Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories. Antimicrobial categories are classifications of antimicrobial agents based on their mode of action and specific to target organisms. The MDR types most threatening to public health are MDR bacteria that resist multiple antibiotics; other types include MDR viruses, parasites (resistant to multiple antifungal, antiviral, and antiparasitic drugs of a wide chemical variety).

Recognizing different degrees of MDR in bacteria, the terms extensively drug-resistant (XDR) and pandrug-resistant (PDR) have been introduced. Extensively drug-resistant (XDR) is the non-susceptibility of one bacteria species to all antimicrobial agents except in two or less antimicrobial categories. Within XDR, pandrug-resistant (PDR) is the non-susceptibility of bacteria to all antimicrobial agents in all antimicrobial categories. The definitions were published in 2011 in the journal Clinical Microbiology and Infection and are openly accessible.

Common multidrug-resistant organisms, typically bacteria, include:

Overlapping with MDRGN, a group of Gram-positive and Gram-negative bacteria of particular recent importance have been dubbed as the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species).

Various microorganisms have survived for thousands of years by their ability to adapt to antimicrobial agents. They do so via spontaneous mutation or by DNA transfer. This process enables some bacteria to oppose the action of certain antibiotics, rendering the antibiotics ineffective. These microorganisms employ several mechanisms in attaining multi-drug resistance:

Many different bacteria now exhibit multi-drug resistance, including staphylococci, enterococci, gonococci, streptococci, salmonella, as well as numerous other Gram-negative bacteria and Mycobacterium tuberculosis. Antibiotic resistant bacteria are able to transfer copies of DNA that code for a mechanism of resistance to other bacteria even distantly related to them, which then are also able to pass on the resistance genes, resulting in generations of antibiotics resistant bacteria. This initial transfer of DNA is called horizontal gene transfer.

Phage-resistant bacteria variants have been observed in human studies. As for antibiotics, horizontal transfer of phage resistance can be acquired by plasmid acquisition.

Yeasts such as Candida species can become resistant under long-term treatment with azole preparations, requiring treatment with a different drug class. Lomentospora prolificans infections are often fatal because of their resistance to multiple antifungal agents.