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Antimicrobial resistance affects health care providers' choice of antibiotics in the treatment of skin and soft tissue infections (SSTIs). Based on local antibiotic susceptibility data showing high clindamycin resistance and high MRSA prevalence, a change in antibiotic regimen for children hospitalized for uncomplicated SSTIs was instituted in an attempt to curb the use of linezolid. A retrospective chart review was performed on 278 pediatric patients with uncomplicated SSTIs hospitalized at Kapi'olani Medical Center for Women and Children in Hawai'i from May 2014 to April 2015 and November 2015 to October 2016. Data consisted of 12 months of baseline data and 12 months of data post-implementation of an antibiotic combination regimen of 2 widely-used antibiotics: high-dose cefazolin and high-dose clindamycin. Practitioners were encouraged to use cefazolin alone if clinical suspicion was high for single-organism infection with group A streptococcus. The measured outcomes included initial antibiotic, switch in antibiotic, and length of stay. The use of the combination of cefazolin and clindamycin as the initial treatment, compared with prior practice of monotherapy with clindamycin or cephazolin, was associated with fewer patients started on linezolid ( P =.03), no increase in patients switching to linezolid ( P =.97), and no significant change in length of stay ( P =.06). When clindamycin resistance and MRSA prevalence are both elevated, the combination of cefazolin and clindamycin is an option that can help with antibiotic stewardship to decrease the use of linezolid., Competing Interests: The authors report no conflicts of interest., (©Copyright 2020 by University Health Partners of Hawai‘i (UHP Hawai‘i).)