Abstract Background: Streptococcus pyogenes cause major infectious problems including pharyngitis, scarlet fever, and rheumatic fever Emergence of resistant strains make such infections and relevant complications (e.g., rheumatic valvular disease and glomerulonephritis) a serious clinical challenge especially in children. Aims and objectives: In a maneuver of overcoming the resistance developed by S. pyogenes and improving the ability of antibiotics to fight such bacteria, a nonsteroidal anti-inflammatory drug NSAID is repurposed as antimicrobial against S. pyogenes, in objective to be united with the usual antibiotic mentioned by WHO principle of care. The combination was evaluated for its MIC and combination index versus S. pyogenes. Materials and Methods: From patients, suffering pharyngitis a multidrug-resistant strain of S. pyogenes was insulated. The maximum dangerous isolate was cultivated for MIC determination ceftriaxonemefenamic acid combination in comparison with each alone to establish the combination index. Results and conclusions: There were a pointed synergism concerning ceftriaxonemefenamic acid (index ˂ 1) at P= 0.012 and Z score= 2.3 additional validation of MIC folds of dilutions are to be evaluated to achieve rational evidence. Recommendations: We suggested to additional validate the antistreptococcal effect of the combined ceftriaxonemefenamic acid on more dilutions of MIC assay and to identify the benefit of this combination in patients developed pharyngitis induced by S. pyogenes.