LAHAINA, HAWAII – Consider the “mutant selection window” to reduce antibiotic resistance when treating acne, Hilary E. Baldwin, MD, advised at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
Dr. Hilary Baldwin
Dermatologists continue to write a disproportionate number of prescriptions for antibiotics, particularly tetracyclines, noted Dr. Baldwin, medical director of the Acne Treatment and Research Center in New York. In addition to limiting unnecessary use of antimicrobials, strategies for slowing antimicrobial resistance include using anti-inflammatory doses of doxycycline; using more retinoids, isotretinoin, spironolactone, and oral contraceptives; and improving patient compliance with treatment.
Dermatologists can also “pay attention to the bug we are treating and ... make sure the concentration of the drug that we are using is appropriate to the bug we’re trying to kill,” while also targeting resistant organisms. Dr. Baldwin referred to a paper in the infectious disease literature titled: “The mutant selection window and antimicrobial resistance,” which points out that a drug concentration range exists for which mutant strains of bacteria are selected most frequently (J Antimicrob Chemother. 2003 Jul;52[1]:11-7). The dimensions of this range, or “window,” are characteristic of each pathogen-antimicrobial combination. A high enough drug concentration will eliminate both resistant and sensitive strains of the pathogen.
The paper notes that the minimum inhibitory concentration (MIC) is the lowest concentration that will inhibit the visible growth of a microorganism. The mutant prevention concentration (MPC) is the minimum drug concentration needed to prevent the growth of resistant strains, Dr. Baldwin said. The mutant selection window is the concentration range that extends from the MIC up to the MPC, the range “within which resistant mutants are likely to emerge.” If the antimicrobial concentration falls within this window, a mutant strain is likely to develop and “you’re going to add to the problem of antibiotic resistance,” she explained. “So the goal is to treat low or to treat high, but not right in the middle.”
“This is not theoretical,” and has been shown over and over again, with, for example, Streptococcus pneumonia and moxifloxacin, she said (J Antimicrob Chemother. 2003 Oct;52[4]:616-22.).
When the therapeutic window does not extend all the way to the MPC, “toxicity starts to kick in before you can get high enough to kill off the whole group of organisms,” in which case a low-dose strategy would reduce the development of resistant organisms, she noted.
“We’re doing this already,” with topical antifungals, Dr. Baldwin pointed out, asking when the last time anyone heard that a fungus developed resistance to topical antifungal therapy. “Never, because we use our antifungals in such a high dose, that we’re 500 times the MPC.”
Using an anti-inflammatory dose of doxycycline for treating acne or rosacea is a low-dose strategy, and the 40-mg delayed-release dose stays “way below” the antimicrobial threshold, she said, but the 50-mg dose falls “right in the middle of that mutant selection window.”
As more treatments become available, it will be important to determine how to dose topical antibiotics so that they do not fall within the mutant selection window and avoid what happened with clindamycin and erythromycin, “where the topical use of these medications led to the development of resistance such that they no longer work for the treatment” of Cutibacterium acnes.
Dr. Baldwin disclosures included being on the speakers bureau, serving as an advisor, and/or an investigator for companies that include Almirall, BioPharmx, Foamix, Galderma, Ortho Dermatologics, Sun Pharmaceuticals, Johnson & Johnson, and La Roche–Posay.
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