How To Minimize Toxic Exposure to Pyridine during Continuous Infusion of Ceftazidime in Patients with Cystic Fibrosis?

Abstract

Ceftazidime is particularly efficient against Pseudomonas aeruginosa in cystic fibrosis patients. Thus, the spontaneous production of pyridine, which is a toxic product, raises some concern. Our aim was to examine the kinetics of degradation of ceftazidime in portable infusion pumps either at 4°C, 22°C, or 33°C and to propose some recommendations in order to reduce the pyridine exposure. Two administration models were studied in vitro. In model 1, we administered 12 g of ceftazidime infused over 23 h (once-daily infusion) compared to 6 g infused over 11.5 h in model 2 (twice-daily regimen). Samples were collected at 0 h and then every 4 and 2 h after the shaping of portable infusion pumps in models 1 and 2, respectively. Both ceftazidime and pyridine were analyzed using an ultraviolet high-performance liquid chromatograph. Production of pyridine is highly depending on the temperature. The in situ production of pyridine per day of treatment decreases at a ratio close to 1/6 and 1/3 between 33°C and 4°C in models 1 and 2, respectively. Regardless of the conditions, the production of pyridine is significantly lower in model 2, whereas the total delivery amount of ceftazidime is significantly higher at 4°C and 33°C compared to that in model 1. According to a the precautionary principle, these findings lead to three major recommendations: (i) exposing a solution of ceftazidime to over 22°C should be strictly avoided, (ii) a divided dose of 6 g over 11.5 h instead of a once-daily administration is preferred, and (iii) infusion should be administered immediately after reconstitution.

Liquid chromatographic method to follow‐up ceftazidime and pyridine in portable elastomeric infusion pumps over 24 h

“…It was found that 10% of the ceftazidime was degraded after an average of 19 h 11 min (n = 4) and 0.79% (n = 4) of pyridine was formed after 24 h. Figures 3 and 4 show the results obtained with one of the PEIPs as an example of this degradation. The increase in concentration of pyridine present in the solution is in line with findings from literature [9,10]. Typical chromatograms obtained at 254 and 285 nm with a sample taken from a PEIP at 20 h are shown in Fig.…”

“…Curti et al examined the stability of a 40 mg/mL ceftazidime solution in saline over 8 h at ambient temperature when stored in 50 mL polypropylene syringes and found that the solution was stable [9]. Ceftazidime aqueous solutions at concentrations around 53 mg/mL in PEIPs were checked by Bourget et al at a temperature of 33°C over 23 h [10]. In these conditions, ceftazidime was stable for only 12 h.…”

“…This has been described by Bourget et al, who used a Polaris (4.6 × 250 mm, 5 μm) C18 column with a flow rate of 1.8 mL/min. Although this column may be suitable, it is difficult to assess that method because no chromatograms are shown and there is no guarantee that pyridine will not elute in the dead volume [10] since it is a small and polar compound that is difficult to retain on a RP stationary phase. In addition, due to economical and environmental considerations, lower flow rates are more interesting because of a reduced consumption of solvents.…”

“…During stability studies of ceftazidime, pyridine was found to gradually increase over time [9,10]. Given its hazardous nature, pyridine requires some additional attention.…”

Systematic review of stability data pertaining to selected antibiotics used for extended infusions in outpatient parenteral antimicrobial therapy (OPAT) at standard room temperature and in warmer climates

“…The introduction of the 2 mg PDE26 27 standard for pyridine exposure means the old standard of the 1.1 mg/mL25 should be disregarded. Bourget et al ,29 measured the total delivered amount of pyridine over various full-day infusions comparing two 6 g infusion over 11.5 hours each for a total of 23 hours of run-out and a single 23 hours infusion of 12 g. This split method (2×6 g infusions) was tested to try to reduce the total daily exposure of pyridine. Although it was a successful reduction, the amount of pyridine the patient still received was 26.4 mg and 30.4 mg when run-out at 22°C and at 33°C, respectively.…”