The treatment of gram-negative bacterial infections exhibiting resistance to all traditional β-lactam and fluoroquinolone agents (i.e., difficult-to-treat resistance [DTR]) poses challenges due to the limited numbers of active antibiotic agents, in addition to limited data on safety and efficacy. Managing DTR gram-negative infections becomes even more complex when present in the central nervous system due to concerns for insufficient concentrations of agents in the cerebrospinal fluid and brain parenchyma. Several newer β-lactam agents with activity against DTR gram-negatives are available including cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-cilastatin-relebactam, meropenem-vaborbactam, and sulbactam-durlobactam. In this article, we review host and drug factors that influence an antibiotic's likely effectiveness for the treatment of bacterial meningitis. We also review the preclinical and clinical data in support of or against each of the aforementioned agents for the treatment of bacterial meningitis.
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