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Abstract Background Antimicrobial resistance is one of the ten major public health threats facing humanity, especially in developing countries. Identification of the pathogens responsible for different microbial infections and antimicrobial resistance patterns are important to help clinicians to choose the correct empirical drugs and provide optimal patient care. Methods During the period from November 2020 to January 2021, one hundred microbial isolates were collected randomly from different specimens from some hospitals in Cairo, Egypt. Sputum and chest specimens were from COVID-19 patients. Antimicrobial susceptibility testing was performed according to CLSI guidelines. Results Most microbial infections were more common in males and in elderly people over 45 years of age. They were caused by Gram-negative, Gram-positive bacteria, and yeast isolates that represented 69%, 15%, and 16%, respectively. Uropathogenic Escherichia coli (35%) were the most prevalent microbial isolates and showed high resistance rates towards penicillin, ampicillin, and cefixime, followed by Klebsiella spp. (13%) and Candida spp. (16%). Of all microbial isolates, Acinetobacter spp., Serratia spp., Hafnia alvei, and Klebsiella ozaenae were extremely multidrug-resistant (MDR) and have resisted all antibiotic classes used, except for glycylcycline, in varying degrees. Acinetobacter spp., Serratia spp., and Candida spp. were secondary microbial infections in COVID-19 patients, while H. alvei was a bloodstream infection isolate and K. ozaenae was recorded in most infections. Moreover, about half of Staphylococcus aureus strains were MRSA isolates and reported low rates of resistance to glycylcycline and linezolid. In comparison, Candida spp. showed high resistance rates between 77 and 100% to azole drugs and terbinafine, while no resistance rate towards nystatin was reported. Indeed, glycylcycline, linezolid, and nystatin were considered the drugs of choice for the treatment of MDR infections. Conclusion The prevalence of antimicrobial resistance in some Egyptian hospitals was high among Gram-negative, Gram-positive bacteria, and candida spp. The high resistance pattern —especially in secondary microbial infections in COVID-19 patients— to most antibiotics used is a matter of great concern, portends an inevitable catastrophe, and requires continuous monitoring to avoid the evolution of new generations.