Incidence, Risk Factors and Impact on Renal Function of the Appearance of Crystalluria Under High-dose Intravenous Amoxicillin

Amoxicillin is an antibiotic of the family of β-lactams and sub-family penicillin A. It has a time-dependent bactericidal activity. It is mainly active on many bacterial species frequently found in infectious diseases. It can be administered orally or parenterally. It is therefore a frequently prescribed antibiotic, alone or in combination. Its elimination is mainly urinary in its active form. It is frequently prescribed intravenously at high doses in infectious disease departments, in indications like meningitis, endocarditis, listeriosis, or documented susceptible osteo-articular infections.

Several amoxicillin treatment side effects have been reported, like hypersensitivity reactions, gastrointestinal adverse reactions, mucocutaneous candidiasis, nervous system toxicity and eventually kidney disease, namely the occurrence of crystalluria or acute interstitial nephritis of whose frequency is undetermined.

Literature concerning the occurrence of crystalluria is mainly based on Case reports and there are no incidence data. Crystalluria is characterized by the presence of amoxicillin trihydrate crystals in urine, after amoxicillin urinary supersaturation. The appearance is that of large needles, isolated or aggregated into "broom bush-like" crystal, 50-300µm, with birefringent under polarized light. Amoxicillin crystalluria may be of varying importance, microscopic or macroscopic, sometimes up to urinary tract obstruction and may cause acute renal failure (ARF) and require renal replacement therapy. A low urine output could be associated with the occurrence of crystalluria, as well as a urine pH between 5 and 7, a high urinary density and high doses of amoxicillin.

Amoxicillin crystalluria is deemed uncommon. In the national pharmacovigilance database, in November 2013, there were only 9 reported cases, from 12 to 78 years old, 5 of whom severe one of which life-threatening. There is a high underreporting in these data, and it seems that this impact is highly underestimated for several reasons: amoxicillin crystalluria is not sought in routine clinical practice in all centers, even with high dose administrated. It is not clinically detectable if microscopic and even if a urine culture is performed, amoxicillin crystals may be mistaken for other crystals. In the investigator's experience automated systems do not always detect these crystals. Moreover, patients likely to receive high doses of amoxicillin are generally subject to severe infections and are more at risk of acute renal failure either due to background or previously initiated therapies (like the association with aminoglycosides), and the imputability of a crystalluria in the occurrence of an episode of acute renal failure among these patients is seldom considered.

Finally, a recent increase in the number of reported cases in the national pharmacovigilance database is an incentive to pay more attention to this complication.