A 2010 review of penetration of different antimicrobials to blood-cerebrospinal fluid/blood-brain barrier (BBB) noted different factors, such as molecular sizes, lipophilicity, plasma protein binding, and active transporters, may affect central nervous system (CNS) penetrations. In the absence of meningeal inflammation, the penetration of beta-lactams is relatively poor. If a high level of activity against susceptible pathogens is confirmed, the daily intravenous (IV) dose of ampicillin can be increased to ≥ 15 g for adults with normal renal function. Among different beta-lactamase inhibitors (e.g., sulbactam and tazobactam), sulbactam was reported with broad clinical experience for CNS infections. High-dose sulbactam (up to 8 g/day) plus ampicillin (16 g/day) had been used successfully to treat Acinetobacter meningitis. In vitro susceptibility testing suggested that larger than standard doses of β-lactamase inhibitors may be necessary to treat CNS infections. Overall, the ideal agent to treat CNS infections should be small, moderately lipophilic, have a low level of plasma protein binding, and have not a strong ligand of P-gp or another efflux pump at the BBB. [1], [2]
An older study from 1981 observed the use of piperacillin in four patients with gram-negative meningitis. Piperacillin was dosed at 324 to 436 mg/kg/day, which resulted in a cerebrospinal fluid level of 23 mcg/mL at 24 hours. Therefore, the mean penetration was determined to be 32% and was deemed adequate for treatment. However, results from older studies are difficult to extrapolate to the current healthcare landscape. [3]
An online textbook on Critical Care (from the authors of EMCrit) states both ampicillin/sulbactam and piperacillin/tazobactam have a 1% entry into uninflamed meninges. However, in inflamed meninges, piperacillin/tazobactam has a 30% meningeal penetration compared to 20% with ampicillin/sulbactam. [4]
A recent review discussing the challenges of managing healthcare-associated ventriculitis and meningitis suggested that many commonly used drug classes, including beta-lactams and glycopeptides, hardly penetrate the cerebrospinal fluid (CSF) and thus may not achieve the therapeutic levels. In the presence of resistant pathogens, higher daily doses and prolonged or continuous administration may be considered to facilitate pathogens clearance. Alternatively, intraventricular antibiotic therapy in addition to IV therapy can be used; however, due to the increased risk of aseptic meningitis and seizures, patients should be treated with caution. The authors do not specifically discuss the roles of piperacillin/tazobactam versus ampicillin/sulbactam in this case. [5]