Stability of Amoxicillin and Clavulanic Acid in Separate Containers for Administration via a Y-Site

Abstract

Rationale With the discovery of new antibiotics diminishing, optimising the administration of existing antibiotics such as amoxicillin-clavulanic acid has become a necessity. At present, the optimal approach for enhancing the effectiveness of time-dependent antibiotics involves extending the time at which antibiotic concentrations are maintained above the minimal inhibitory concentration by prolonging the infusion time. This pharmacodynamic rationale cannot be applied to co-amoxiclav because of poor stability at room temperature. The aim of this study was to establish the shelf-life of amoxicillin and clavulanic acid prepared in separate containers to determine the feasibility of 24-hr continuous infusion therapy. Methods A previously developed and validated stability-indicating HPLC method was used to establish the shelf-life of reconstituted amoxicillin and clavulanic acid when prepared in separate containers. Stability at clinical concentration was evaluated at three temperatures. To establish whether there were significant differences at the level of both active ingredients and temperature, results were analysed using analysis of covariance (ANCOVA) to assess differences between the attained slopes of regression. Results Data obtained indicated amoxicillin and clavulanic acid stability superior to that previously proposed making it suitable for continuous infusion therapy. Analysis of regression slopes via ANCOVA showed that temperature significantly affected amoxicillin and clavulanic acid stability. Amoxicillin retained 90% of its initial concentration for 80.3 hrs when stored at 4°C, 24.8 hrs at 25°C and 9 hrs when incubated at 37°C. Clavulanic acid retained 90% of its initial concentration for 152 hrs when stored at 4°C, 26 hrs at 25°C and 6.4 hrs when incubated at 37°C. Conclusion Amoxicillin and clavulanic acid are suitable for administration via continuous infusion when prepared, stored, and administered in separate containers. Results obtained from this study aid in ameliorating current dosing regimens to optimise antibiotic efficacy; however, more in-depth amoxicillin and clavulanic acid y-site compatibility studies are warranted.

Defining minimal selective concentrations of amoxicillin, doxycycline and enrofloxacin in broiler-derived cecal fermentations by phenotype, microbiome and resistome

“…However, other factors could have influenced the caecal fermentations with the amoxicillin treatment as a result of the poor stability of amoxicillin (8). Amoxicillin is temperature sensitive and since we incubated the caecal fermentations at 41 °C its stability might have decrease during the fermentation (41). In addition, the existing resistance could also influence the effectiveness of amoxicillin, since beta-lactamase is able to hydrolyse the beta-lactam ring and therefore inactivate the compound (42).…”

Predicting bioactivity of antibiotic metabolites by molecular docking and dynamics

“…Penicillins are relatively unstable in the environment, e.g. piperacillin can remain stable with 5% tazobactam sodium for 2 days at 25°C (38), amoxicillin remains stable with clavulanic acid for 26 hours at 25°C (39) and penicillin G could be stable for 24 hours at 25°C (40). Although there is little evidence about the stability of penicillin metabolites in laboratory or environmental conditions, the penillic acid, penicilloic acid and penicillenic acid can be highly unstable metabolites with an unstable beta-lactam ring (25), so the evidence for the uncertain stability of the metabolite is required.…”

“…It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted September 6, 2022. ; https://doi.org/10.1101/2022.09.06.506739 doi: bioRxiv preprint Penicillins are relatively unstable in the environment, e.g. piperacillin can remain stable with 5% tazobactam sodium for 2 days at 25°C (38), amoxicillin remains stable with clavulanic acid for 26 hours at 25°C (39) and penicillin G could be stable for 24 hours at 25°C (40). Although there is little evidence about the stability of penicillin metabolites in laboratory or environmental conditions, the penillic acid, penicilloic acid and penicillenic acid can be highly unstable metabolites with an unstable betalactam ring (25), so the evidence for the uncertain stability of the metabolite is required.…”

Stability Studies of the Dilution Series of Different Antibiotic Stock Solutions in Culture Medium Incubated at 37 °C

“…Among these studies, amoxicillin has garnered the most attention, with its instability primarily attributed to hydrolysis, influenced by temperature, pH [ 14 ], and solution concentration [ 15 ]. Experimental data indicate that amoxicillin solutions maintain over 90% stability for 1–3 days at 20–25 °C [ 16 , 17 ], with a notable reduction at 37 °C [ 17 , 18 ]. Similarly, cefotaxime’s stability is compromised by hydrolysis, affected by temperature [ 19 , 20 ], and diminishes with high concentrations of macromolecules [ 21 ].…”