Quantification of Cefepime, Meropenem, Piperacillin, and Tazobactam in Human Plasma Using a Sensitive and Robust Liquid Chromatography-Tandem Mass Spectrometry Method, Part 2: Stability Evaluation

Abstract

Although the stability of β-lactam antibiotics is a known issue, none of the previously reported bioanalytical methods had an adequate evaluation of the stability of these drugs. In the current study, the stability of cefepime, meropenem, piperacillin, and tazobactam under various conditions was comprehensively evaluated. The evaluated parameters included stock solution stability, short-term stability, long-term stability, freeze-thaw stability, processed sample stability, and whole-blood stability. When stored at -20°C, the stock solution of meropenem in methanol was stable for up to 3 weeks, and the stock solutions of cefepime, piperacillin, and tazobactam were stable for up to 6 weeks. All four antibiotics were stable in human plasma for up to 3 months when stored at -80°C and were stable in whole blood for up to 4 h at room temperature. Short-term stability results indicated that all four β-lactams were stable at room temperature for 2 h, but substantial degradation was observed when the plasma samples were stored at room temperature for 24 h, with the degradation rates for cefepime, meropenem, piperacillin, and tazobactam being 30.1%, 75.6%, 49.0%, and 37.7%, respectively. Because the stability information is method independent, our stability results can be used as a reference by other research groups that work with these antibiotics.

Analytical methods for the determination of certain antibiotics used in critically ill patients

“…Analytical separation of Cefepime, meropenem, piperacillin, tazobactam, meropenem, and piperacillin with LC-MS/MS was carried out using C18 100 A LC column (50 mm × 2.1 mm × 2.6 µm) coupled with Ultra UPLC Evo C18 cartridge using a mobile phase composed of a mixture of solvent A (water with 0.1% formic acid) and solvent B (acetonitrile with 0.1% formic acid) with flow rate at 0.25 ml/min. The total run time was 7.0 min, and gradient elution was performed as follows: 2% solvent B (0 to 0.3 min), 40% solvent B (0.3 to 2.8 min), and a hold at 2% solvent B until the end of the run [9] .…”

The Utility of Pharmacometric Models in Clinical Pharmacology Research in Infants

“…A typical example is βlactams, a class of antibiotics that are frequently prescribed in infant patients. We conducted short-term stability of cefepime, meropenem, piperacillin, and tazobactam and found that all four antibiotics were unstable after 24 hours at room temperature, with average degradation ranging from 30.1% for cefepime to 75.6% for meropenem [36]. In addition, meropenem was even unstable after 24 hr at 4°C with an average degradation of 25.9% [36].…”

“…We conducted short-term stability of cefepime, meropenem, piperacillin, and tazobactam and found that all four antibiotics were unstable after 24 hours at room temperature, with average degradation ranging from 30.1% for cefepime to 75.6% for meropenem [36]. In addition, meropenem was even unstable after 24 hr at 4°C with an average degradation of 25.9% [36]. Although we did not test their 3-day stability, it is reasonable to anticipate that the stability data can only be worse than the 24 hr stability data we have.…”

Meropenem Stability in Human Plasma at −20 °C: Detailed Assessment of Degradation

“…As a result, meropenem samples collected during clinical studies are often processed and frozen until shipment and/or batch analysis. Studies have reported that β-lactams show substantial degradation in plasma depending on the storage temperature and storage time [4][5][6]. For meropenem, significant degradation has been shown beyond 6 h at 24 • C or 3 days at 4 • C [7].…”

“…Stability at −20 • C has only been demonstrated for 3 days up to 20 days [7][8][9][10]. Mortensen et al [7] recommend that plasma samples for quantification of meropenem stored for longer than 3 days should be kept at −80 • C. To date, stability of meropenem in human plasma at −80 • C has been shown for at least 3-9 months [5,6,11]. However, in several PK studies, meropenem plasma samples were stored at −20 • C for longer than 3 days, or the storage time was not mentioned in the paper [12][13][14][15].…”