Infectious disease: how to manage Gram-positive and Gram-negative pathogen conundrums with dual beta-lactam therapy

Antimicrobial resistance is a global public health threat due to its associated increase in mortality, and the most appropriate treatment algorithms for resistant and persistent Gram-positive and Gram-negative infections have yet to be elucidated. Whilst combination therapy has been touted as a viable method to overcome prominent resistant mechanisms represented amongst these microbes, the optimal agents to utilize remains controversial. Beta-lactams have a safe profile and are bactericidal against most Gram-positive and Gram-negative microorganisms. Thus, the use of dual beta-lactam therapy to overcome multidrug-resistant pathogens is of supreme interest. This article reviews the mechanisms of beta-lactam resistance in Gram-positive and Gram-negative bacteria, discusses the rationale for dual beta-lactam use against multidrug-resistant infections (and other scenarios in which this strategy may be most utilized in clinical practice), explores the available in vitro, in vivo and clinical data, and provides considerations for the use of dual beta-lactam therapy against Enterococcus faecalis, Listeria monocytogenes, Staphylococcus aureus, Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii pathogens.