Resistance to other drugs within an antibiotic class or to unrelated drugs.

Resistance arises when bacteria acquire drug resistance genes or mutations in genes that alter their sensitivity to an antibiotic. For instance, enzymes that confer drug resistance, e.g., beta-lactamases can confer resistance to many beta-lactam drugs. Some drug resistance mutations in the bacterial genome affect how an antibiotic interacts with its target. Therefore, antibiotics that interact with the same target generally have similar mechanisms of action, and so these mutations can also affect the potency of some or all other antibiotics in the same class or others that interact with the same target.

Cross-resistance can also apply to antibiotics of different classes and with different mechanisms of action. For example, mutations affecting drug efflux mechanisms can confer drug resistance (see efflux-mediated resistance) to multiple classes of antibiotics. Therefore, exposure to a single antibiotic can lead to reduced sensitivity to multiple antibiotics and thus multidrug resistance.