Background: Topical antimicrobials are employed for prophylaxis and treatment of burn wound infections despite no established susceptibility breakpoints, which are becoming vital in an era of multidrug-resistant (MDR) bacteria. We compared two methods of determining topical antimicrobial susceptibilities. Methods: Isolates of Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), extended spectrum beta-lactamase (ESBL) producing Klebsiella pneumoniae, and Acinetobacter baumanii-calcoaceticus (ABC) from burn patients were tested using broth microdilution and agar well diffusion to determine minimum inhibitory concentrations (MICs) and zones of inhibition (ZI). Isolates had systemic antibiotic resistance and clonality determined. MDR included resistance to antibiotics in three or more classes. Results: We assessed 22 ESBL-producing K. pneumoniae, 20 ABC (75% MDR), 20 P. aeruginosa (45% MDR), and 20 MRSA isolates. The most active agents were mupirocin for MRSA and mafenide acetate for the gram-negatives with moderate MICs/ZI found with silver sulfadiazene, silver nitrate, and honey. MDR and non-MDR isolates had similar topical resistance. There was no clonality associated with resistance patterns. Conclusion: Despite several methods to test bacteria for topical susceptibility, no defined breakpoints exist and standards need to be established. We recommend continuing to use silver products for prophylaxis against gram-negatives and mafenide acetate for treatment, and mupirocin for MRSA.