AbstractThe phenomenon of attenuated antibacterial activity at inocula above those utilized for susceptibility testing is referred to as the inoculum effect. Although the inoculum effect has been reported for several decades, it is currently debatable whether the inoculum effect is clinically significant. The aim of the present review was to consolidate currently available evidence to summarize which β-lactam drug classes demonstrate an inoculum effect against specific bacterial pathogens. Review of the literature showed that the majority of studies that evaluated the inoculum effect of β-lactams were in vitro investigations of Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae and Staphylococcus aureus. Across all five pathogens, cephalosporins consistently displayed observable inoculum effects in vitro, whereas carbapenems were less susceptible to an inoculum effect. A handful of animal studies were available that validated that the in vitro inoculum effect translates into attenuated pharmacodynamics of β-lactams in vivo. Only a few clinical investigations were available and suggested that an in vitro inoculum effect of cefazolin against MSSA may correspond to an increased likeliness of adverse clinical outcomes in patients receiving cefazolin for bacteraemia. The presence of β-lactamase enzymes was the primary mechanism responsible for an inoculum effect, but the observation of an inoculum effect in multiple pathogens lacking β-lactamase enzymes indicates that there are likely multiple mechanisms that may result in an inoculum effect. Further clinical studies are needed to better define whether interventions made in the clinic in response to organisms displaying an in vitro inoculum effect will optimize clinical outcomes.