Background: Antibiotic de-escalation is a key element of antimicrobial stewardship programs that restrict the spread and emergence of resistance. This study was performed to evaluate the impact of positive culture sensitivity reports of E. coli or Methicillin sensitive Staphylococcus aureus (MSSA) on de-escalation of antibiotic therapy. Methods: This prospective observational study was performed on 256 infected patients. The samples were obtained principally from the pus of infected sites for the identification of pathogens and culture-sensitivity testing. The data were collected from patient medical files, which included their demographic data, sample type, causative microbe and antimicrobial treatment as empiric or definitive treatment based on cultures. Data were analyzed using SPSS. Results: Of 256 isolated microbes, 138 (53.9%) were MSSA and 118 were E. coli (46.1%). MSSA showed 100% sensitivity to cefoxitin, oxacillin, vancomycin, fosfomycin, colistin and more than 90% to linezolid (95.3%), tigecycline (93.1%), chloramphenicol (92.2%) and amikacin (90.2%). E. coli showed 100% sensitivity to only fosfomycin and more than 90% to colistin (96.7%), polymyxin-B (95.1%) and tigecycline (92.9%). The high use of cefoperazone+sulbactam (151), amikacin (149), ceftriaxone (33), metronidazole (30) and piperacillin + tazobactam (22) was seen with empiric prescribing. Following susceptibility testing, the most common antibiotics prescribed for E. coli were meropenem IV (34), amikacin (34), ciprofloxacin (29) and cefoperazone+sulbactam (25). For MSSA cases, linezolid (48), clindamycin (30), cefoperazone+ sulbactam IV (16) and amikacin (15) was used commonly. Overall, there was 23% reduction in antibiotic use in case of E. coli and 43% reduction in MSSA cases. Conclusion: Culture sensitivity reports helped in the de-escalation of antimicrobial therapy, reducing the prescribing of especially broad-spectrum antibiotics. Consequently, it is recommended that local hospital guidelines be developed based on local antimicrobial susceptibility patterns while preventing the unnecessary use of broad-spectrum antibiotics for empiric treatment.