Concomitant Ceftriaxone Induced Nephrolithiasis And Biliary Psedolithiasis In a Small Toddlerdocx

=== Concomitant ceftriaxone – induced nephrolithiasis and biliary psedolithiasis in a small toddler ===

CONCOMITANT CEFTRIAXONE-INDUCED NEPHROLITHIASIS AND BILIARY PSEUDOLITHIASIS IN A SMALL TODDLER

Introduction: Ceftriaxone, third generation cefalosporin is largely used in hospitals due to favorable spectrum of activity. The administration rate of ceftriaxone reach in hospitals 82% in America, 65% in Spania, 62% in Koreea and Africa. (1) In Romania the inappropiate use of ceftiaxone in hospitals range 57%.(2) The adverse effects from local reaction (phlebitis), gastrointestinal (diarrhea), hematological (trombocitisis, leukopenia, haemolitic anemia) to rare adverse effects (allergic pneumonitis, bronchospasm,  gallbladder sludge,vbilliary pseudolithiasis, nephrolitiasis) are known. (3) The frequncy of lithiasis and biliary sludge has been reported in population-based studies from USA as 1.9% and respectively 1.46%; the same studies indicate an increase in the incidence and prevalence of the disease, caused by a possible underestimation in the previous years, as well as by the extensive use of ultrasonography.(4) Etiology of biliary lithiasis comprises from the hormonal factors to drugs: oral contaceptives and cefalosporines especially ceftriaxone in hight doses and prolonged administration. The exact prevalence of gallstones in children is not known, studies from Europe have shown an overall prevalence of gallstone disease of 0.13% to 0.2% in children(5).In Japan, the prevalence of gallstone disease is reported to be less than 0.13% of children. Essential is evoking diagnosis before clinical suggestive signs and less effective therapeutic measures, the first of which is discontinuing antibiotic.(6)

Material and Methods: Data was collected from clinical records and ultrasonography charts of the patient. Parents signed an informed consent that allows the usage of patient’s data for research and teaching purposes. The references were selected after performing a literature review conducted in Medline using the keywords ceftriaxone combined with biliary pseudolithiasis and nephrolithiasis.

Case Presentation: A five-months-old male toddler was admitted into our unit with extreme psychomotor agitation and mild respiratory symptoms. Before admission in our unit the child received intravenously ceftriaxone bid for 7 days in a county hospital for interstitial pneumonia. Physical examination confirmed afebrile boy, productive cough, mild systolic murmur and small crystals in diaper (fig. 1)

Fig.1: Small CaCo3 crystals

Laboratory data: complete blood count, urea, creatinine, creatinine clearance, calcium (total and ionized), serum phosphorus, bilirubinemia, alkaline phosphatase, serum glucose were within normal limits, slight calciuria in urinalysis and increased calcium/creatinine ratio. Ultrasound examination revealed the presence of sediment in the bladder and a hyperechoic image of 4 mm in the gallbladder (fig.2)

Fig. 2: Hyperechoic image in the gallbladder

EKG, EEG were normal, chest X-Ray revealed discrete bilateral interstitial infiltrate. The echocardiography found permeable foramen ovale and left ventricular diastolic dysfunction. Treatment consists in suspending ceftriaxone administration, age appropriate diet without supplemental calcium intake, hydrochlorothiazide 6,25 mg/daily, adequate hydration and antispasmodics. The child was dismissed after 3 days of hospitalization in good general condition, disappearance of bladder sediment but persistence of gallbladder image. Subsequent evaluations showed disappearance of gallbladder image after 5 weeks of therapy interruption.

Discussions: Ceftriaxone, an antibiotic commonly used for child infection treatement has been associated to biliary pseudolithiasis, nephrolithiasis and bladder sludge. The kidneys eliminate approximately 33-67% of this agent, and the remainder is removed throught the biliary system. Formation of urine crystals that cling to renal tubular cells has been observed during ceftriaxone treatment, with the potential for causing acute renal failure, however, only few studies have reported ceftriaxone-associated paediatric acute renal failure (in pediatric doses), anyway this phenomenon is quite rare.(7) Ceftriaxone is an anion and, if the drug concentration in blood is high, these anions can bind with calcium ions to form insoluble complexes that precipitate in the biliary system, the same mechanism is avaible for stones formation in the renal collecting system (8). Some studies sugest that ceftriaxone can lead to a reversible precipitation in the gall bladder resembling the cholelithiasis, complication named biliary pseudolithiasis or a reversible cholelithiasis (this complication appeared in 15–57% of patients who were treated with ceftriaxone) (9). Risk factors that may contribute to ceftriaxone- induced nephrolithiasis are: a positive family history, urinary tract infection and obstruction ,high doses of ceftriaxone (over 2g/day), quick application of the drug, dehydration, together with the administration of nephrotoxic drugs, and metabolic disorders, such as hypercalciuria, could also favorize crystallization of calcium ceftriaxonate. Urinary calcium excretion is conditioned by complex interrelationships between intestinal calcium absorption, renal calcium reabsorption and bone activity.(10) Hypercalciuria or excessive urinary calcium excretion, occurs in about 5-10% of the population and is the most common identifiable cause of calcium kidney stone disease, (11)

