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• What is currently known about this topic? Comparative morbidity outcomes for antibiotics with similar microbiological spectrum of activity in treatment of acute appendicitis is unknown. • What new information is contained in this article? Despite increased surgical site infection with single agent antibiotic treatment (amoxicillin/clavulanic acid), overall morbidity relating to ICU admission, relook rate and length of hospital stay is similar, when compared to traditional triple agent cover for paediatric post-operative complicated appendicitis treatment. Antibiotic choice for complicated appendicitis should be based on both microbiological effectiveness as well as ease of administration and cost especially in lower resourced settings. Data is limited on comparative morbidity outcomes for antibiotics with similar microbiological spectrum of activity. Incidence and morbidity of surgical site infection after appendectomy for complicated appendicitis was assessed after protocol change from triple antibiotic (ampicillin, gentamycin, and metronidazole) regimen to single agent (amoxycillin/clavulanic acid). Surgical site infection (SSI) rate, relook surgery rate and length of hospital stay were retrospectively compared in patients treated for acute appendicitis preceding (2014, 2015; "triple-therapy, TT") and following (2017, 2018; "single agent, SA") antibiotic protocol change. The rate of complicated appendicitis was similar between groups; 72.6% in TT and 66% in SA (p = 0.239). Significantly, SSI occurred in 22.7% of the SA group compared to 13.3% in TT group (OR 1.920, 95% CI 1.000–3.689, p = 0.048). Use of laparoscopy increased from 31% in TT to 89% in SA, but with subgroup analysis this was not associated with increased SSI (17.3% in open and 20.6% in laparoscopic; OR 0.841, 95% CI 0.409–1.728, p = 0.637). Relook rate (OR 1.444, 95% CI 0.595–3.507, p = 0.093) length of hospital stay (U = 6859, z = -1.163, p = 0.245), and ICU admission (U = 7683, z = 0.634 p = 0.522) were equivocal. Neither group had mortalities. Despite increased SSI with SA, overall morbidity relating to ICU admission, relook rate and length of hospital stay was similar in both groups. More prospective research is required to confirm equivalent overall morbidity and that single agent therapy is more cost-effective with acceptable clinical outcomes. [ABSTRACT FROM AUTHOR]