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The emergence of multi-drug resistant (MDR) strains and even pan drug resistant (PDR) strains is alarming. In this study, we studied the resistance pattern of <i>E. coli</i> pathogens recovered from patients with different infections in different hospitals in Minia, Egypt and the co-existence of different resistance determinants. <i>E. coli</i> was the most prevalent among patients suffering from urinary tract infections (62%), while they were the least isolated from eye infections (10%). High prevalence of MDR isolates was found (73%) associated with high ESBLs and MBLs production (89.4% and 64.8%, respectively). <i>bla_TEM</i> (80%) and <i>bla_NDM</i> (43%) were the most frequent ESBL and MBL, respectively. None of the isolates harbored <i>bla_KPC</i> and <i>bla_OXA-48</i> carbapenemase like genes. Also, the fluoroquinolone modifying enzyme gene <i>aac-(6′)-Ib-cr</i> was detected in 25.2% of the isolates. More than one gene was found in 81% of the isolates. Azithromycin was one of the most effective antibiotics against MDR <i>E. coli</i> pathogens. The high MAR index of the isolates and the high prevalence of resistance genes, indicates an important public health concern and high-risk communities where antibiotics are abused.