Biliary and renal lithiasis by ceftriaxone

The ARNO Children Observatory Report of 2011 states that more than 30% of antibiotic treatments in paediatric age consist of cephalosporins.¹ Among cephalosporins, ceftriaxone prescriptions have grown more than 75% from 2001 to 2008.
² This third generation cephalosporin, however, is no risk-free: in fact, ceftriaxone is the most reported drug in his class for paediatric age, even though, considering the authorized indications for the product, inappropriate use emerges sometimes from these reports. Among the most relevant and frequently reported adverse effects, there is the capability of developing calculi at biliary and renal level.

Biliary pseudolithiasis - About 40% of ceftriaxone excretion is at biliary level, where the drug reaches concentration 20-150 times higher than in plasma and tends to form insoluble calcium salts, precipitating. Risk factors are hypercalcemia, fasting, dehydration, parenteral nutrition, renal failure and prolonged treatment with high doses. Reduced activity of UDP-glucosyltransferase (UDPG), genetically correlated to a polymorphism of the gene UGT1A1, is considered another predisposing factor.⁴
Pseudolithiasis and biliary sludge have been prospectively observed in 15-46% treated children.⁵ Less than 20% resulted symptomatic. Pseudolithiasis can appear 6-9 days after the beginning of the therapy, but ultrasound scan detectable cases have been described only after two days of treatment. Precipitates usually disappear when ceftriaxone is discontinued within 15 days, in some cases it is necessary to wait from 2 to 5 months.
Even though conclusive data are yet to be available, risk seems to increase for doses higher than 2 g/day and when 100 mg/kg/day of ceftriaxone instead of 50-75 mg/kg/day are administered. In any cases, including the symptomatic ones, conservative approaches should be adopted in order to avoid ill-timed surgeries.

Renal lithiasis - Ceftriaxone has the tendency to precipitate with urinary calcium, forming needle-like crystals that aggregate in stellar structures with diameters of 40-200 µm. Crystals obstruct renal tubules and lead to calculi development.
From 1.4% to 7.8% of ceftriaxone-treated children develop renal lithiasis detectable by ultrasound scan within 7 days from the start of the therapy.^6-8 The majority of cases remains asymptomatic. But some children might have haematuria, anuria, hyperazotemia and renal colic. Isolated cases of renal failure have been reported.
The 60% of ceftriaxone is excreted at renal level, where calculi formation can take place at usual doses and in physiological urinary conditions. High doses of ceftriaxone, hypercalciuria and pathologies that favour urinary stasis are all additional risk factors. Ceftriaxone itself seems able to cause hypercalciuria by favouring the calculi deposition process.⁹ Renal lithiasis tends to spontaneously resolve within few weeks after the drug suspension, with rehydration and eventual spasmolytic therapy. Ultrasound scan follow up is sufficient for monitoring the condition progress.

In practice - The possibility of ceftriaxone precipitation in presence of calcium has two important implications. Firstly, biliary and renal calculi development – despite being a benign event – must be taken into consideration and suspected for symptomatic subjects. Secondly, drug dilution in calcium solution and, in particular for newborns and prematures infants, administration of ceftriaxone in time proximity (within 48 hours) with calcium solution should be avoided for the high risk of calcium-ceftriaxone precipitates in lungs and kidneys.¹⁰