The increasing spread of antibiotic resistance among bacteria poses a major threat to the public health. There is an urge for the development of innovative formulations of existing and new antibiotics. One area of interest is in wound care, where two interesting antimicrobials are the conventional antibiotic amoxicillin and the antimicrobial peptide AP114. The objective of this work was to systemically evaluate topical gel formulations of these APIs by following a Quality by Design approach. A short excipient compatibility study was performed and the thickening agents poloxamer 407 and HPMC were chosen to be included in the following Design of Experiment (DoE) study of formulation composition and storage climate. The DoE set up was generated by the software MODDE Pro® and a short stability study of four weeks was performed, including analysis of the apparent pH, rheology stability, appearance, BCA assay, UV-Vis and FTIR spectroscopy and Franz cell diffusion. The results showed that AP114 formulations stored at 2-8˚C with poloxamer 407 should be with buffer pH 5-6 and 5-15 wt% organic phase to maximize stability, while HPMC based AP114 gels should be with buffer pH 6-8 and 10-40 wt% organic phase. Poloxamer 407 was not preferrable for amoxicillin formulations. The optimal HPMC based amoxicillin formulations included the storage temperature 25˚C, a buffer pH 7-8 and 40-60 wt% organic phase. HPMC based amoxicillin gels stored at 2-8˚C should be composed with buffer pH 6-8 and 10-40 wt% organic phase.