A Kinetic Oxymoron: Concentration-Dependent First-Order Rate Constants for Hydrolysis of Ceftazidime

Abstract

The influence of pH, temperature, and buffers on the hydrolysis of 10(-4) M ceftazidime was previously reported. The pH-rate profiles showed that maximum stability occurred in the pH-independent region from 4.5 to 6.5. In the present study, hydrolysis rates of 0.031, 0.14, 0.25, and 0.35 M ceftazidime were measured at 30 and 65 degrees C, pH 5.5-6.2. The data were consistent with beta-lactam hydrolysis and the rapid release of pyridine. The sum of the time-dependent concentrations of ceftazidime and pyridine provided mass balance. Simultaneous nonlinear regression for ceftazidime loss and pyridine formation provided similar rate constants (k) to those determined from first-order plots of ceftazidime loss. Although the loss of ceftazidime was first-order for each initial concentration, the k values increased as the initial concentrations increased. Plots of k versus initial concentration were linear with intercepts similar to the k values for 10(-4) M solutions, thus implying that ceftazidime catalyzed its own degradation. At the pH of these studies ceftazidime exists as a base. The ceftazidime catalytic constant, calculated from the slope of the plot, was similar to that found for the general-base catalyst, HPO4(2-). Therefore, it is feasible that ceftazidime also behaved as a intermolecular general-base catalyst. However, first-order plots exhibited excellent linearity even though the catalyst (ceftazidime) was consumed. This would require that the catalytic moieties on ceftazidime remained relatively constant throughout its hydrolysis. This hypothesis was shown to be consistent with literature reports which indicate that the general-base catalytic groups can remain relatively constant during cephalosporin hydrolysis.

Stability and Antibacterial Activity of Cefepime during Continuous Infusion

“…Mass spectrometry data indicated that degradation of cefepime includes cleavage of N-methylpyrrolidine (R2 side chain) and opening of the cephem (␤-lactam ring). This was the expected breakdown of cefepime, since two related compounds, ceftazidime and cefpirome, have shown similar breakdown (5,11). It also indicates that the ring opening occurs before the cleavage of N-methylpyrrolidine.…”

Stability of ceftazidime in a viscous eye drop formulation

“…Pyridine is formed quantitatively from the degradation of ceftazidime in buffered aqueous solutions (13). In the present study, the mass of pyridine produced was close to the theoretical values, with a reduction to around 95% after 14 days at 7 °C.…”

Clavulanic Acid Decomposition Is Catalyzed by the Compound Itself and by Its Decomposition Products

“…Similar observations were made for other antibiotics. For example the hydrolysis of ceftazidime is self-accelerated at higher concentration because ceftazidime and its decomposition product act as similarly strong general-base catalysts, 13 and the authors concluded that all antibiotics which are sensitive to general acid-base catalysis and contain functional groups such as amino-or hydroxyl groups, which can act as such catalysts, are likely to selfcatalyze their own decomposition. Indeed, the isomerisation of ceftibuten is facilitated by itself as a general acid or base catalyst, 14 so is the hydrolysis of amoxicillin by the catalytic action of the phenolic hydroxyl group 15 and the degradation of imexon.…”