Negative family history of kidney stones, normal intake of vitamin D3, the absence of biochemical abnormalities (normal serum calcium, phosphoremy, alkaline phosphatase) and the absence of clinical changes excluded the mentioned etiologies, except for drug toxicity and idiopathic hypercalciuria: our patient received drug doses of 100mg/kg/day (a hight dose) for 7 days, (in most reports, the ceftriaxone-induced nephrolithiasis occurred during 8–10 days of treatment, with the doses of 50 to 100mg/kg/day),(12) and idiopathic hypercalciuria contributed bouth with the administration of high-dose ceftriaxone to mentioned complication (drug induced nephrolithiasis or biliary pseudolithiasi) an event rarely described in children. The youg age (five mounth) in addition to high doses of drug and metabolic factors led to complications, similar results to other reports. The evolution of the child was favorable, with disappearance of gallbladder image after 5 weeks of therapy interruption and without other complication.

Conclusions: Ceftriaxone is a frequent choice in Romanian hospitals for empiric antimicrobial therapy because of its broad spectrum, long half-life, safety and tolerability, however, some relatively rare side effects as renal lithiasis and biliary pseudolithiasis may occur. Ceftriaxone treatements requires ultrasounds monitoring of the urinary tract and biliary sistem, as well as the adequate hydration of the child. Ceftriaxone-induced urolithiasis or pseudolithiasis is self-limited without long-term complications.

References:

1. Ammishaddai Adu, Carol L. Armour. Drug Utilisation Review (DUR) of the Third Generation Cephalosporins. Drugs, 2012, 423-439

2. Gabriel-Adrian Popescu Adriana Pistol Roxana Șerban. Consumul de antibiotice, Rezistența microbiană și Infecții Nosocomiale în România – 2012. CARMIN-ROM 2012, 37-42.

3. Stork CM (2006). "Antibiotics, antifungals, and antivirals". In Nelson LH, Flomenbaum N, Goldfrank LR, Hoffman RL, Howland MD, Lewin NA. Goldfrank's toxicologic emergencies. New York: McGraw-Hill.  2009,847

4.Wesdorp I, Bosman D, de Graaf Aet al – Clinical presentations and predisposing factors of cholelitiasis and sludge in children. J Pediatr Gastroenterol Nutr.Oct 2000;31(4):411-7

5. Youssef DM, Sherief LM, Sherbiny HS, Al Attar MY, El Sheikh AR, Fawzy FM, Adham T. Prospective study of nephrolithiasis occurrence in children receiving Cefotriaxone. Nephrology (Carlton). 2015 Sep 15. doi: 10.1111/nep.12625.

6.Wesdorp I, Bosman D, de Graaff A, Aronson D, van der Blij F, Taminiau J. Clinical presentations and predisposing factors of cholelithiasis and sludge in children. J Pediatr Gastroenterol Nutr 2000; 31: 411-417

7. Ning Li, Xuefeng Zhou, Jiyan Yuan, Guiying Chen, Hongliang Jiang and  Wen Zhang: Ceftriaxone and Acute Renal Failure in Children ,Pediatrics peds.2013-2103.

8. Bruce R Dalton, PharmD BScPharm; Danny J Zuege, MD MSc; Reza Shahpori, MSc; Kevin B Laupland MD MSc. Concomitant Ceftriaxone and High-concentration Intravenous Calcium Therapy in Adult Critical Care Patients: A Matched Cohort Study. The Annals of Pharmacotherapy. 2010;44(7):1158-1163

9. Rodríguez Rangel DA, Pinilla Orejarena AP, Bustacara Diaz M, Henao García L, López Cadena A, Montoya Camargo R, Moreno LA. Gallstones in association with the use of ceftriaxone in children. An Pediatr (Barc). 2014 Feb;80(2):77-80. doi: 10.1016/j.anpedi.2013.04.001. Epub 2013 Jun 5.

10. Nacaroglu HT, Demircin G, Bülbül M, Erdogan O, Akyüz SG, Caltik A. The association between urinary tract infection and idiopathic hypercalciuria in children. Ren Fail. 2013;35(3):327-32

11. Lozanovski VJ, Gucev Z, Avramoski VJ, Kirovski I, Makreski P, Tasic V. Ceftriaxone associated urolithiasis in a child with hypercalciuria. Hippokratia. 2011 Apr;15(2):181-3.

12. Hernandez JD, Ellison JS, Lendvay TS. Current Trends, Evaluation, and Management of Pediatric Nephrolithiasis. JAMA Pediatr. 2015 Aug 24. doi: 10.1001/jamapediatrics.2015. 1419