Cerebrospinal fluid and plasma pharmacokinetics of ceftazidime/avibactam in a neurocritical patient with CRKP intracranial infection and augmented renal clearance.

BACKGROUND

Intracranial infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) pose significant therapeutic challenges, primarily due to the limited penetration of antimicrobial agents across the blood-brain barrier. Ceftazidime/avibactam demonstrates efficacy against multidrug-resistant Gram-negative pathogens. However, its CSF pharmacokinetics and optimal dosing in patients with augmented renal clearance (ARC; CrCl > 130 mL/min/1.73 m²) remain inadequately characterized.

METHODS

We utilized validated high-performance liquid chromatography to quantify ceftazidime/avibactam concentrations in paired plasma and CSF samples obtained from a traumatic brain injury patient with CRKP ventriculitis and ARC (CrCl 154.37 mL/min/1.73 m²). The MIC of ceftazidime/avibactam was determined using broth microdilution in accordance with Clinical and Laboratory Standards Institute guidelines.

RESULTS

Standard Ceftazidime/avibactam dosing (2.5 g q8h) resulted in subtherapeutic trough concentrations in both plasma (ceftazidime/avibactam: 10.39/0.96 µg/mL) and CSF (ceftazidime/avibactam: 20.4/0.68 µg/mL) against the target pathogen (MIC = 4 mg/L). Dose intensification to 2.5 g q6h administered via 3-h prolonged infusion achieved supra-therapeutic exposures (troughs: plasma 65.60/8.70 µg/mL; CSF 58.90/10.82 µg/mL; CSF/plasma ratio = 0.9 for ceftazidime), which correlated with CSF sterilization and resolution of inflammatory markers.

CONCLUSION

This first-in-human pharmacokinetic evidence in a patient with ARC underscores the inadequacy of conventional ceftazidime/avibactam regimens in this population. Our findings advocate for therapeutic drug monitoring-guided dose optimization incorporating extended infusions to achieve therapeutic targets. These results emphasize the critical need for personalized dosing algorithms in the neurocritical care setting.