Plasma and cerebrospinal fluid concentrations of cefiderocol during successful treatment of carbapenem-resistant Acinetobacter baumannii meningitis

Abstract

Background To date, no real-world data are available to describe cefiderocol use in carbapenem-resistant Acinetobacter baumannii (CRAB) meningitis. Furthermore, cefiderocol pharmacokinetic (PK) data to support CNS penetration in human subjects are limited. These gaps pose a significant concern for clinicians who are faced with treating such infections when considering cefiderocol use. Objectives To describe cefiderocol CSF and plasma PK and pharmacodynamic (PD) data from two different dosing regimens [2 g IV q6h (regimen 1) and 2 g IV q8h (regimen 2)] during treatment of CRAB meningitis. Patients and methods A 61-year-old woman with CRAB meningitis was treated with cefiderocol and intraventricular gentamicin. Steady-state plasma and CSF cefiderocol concentrations were evaluated on Day 19 (regimen 1) and Day 24 (regimen 2) during the cefiderocol treatment course. Results CSF AUC was 146.49 and 118.28 mg·h/L, as determined by the linear-log trapezoidal method for regimens 1 and 2, respectively. Penetration into CSF estimated as the AUCCSF/AUCfree plasma ratio was 68% and 60% for regimens 1 and 2, respectively. Estimated free plasma and CSF concentrations exceeded the MIC of the isolate for 100% of the dosing interval. Microbiological and clinical cure were achieved, and no cefiderocol-associated adverse effects were observed. Conclusions Cefiderocol, when given as 2 g q8h and 2 g q6h, attained CSF concentrations that exceeded the organism-specific MIC and the CLSI susceptible breakpoint (≤4 mg/L) for 100% of the dosing interval.

Real-Life Data on the Effectiveness and Safety of Cefiderocol in Severely Infected Patients: A Case Series

“…To date, the main limitation of cefiderocol TDM is broad availability. Cefiderocol concentrations were measured in only three previously published case series [ 16 , 17 , 30 ]. Two cases of TDM have been reported in patients with meningitis; one due to DTR-PA [ 14 ] and the other due to CRAB [ 30 ].…”

“…Cefiderocol concentrations were measured in only three previously published case series [ 16 , 17 , 30 ]. Two cases of TDM have been reported in patients with meningitis; one due to DTR-PA [ 14 ] and the other due to CRAB [ 30 ]. Since cefiderocol is a time-dependent antibiotic, the optimal dose and administration for PK/PD target attainment in the licensed dosing regimens were based on maintaining the free plasma concentration above the MIC during 75–100% of the dosing interval ( fT > MIC of 75–100% or a ratio f C min /MIC of 0.75–1) [ 11 , 12 , 31 ].…”

Cefiderocol Efficacy in a Real-Life Setting: Single-Centre Retrospective Study

“…In our study, two patients with CNS CRAB infections were treated and both died. Although evidence on CNS infections CFD use is lacking ( Table 4 ), few PK/PD studies suggest that CFD could be a promising option for lactose non-fermenters CR-GN treatment, with drug concentration in cerebrospinal fluid above bacterial MIC [ 17 , 28 ].…”

Pharmacokinetic/Pharmacodynamic Analysis of Continuous-Infusion Fosfomycin in Combination with Extended-Infusion Cefiderocol or Continuous-Infusion Ceftazidime-Avibactam in a Case Series of Difficult-to-Treat Resistant Pseudomonas aeruginosa Bloodstream Infections and/or Hospital-Acquired Pneumonia

“…Administration of fosfomycin by CI could be the best strategy for both maximizing PK/PD target attainment and preventing resistance emergence among MDR Gram-negative infections [ 17 , 18 , 19 ]. In this regard, we showed in a previous case of carbapenem-resistant PA ventriculitis treated with CI fosfomycin in combination with CI ceftazidime/avibactam that the penetration rate of fosfomycin into the CSF was as high as 50% and that attaining optimal joint PK/PD targets at the infection site was fundamental for granting microbiological eradication and clinical success [ 20 , 21 , 22 , 23 , 24 , 25 ].…”

“…A therapeutic drug monitoring (TDM)-guided personalized antimicrobial dosing with expert clinical pharmacological interpretation could represent a useful tool for promptly maximizing the attainment of optimal PK/PD targets in this challenging scenario. To this regard, different real-world studies recently highlighted the clinical relevance of a TDM-guided approach for personalized tailored therapy with novel BLs and/or BL/BLIc in deep-seated infections [ 20 , 21 , 22 , 23 , 24 , 25 ]. However, real-world data testing of the effectiveness of fosfomycin in combination with novel BLs or BL/BLIc in DTR-PA infections in relation to PK/PD target attainment is currently lacking [ 5 , 6 ].…”