Purpose: This study aimed to analyze the epidemiology, etiology, and changes in antibiotic susceptibility patterns of the first episode of acute pyelonephritis (APN) in children. Methods: This was a retrospective observational cohort study of children below 18 years old, diagnosed and treated for their first febrile episode of APN between 2006 and 2016. Electronic medical records were analyzed and radiologic images re-evaluated. Results: A total 359 patients fit the inclusion criteria, with 80.0% (n=280) below 12 months old and the median age 5.1 (IQR 3.0-10.5) months old. The male to female ratio was 5.3:1 between ages 0 to 2 months, 2.1:1 between 3 to 5 months; and 1.6:1 between 6 to 11 months old. Beyond 12 months, there was female predominance, with the female to male ratio 1.9:1 up to 4 years old, and over 17:1 beyond 5 years old. Escherichia coli was the leading cause of APN (83.8%) followed by Enterococcus species (6.7%), and Klebsiella pneumoniae (3.6%). Of the cases caused by enteric GNR, 43.5% (n=143/329) were multidrug resistant (MDR), and 16.4% (n=54/329) were extended spectrum beta-lactamase (ESBL) producers. During the 11-year period, a significant yearly increase in the proportion of MDR strains (p0.001) and ESBL producers (p0.001) was observed. Also, a significant yearly increasing trend in resistance to ampicillin/sulbactam (p=0.05), all generations of cephalosporin (p0.05), ciprofloxacin (p=0.003), and imipenem (p=0.001) was also observed. From 2006, resistance rates to ampicillin (71.4%) and trimethoprim-sulfamethoxazole (31.3%) were already high. Comparing ESBL versus non-ESBL producers, there were no differences in the total fever duration (3 vs. 3 days, p=0.904), time to defervescence (1 vs. 1 day, p=0.743), and admission duration (6 vs. 6 days, p=0.342). Also, the recurrence rates of APN in patients without vesicoureteral reflux (VUR) were similar amongst ESBL vs. non-ESBL producers (6.5% vs. 4.7%, p=0.602). However, in patients with VUR, there was a higher recurrence rate within six months in cases caused by ESBL-producers (75.0% vs. 30.0%, p= 0.03). Conclusions: The prevalence of APN remains highest during the first year of life. The proportion of ESBL-producers is significantly increasing; with an increased risk in recurrence within 6 months in patients with underlying VUR.