Avoiding the Danger of Rising Resistance in Cutibacterium acnes: Criticality of Benzoyl Peroxide and Antibiotic Fixed Combinations

Abstract

Background: Antibiotic resistance is a global concern, with several countries reporting resistance in >50% of Cutibacterium acnes (C. acnes) strains. Combination formulations containing an antibiotic and the antimicrobial benzoyl peroxide (BPO) may reduce this resistance risk, especially with prolonged use. This four-part study tested susceptibility of 31 C. acnes clinical strains to antibiotics alone or in combination with BPO.
 Methods: Part 1: C. acnes susceptibility to single-drug antibiotics was assessed via minimum inhibitory concentration (MIC) values obtained from epsilometer tests, with lower MIC indicating higher susceptibility. Part 2: Susceptibility to fixed-dose antibiotic/BPO combination products (branded/in-development) was determined by measuring zone of inhibition using agar diffusion method, with larger diameter indicating increased bacterial inhibition. Part 3: The effect (synergistic, additive, antagonistic, or neutral) of combining clindamycin with BPO on C. acnes inhibition was evaluated using a checkerboard assay, wherein two test compounds are combined in varying concentrations. Part 4: Development of resistance was assessed using serial passage of bacterial cultures in increasing concentrations of clindamycin alone or in combination with BPO.
 Results: Part 1: All antibiotics tested—clindamycin, doxycycline, erythromycin, and minocycline—had similar activity. Susceptibility was highly strain dependent, as some C. acnes strains had elevated MIC—an indication of resistance—against different antibiotics. Part 2: For the 6 C. acnes strains that had no inhibitory zone (0 cm) with clindamycin alone, formulations with BPO enhanced activity against the same isolates (range: 0.8-2.2 cm with clindamycin phosphate 1.2%/adapalene 0.15%/BPO 3.1%, clindamycin phosphate 1.2%/BPO 5%, or clindamycin phosphate 1.2%/BPO 3.75%). Part 3: The combination of clindamycin and BPO resulted in an additive effect for 4 of the 7 acne-associated strains tested and was neutral for 3 strains. Part 4: Bacterial cultures repeatedly exposed to a combination of clindamycin and BPO did not develop resistance to C. acnes, which occurred with exposure to antibiotic alone.
 Conclusions: Overall, antibiotic susceptibility was highly strain dependent and antibiotic formulations with BPO exhibited enhanced activity against less susceptible C. acnes strains. Fixed combinations of BPO with an antibiotic may improve antimicrobial activity and protect against resistance development.
 
 Funding: Ortho Dermatologics.