Crystal nephropathy and amoxicillin: insights from international spontaneous reporting systems

Background: A substantial increase in amoxicillin-induced crystal nephropathy was recently reported in France. Our study aims to further characterize this safety issue from a worldwide perspective. Methods: We queried both the FDA Adverse Event Reporting System (FAERS) and the Eudravigilance databases, and performed disproportionality analysis, selecting only adverse events (AEs) related to crystal nephropathy where amoxicillin or amoxicillin/clavulanic acid were reported as suspect. In FAERS, the reporting odds ratios were calculated and deemed significant by the lower limit of the 95% confidence interval (LL95%CI) > 1, selecting all other drugs/events recorded in FAERS as comparator. Deduplication followed by case-by-case assessment and comparison between French and non-French cases were also performed in both databases. Results: Overall, 57,754 and 84,764 AE reports with amoxicillin or amoxicillin/clavulanic acid were recorded in FAERS and Eudravigilance, respectively, with France accounting for 18.7% and 22.0% of cases. Specific AEs of interest were retrieved in 144 and 239 cases, respectively. Increased reporting was found in FAERS for crystalluria (N = 99; LL95%CI 53.18), crystal nephropathy (24; 27.01), medication crystal in urine present (9; 92.00), crystal urine (8; 11.90), and crystal urine present (4; 1.57). In FAERS and Eudravigilance databases, reports were classified as serious in 98.8% and 91.2% of cases, respectively. Acute kidney injury (AKI) was found in 81.2% and 71.1% of patients. Amoxicillin was mainly given intravenously, and a dose ≥ 12 g/day was administered in 50.0% and 19.7% of cases in the FAERS and Eudravigilance databases, respectively. Conclusion: Although causal association cannot be firmly inferred, a consistent signal of crystal nephropathy with amoxicillin emerged, especially in France. Clinicians should monitor patients for possible early AKI onset, especially when dealing with intravenous administration of daily doses > 12 g. Graphical abstract: [Figure not available: see fulltext.]