In 1940, Edard Abraham and Ernst Chain reported that an E. coli strain was able to inactivate penicillin by producing penicillinase. The first sign of antibiotic resistance became apparent soon after the discovery of penicillin.

The spread of penicillin resistance was already documented by 1942, when four Staphylococcus aureus strains were found to resist the action of penicillin in hospitalized patients [21]. During the next few years, the proportion of infections caused by penicillin-resistant S. aureus rapidly rose, spreading quickly from hospitals to communities. By the late 1960s, more than 80 percent of both community and hospital-acquired strains of S. aureus were penicillin-resistant [22]. The rapid spread of penicillin resistance temporarily came to a halt after the introduction of the second-generation, semisynthetic methicillin in the 1960s.