Optimizing intravenous amoxicillin for outpatient parenteral antimicrobial therapy

Poor aqueous stability limits the use of continuous infusion of intravenous (IV) amoxicillin in outpatient parenteral antimicrobial therapy. This study aimed to evaluate whether buffering improves amoxicillin stability and whether co-administration of probenecid enhances amoxicillin exposure.

Amoxicillin solutions (4.17, 50, and 66.6 mg/mL) were prepared in 0.3% citrate-buffered saline (pH 7), water for injection, and 0.9% w/v saline, then stored at 2-8°C for 10 days, followed by 24 h at 32°C. Stability was assessed using a validated assay method and tested against the UK Yellow Cover Document (YCD) acceptance criteria. A population pharmacokinetic model was developed and used to perform Monte Carlo dosing simulations to evaluate the PTA (95% time above MIC) for various IV amoxicillin regimens, with and without probenecid.

Citrate buffering did not improve the stability of amoxicillin, and none of the tested conditions met YCD criteria. Co-administration of probenecid significantly increased the PTA for amoxicillin. Administration of 3-6 g of IV amoxicillin every 12 h, with 1 g of probenecid once daily, achieved ≥90% PTA against pathogens with MICs up to 4-8 mg/L depending on infusion durations. For MICs up to 16 mg/L, 4-6 g of IV amoxicillin every 12 h plus 2 g of probenecid once daily achieved a favourable PTA (>90%).

Amoxicillin's aqueous instability was not resolved by citrate buffering. However, for patients requiring IV therapy, probenecid-boosted intermittent and extended infusion regimens of amoxicillin appear to be promising alternatives that warrant further clinical investigation.