Background: The multidrug resistant among uropathogenic E. coli has become a potential threat to global health. The aim of the current study to evaluate the antimicrobial activities of nitrofurantoin and fosfomycin along with other antimicrobials against Extended Spectrum β-Lactamases (ESBL) and AmpC producer isolates from the most common organism E. coli . Methods: A total of 6046 clean catch midstream urine samples were collected and processed in Microbiology department of tertiary care hospital. The antimicrobial susceptibility of E. coli isolates was initially screened by Kirby-Bauer disk diffusion method. The resistant isolates were confirmed to be ESBL and AmpC producers by their respective phenotypic confirmatory tests of combined disc method. Results: Out of 6046 patients there were 1855 E. coli positive patients. Maximum patients in the age group of 21-30 years were 51.5% followed by 31-40 years where patients were 26%. 64.4% E. coli were isolated from female patients and 35.6% from male patients. E. coli showed higher sensitivity towards, fosfomycin (100%), imipenem (100%), nitrofurantoin (84.1%), piperacillin and tazobactam (77.3%), amikacin (76.1%) and while they showed high degree resistance pattern against Penicillin, cotrimoxazole, ciprofloxacin, norfloxacin and 2 nd and 3 rd generation cephalosporin. Out of 1855 E. coli , multi drug resistance was seen in 520 E. coli isolates. ESBL production was observed among 50% of E. coli isolates by combined disk method. Out of 520 isolates, 150 isolates showed resistance to one or more extended-spectrum cephalosporins and cefoxitin by Kirby-Bauer disk diffusion method. These were selected and screened for ESBL and AmpC production. Among 150 cefoxitin-resistant isolates, AmpC phenotype was detected in 100 isolates (66.6%) by AmpC disc method. The overall occurrence of AmpC in the study was found to be 19.2%. Susceptibility of ESBL and AmpC producers to fosfomycin, imipenem, nitrofurantoin and amikacin were found to be 100%, 98.5%, 89% and 75% respectively. Conclusions: There is increased prevalence of ESBL and AmpC producing E. coli. Thus, early detection of ESBL and AmpC producer E. coli by simple phenotypic methods is necessary to avoid treatment failure, where molecular techniques are not available.