The onset of the COVID-19 pandemic challenged healthcare systems focusing their activity on patients infected with SARS-CoV-2. Previous experience with co-infections and superinfections in patients infected with other coronaviruses (SARS-CoV and MERS), the influenza patients admitted to hospitals and prevention of the unknown led to the increased empirical use of broad-spectrum antibiotics in hospitals. The breakdown of antimicrobial stewardship and infection control programs determine an increase in infections due to multidrug-resistant bacteria, particularly in intensive care units. Most of these infections are related to high-risk carbapenemase-producing clones and occasionally with resistance to new β-lactam-β-lactamase inhibitor combinations. On the contrary, in the primary care, there has been a decrease in the use of antimicrobials during the first wave, although it would not have had a significant impact on pathogens associated with community-acquired infections. The accumulated experience reaffirms the need to maintain antimicrobial stewardship and infection control programs in future health crises.