Comparative Stability Studies of Antipseudomonal β-Lactams for Potential Administration through Portable Elastomeric Pumps (Home Therapy for Cystic Fibrosis Patients) and Motor-Operated Syringes (Intensive Care Units)

Abstract

The stability of antipseudomonal ␤-lactams in concentrated solutions was examined in view of their potential administration by continuous infusion with external pumps (for intensive care patients) or with portable pumps carried under clothing (for cystic fibrosis patients). Aztreonam (100 g/liter), piperacillin (128 g/liter, with tazobactam), and azlocillin (128 g/liter) remained 90% stable for up to more than 24 h at 37°C (mezlocillin [128 g/liter] was stable at 25°C but not at 37°C). Ceftazidime (120 g/liter), cefpirome (32 g/liter), and cefepime (50 g/liter) remained 90% stable for up to 24, 23.7, and 20.5 h at 25°C but only for 8, 7.25, and 13 h at 37°C, respectively. The control of temperature therefore appears to be critical for all three cephalosporins that cannot be recommended for use in portable pumps carried under clothes for prolonged periods for reasons of stability. Cefpirome and cefepime solutions developed an important color change (from light yellow to dark red) upon exposure when stored at 30°C or higher. Degradation of ceftazidime was accompanied by the liberation of pyridine which, at 37°C, was in excess of what is allowed by the U.S. Pharmacopeia, i.e., 1.1 mg/liter, after 8 and 12 h for drug concentrations of 12 and 8.3%, respectively. Imipenem and meropenem are too unstable (10% degradation at 25°C after 3.5 and 5.15 h, respectively) to be recommended for use by continuous infusion. Faropenem, examined in comparison with imipenem and meropenem, proved as stable as aztreonam or piperacillin.␤-Lactams are one of the most typical antibiotic classes for which the pharmacodynamic data, collected in vitro, as well as in animal studies, clearly indicate a potential advantage of a continuous infusion over the more conventional, discrete mode of administration (see references 6, 22, 23, 38, and 41 for reviews). Accordingly, several clinical trials have been initiated over the last half-decade, most notably in difficult-to-treat situations such as suspected gram-negative infections in critically ill patients (3), severe infections in intensive care patients (8,16,21,24,37), septicemia (1), severe sepsis (20), and cystic fibrosis (29,40). Yet, as clearly pointed out by one of the first promoters of the continuous infusion of ␤-lactams (6), this mode of administration, through programmable pumps or other similar devices, requires the drug to remain sufficiently stable in solution over the projected duration of the infusion. In a previous study (30), we examined the stability of ceftazidime in solution and found it to be critically dependent on the temperature within the 20 to 37°C range (68 to 99°F). This sets clear limitations on the potential use of ceftazidime by continuous infusion if administrations every 24 h are contemplated without periodic changes of the solutions. Chemical considerations suggest that the stability of the main ␤-lactams currently registered for human medicine use may vary to a meaningful extent. Unfortunately, these variations, and their consequences as far as continuous infu...

Meropenem-Clavulanic Acid Shows Activity against Mycobacterium tuberculosis In Vivo

“…In addition, plasma protein binding is reported to be only 2% (7); therefore, binding to albumin in fetal bovine serum (FBS) supplemented with Dulbecco's modified Eagle medium (DMEM) is not expected to be a significant factor. Meropenem has been reported to be thermally unstable in aqueous solutions (10,12,17); therefore, we determined the stability of meropenem and the other carbapenems at 37°C in water, 7H9 broth medium, and the medium used with the infected macrophages in the susceptibility assay (DMEM) by liquid chromatography (LC)-mass spectrometry (MS) using a Luna NH2 column with a single quadrupole mass-selective detector (Agilent MSD, model G1946DSL). Additional details for this and other experiments can be found in the supplemental material.…”

Rapid analysis of N-methylpyrrolidine in cefepime with thermal desorption ion mobility spectrometry

“…(2002) reported that when stored at temperatures of 30 °C and higher, aqueous solutions of cefepime, exhibited a colorimetric change from light yellow to dark red. [10] This colour change was accompanied by a significant increase in the pH of the solution, thus, suggesting the presence of alkaline degradation products. Fubara et.…”

“…The instability of cephalosporins in aqueous media is as a result of the highly reactive beta lactam ring, which is susceptible to base catalysed hydrolysis. [10] Degradation studies of cefepime conducted by Sprauten et al (2003) indicated that ring opening of the beta lactam moiety occurred initially, followed by cleavage of the C3 substituent, N-methylpyrrolidine (NMP, II), an acyclic tertiary amine. [4] As NMP is a recognised degradation product, the United States Pharmacopoeia (USP) states that in cefepime for injection the limit of N-methylpyrrolidine 'must not exceed more than 1.0% w/w relative to cefepime [12] and in cefepime hydrochloride 'must not exceed more than 0.3% w/w relative to cefepime.…”

“…[13] The analysis of NMP in cefepime poses a challenge to the analyst due to the labile nature of cefepime in aqueous solution. Liquid chromatographic separations have been previously used to determine NMP in cefepime using both reversed phase [10,14] and ion chromatography [15] methodologies. Separation of NMP from cefepime has also been accomplished using capillary electrophoresis.…”

Impact of Severe Sepsis or Septic Shock on Drug Response

“…Meropenem and imipenem are not good candidates. On the other hand, some other antibiotics are stable such as piperacillin/tazobactam; ceftazidime and vancomycin (Viaene et al, 2002). So, not only the appropriate dose, usually larger doses than standard regimen are necessary, but also the right mode of administration could help to resolve this clinical situation.…”