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Multiple strategies have been suggested to alleviate this problem, including the use of antibiotic combinations and cyclic therapies. We examine how adaptation to (1) combinations of drugs affects resistance to individual drugs, and to (2) individual drugs alters responses to drug combinations. To evaluate this, we evolved multiple strains of drug resistant <jats:italic>Staphylococcus epidermidis<\/jats:italic> in the lab. We show that evolving resistance to four highly synergistic combinations does not result in cross\u2010resistance to all of their components. Likewise, prior resistance to one antibiotic in a combination does not guarantee survival when exposed to the combination. We also identify four 3\u2010step and four 2\u2010step treatments that inhibit bacterial growth and confer collateral sensitivity with each step, impeding the development of multidrug resistance. 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