Amoxicillin Blood Concentration in High-Dose Intravenous Discontinuous Amoxicillin: Look Beyond Numbers. Max-Amox Study.

Purpose: High doses of amoxicillin are recommended to treat severe infections such as endocarditis. Amoxicillin causes dose-dependent toxicities, in particular crystal nephropathy. Toxicity could be avoided by monitoring of amoxicillin trough plasma concentrations (ATPC). However, the relevance of ATPC testing in routine medical practice remains poorly studied.

Methods: We conducted a prospective clinical trial in adults treated with high doses of discontinuous intravenous amoxicillin in a French university hospital. The primary outcome was the distribution of ATPCs over three days during the first week of treatment. Urine tests for amoxicillin crystalluria (AC), pH, and density were also performed.

Findings: Seventy patients were included. Overall intra-class correlation (ICC) was 0.35 IC95% [0.21; 0.53] with the following pairwise concordances: D1-D4 (n= 55) 0.23 IC95% [-0.02; 0.47], D1-D7 (n= 47) 0.41 IC95% [0.19; 0.63], and D4-D7 (n= 50) 0.17 IC95% [-0.10; 0.43]. Inter-individual variability was also significant, with coefficients of variation being 0.87 at D1, 1.20 at D4, and 1.35 at D7. AC occurred in 32 patients (47.8%). Risk of AC increased when pH was below or equal to 6 (P = 0.002). ATPCs were higher in patients with AC and/or acute kidney injury.

Implications: Variability in ATPC was high and ATPC cannot be considered as the only monitoring tool to adjust amoxicillin dosage. High ATPC, low urinary pH, and presence of AC can alert physicians to a potential iatrogenic effect and lead to the decision to hydrate the patient, alkalinize urine and decrease the dosage of amoxicillin.