, acne can be pretty painful,” which provides another rationale for standard-dose oral antibiotics - and lowers the threshold for isotretinoin, he says. Similarly, Dr. Johnson considers acne duration, previous treatments and patient expectations when she chooses medications for acne.

Regarding efficacy, “No study shows conclusively that doxycycline or minocycline better than the other. So it’s basically a judgment call” based not on data, but on a dermatologist’s experience, Dr. Baldwin says. In this regard, “I believe most people feel that minocycline is a bit more effective. Because it’s more lipophilic, you can use a lower dose. And there is less risk of antibiotic resistance developing with minocycline, for some reason, and less phototoxicity. Also, minocycline can be taken with food, including dairy products,” while doxycycline cannot.

Conversely, she says, “Doxycycline has more short-term side effects in terms of gastrointestinal issues, but fewer long-term or severe side effects.” Long-term minocycline use is associated with hyperpigmentation, a possible lupus-like drug reaction and other immune hypersensitivity, she says.

Dermatologists also must consider patients’ ability to comply with treatment regimens, say Drs. Bhatia and Johnson.

“Teenagers may take their antibiotic dose one day, but then skip a day or two, just out of forgetfulness. And if their acne clears up, they may stop taking their medication for a while. Then they may flare, and start up again. It’s that chronic, intermittent use that concerns me most for antibiotic resistance,” Dr. Johnson says.

Such usage can foster unusual resistance patterns that don’t appear in studies, which use consistent dosing, she explains. To avoid this problem, Dr. Johnson generally gives teenagers SD antibiotics, and switches to isotretinoin if the antibiotic isn’t working after three months.

‘Resistance hit parade’

As resistance to tetracyclines grows, dermatologists’ lack of other options represents the “elephant in the room. If the tetracycline family is next on the resistance hit parade, then what do we do?” Dr. Bhatia says.

“Development of resistance in P. acnes is not the most pressing issue that we face,” Dr. Baldwin says. “Once antibiotics are discontinued, P. acnes often returns to the wild type, and concurrent use of benzoyl peroxide can prevent the development of resistance or reduce resistant strains.” A much bigger worry, she says, is whether resistant P. acnes will pass along resistance to other organisms such as Staphylococcus aureus or Streptococcus.

To prevent such problems, Dr. Bhatia says, “We must go back to looking at prescribing patterns, with an eye toward minimizing antibiotic dosage and duration and maximizing topical regimens.”

He traces dermatologists’ slow acceptance of SD antibiotics partly to the way the manufacturer of SD doxycycline introduced the product.

“There haven’t been any new studies on the use of doxycycline at that dose for acne,” since the product debuted, he says. At press time, however, a study of doxycycline 40 mg daily was ongoing, according to Galderma.

Without pharmaceutical funds supporting such research and publications, Dr. Johnson says, “Changing our beliefs and thought process is an uphill battle.”

Going forward, Dr. Bhatia says he believes dermatologists’ use of extended-release minocycline will decline mainly due to the reduced support for the drug from manufacturer Valeant as compared to Medicis.

“There are many doubters who don’t believe SD doxycycline works for acne. Many dermatologists must get into the habit of using it. But that’s really up to us, because we must get into the mindset of incorporating more of the low dose, especially for facial, perioral or perimenstrual acne, where we don’t believe there’s a huge infectious component. We can probably use it more first-line to reduce the rate of exposure to unnecessary antibiotics,” he says.

To nudge dermatologists along, opinion leaders must synthesize existing data for clinical application, and ultimately they may have to perform more investigator-initiated studies, according to Dr. Bhatia.

Dr. Johnson adds that shifting dermatologists’ habits will require peer discussions in settings ranging from small groups to national conferences. Likewise, she says, “Media coverage can make people think about a problem that they may not be aware is a problem.”

Disclosures: Dr. Johnson is a speaker for Galderma. Dr. Bhatia is a consultant and/or investigator for Galderma, Valeant, Onset Therapeutics, Ferndale, Promius and Quinnova. Dr. Baldwin is a speaker for Allergan, Galderma, Valeant Dermatology, Medicis and Onset Therapeutics.