Physicochemical stability of cefiderocol, a novel siderophore cephalosporin, in syringes at 62.5 mg/mL for continuous administration in intensive care units

Abstract

IntroductionCefiderocol is a new siderophore time-dependent antibiotic of last resort. The manufacturer reports a stability of 6 hours for the infusion solution diluted in normal saline (NS) or dextrose 5% in water (D5W) for a concentration between 7.5 and 20 mg/mL. Optimising its effectiveness by continuous infusion is crucial. The aim of this work was to study the physicochemical stability of cefiderocol diluted in NS or D5W in polypropylene syringes for 48 hours at a concentration of 62.5 mg/mL stored at room temperature, protected or not from light.Materials and methodsThree preparations for each condition were performed. At each time of the analysis, one sample for each preparation was analysed in triplicate by a validated high performance liquid chromatography method coupled to a photodiode array detector at 260 nm. Particle contamination, absorbance measurement, visual inspection and pH measurement were assessed. The limit of stability was set at 90% of the initial concentration, without physical modification.ResultsThe linearity was validated with an R² of 0.9999. The coefficients of variation for repeatability and intermediate precision were less than 2%. In NS and D5W, cefiderocol retained more than 90% of the initial concentration after 12 hours in syringes, exposed or not to light. Two degradation products (nos 2 and 11, observed during forced degradation) were detected during the stability study. The absorbance at 410 nm increased progressively, regardless of the storage conditions. The particulate contamination test met the specifications of the container. pH values were all between 5.22 and 5.32. No visual changes were detected.ConclusionIn polypropylene syringes, cefiderocol 62.5 mg/mL (3 g in 48 mL) diluted in NS or D5W was stable for 12 hours at room temperature. These new data allow the use of cefiderocol in continuous infusion.

Effectiveness of First-Line Therapy with Old and Novel Antibiotics in Ventilator-Associated Pneumonia Caused by Carbapenem-Resistant Acinetobacter baumannii: A Real Life, Prospective, Observational, Single-Center Study

“…Beta-lactams are known to exhibit time-dependent killing and better target attainments and clinical outcomes have been related to prolonged or continuous compared to standard infusion [ 44 , 45 ]. As for our institutional protocol, beta-lactams, including cefiderocol, are administered via continuous infusion preceded by a loading dose [ 23 ]. Thus, our dosing approach may possibly have favored timely optimal cefiderocol lung exposure [ 43 ], contributing to the low rates of clinical failure observed in our cohort, as has been reported for the prolonged infusion of ceftazidime–avibactam in infections caused by carbapenem-resistant Enterobacterales [ 42 ].…”

“…Patients treated with colistin received 1 g of ascorbic acid 30 min before iv colistin administration, to prevent colistin-induced nephrotoxicity [ 21 ]. Cefiderocol was administered as a LD of 2 g followed by a 8 h infusion of 2 g every 8 h in patients with normal renal function and by a 6 h infusion of 2 g every 6 h in patients with ARC [ 22 , 23 ]. For all administered antibiotics, maintenance dose adjustments were performed in patients with renal impairment, according to the manufacturer’ recommendations.…”

Systematic review of room temperature stability of key beta-lactam antibiotics for extended infusions in inpatient settings

“…While there is insufficient evidence to extend the shelf life of cefepime or cefiderocol using 95–105% limits, for those using 90–110% limits cefepime 8 mg/mL in either glucose 5% or sodium chloride 0.9%, stability can be extended to 24 hours 17–19 47–49. Similarly, cefiderocol 62.5 mg/mL in glucose 5% or sodium chloride 0.9% can be extended to 12 hours at room temperature 50 51…”

“…Data from included papers for cefepime,48 49 cefiderocol,50 51 cefotaxime60 61 or ceftolozane-tazobactam62–64 was insufficient to extend the shelf-life beyond that stated in the SmPC.…”

Cefiderocol

“…The standard cefiderocol dose is 2000mg every 8h in extended perfusion over 3 h [6]. Cefiderocol shows physicochemical stability in syringes for 12 h, opening the possibility of continuous infusion [7]. The dose of cefiderocol requires dose adjustment based on renal function, either in dysfunction or in hyper-clearance states that require daily dose increase to 2000 mg every 6h with creatinine clearance >120ml/min [6].…”