Skin and soft tissue infections (SSTIs) are common and can have serious implications.Nadifloxacin’s broad-spectrum antibiotic activity may potentially provide therapeutic benefits for skininfections. Also, it offers a viable alternative therapy for topical agent resistance.This study investigates the antimicrobial susceptibility of eight micro-organisms to four important topical antibiotics: Mupirocin, Clindamycin, Fusidic acid, and Nadifloxacin.Antibiotic susceptibility and minimum inhibitory concentration (MIC) were determined using Kirby-Bauer disk diffusion, Epsilometer test (E-Test), and Micro-broth dilution methods. Mueller Hinton and Brucella blood agar served as growth media. HiComb strips from HiMedia were used, and QC strains were tested. Kirby-Bauer assessed Zone of Inhibition; HiComb determined MIC via gradient; Micro-broth dilution gauged growth in antibiotic-diluted broth.The disk diffusion method revealed varying resistance percentages for antibiotics. Clindamycin had the highest resistance (62%) followed by fusidic acid (47%), Nadifloxacin (15%), and mupirocin (5%). Among gram-positive isolates, Nadifloxacin and mupirocin had 100% sensitivity, while Fusidic acid showed moderate resistance (19%) and clindamycin highest resistance (42%). Among gram-negative isolates, clindamycin and fusidic acid had 100% resistance, while Nadifloxacin (42%) and mupirocin (15%) showed comparatively low resistance. Among the 57 species isolates, including 49 isolates of and 8 isolates of the antibiotic susceptibility testing revealed a MIC value <4 μg/ml of Nadifloxacin, with a high level of sensitivity across all isolates. Nadifloxacin’s superior efficacy in the study can be attributed to its mechanism of action, targeting bacterial DNA gyrase and topoisomerase IV, making it suitable for bacterial infections, particularly those involving the skin and soft tissuesOut of four antibiotics tested, Nadifloxacin was found to be effective against both gram-positive and gram-negative strains of bacteria.