Overcoming stability challenges during continuous intravenous administration of high-dose amoxicillin using portable elastomeric pumps

Abstract

While treatment of serious infectious diseases may require high-dose amoxicillin, continuous infusion may be limited by lack of knowledge regarding the chemical stability of the drug. Therefore, we have performed a comprehensive study so as to determine the chemical stability of high-dose amoxicillin solutions conducive to safe and effective continuous intravenous administration using portable elastomeric pumps. First, amoxicillin solubility in water was assessed within the range of 25 to 300 mg/mL. Then, amoxicillin solutions were prepared at different concentrations (25, 50, 125, 250 mg/mL) and stored in different conditions (5±2°C, 25±1°C, 30±1°C and 37±1°C) to investigate the influence of concentration and temperature on the chemical stability of amoxicillin. Finally, its stability was assessed under optimized conditions using a fully validated HPLC-UV stability-indicating method. Degradation products of amoxicillin were investigated by accurate mass determination using high-resolution mass spectrometry. Amoxicillin displayed limited water solubility requiring reconstitution at concentrations below or equal to 150 mg/mL. Amoxicillin degradation were time, temperature as well as concentration-dependent, resulting in short-term stability, in particular at high concentrations. Four degradation products of amoxicillin have been identified. Among them, amoxicilloic acid and diketopiperazine amoxicillin are at risk of allergic reaction and may accumulate in the patient. Optimized conditions allowing for continuous infusion of high-dose amoxicillin has been determined: amoxicillin should be reconstituted at 25 mg/mL and stored up to 12 hours at room temperature (22 ± 4°C) or up to 24 hours between 4 and 8°C.

International consensus recommendations for the use of prolonged‐infusion beta‐lactam antibiotics: Endorsed by the American College of Clinical Pharmacy, British Society for Antimicrobial Chemotherapy, Cystic Fibrosis Foundation, European Society of Clinical Microbiology and Infectious Diseases, Infectious Diseases Society of America, Society of Critical Care Medicine, and Society of Infectious Diseases Pharmacists

“…Of the agents reviewed, β‐lactam stability data exist to varying degrees around amoxicillin, 74,75 ampicillin, 76,77 benzylpenicillin, 76,78‐80 cefepime, 73,81 cefoxitin, 80 ceftaroline, 82 ceftazidime, 83,84 ceftolozane/tazobactam, 85 flucloxacillin, 73,80,86 piperacillin–tazobactam, 73,87,88 and meropenem 89‐92 . In recent years, there is emerging evidence to suggest that a number of key pharmaceutical criteria are important and should be explored when considering stability concerns.…”

“…In recent years, there is emerging evidence to suggest that a number of key pharmaceutical criteria are important and should be explored when considering stability concerns. The final concentration of drug recovered in the device can potentially be altered by temperature, pH changes and associated buffers, altering the starting drug concentration of the solution, degradant rate, formation of toxic impurities, and altered flow rates of devices 75,80,88,93‐95 . These variables are particularly important if infusions are going to be utilized outside of an inpatient setting and not for immediate use.…”

Systematic review of room temperature stability of key beta-lactam antibiotics for extended infusions in inpatient settings

“…Penicillins are known to have limited stability in aqueous solution. Amoxicillin stability is concentration dependent, with higher concentrations being less stable – we found data to support a 6 hour infusion at a concentration of 25 mg/mL in sodium chloride 0.9% 19–23…”

Stability of Antimicrobials in Elastomeric Pumps: A Systematic Review

“…The principal characteristics of each antimicrobial group, such as drug, reference [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ], main conditions (composition of the elastomeric device chosen, concentration, diluent, temperature, and duration of storage), chemical and physical stability obtained, and the most relevant comments for the systematic review, are summarized in Table 1 , Table 2 , Table 3 , Table 4 , Table 5 , Table 6 , Table 7 and Table 8 .…”