A Reminder to Vigilantly Monitor Even the Most Common Pediatric Medications
The potential for serious or even fatal adverse events associated with ceftriaxone, an intravenous antibiotic that is commonly used in the pediatric population, has been reported in clinical studies, prompting the U.S. Food and Drug Administration in 2007 to add warnings to the drug’s labeling.1 These reports have focused primarily on ceftriaxone as it interacts with intravenously administered calcium-containing solutions in neonates, leading to pseudolithiasis and nephrolithiasis.
In their recent report, Li and colleagues2 evaluated the clinical profile, treatment, and outcome of ceftriaxone-associated postrenal acute renal failure (PARF), a rarely reported adverse event in children. This research serves as a reminder that even the most commonly used medications should be prescribed with caution.
Ceftriaxone, a third-generation cephalosporin, has broad-spectrum activity against Gram-positive and Gram-negative bacteria, a long plasma half-life, and once daily dosing, advantages that contribute to its wide use. Much of the medication is excreted unmetabolized in the urine; the rest is excreted through the biliary tract.
At therapeutic doses, ceftriaxone can crystallize with calcium in the urine. These crystals adhere to the surface of tubular cells in the kidneys, eventually building up to form renal calculi that block the ureters. Moreover, ceftriaxone can increase the urinary excretion of calcium, exacerbating the problem. The resulting PARF must be identified and treated quickly, especially in children, to avoid serious permanent renal injury or even death.
Li and colleagues retrospectively reviewed the medical records of 23 boys and 8 girls with a diagnosis of PARF who were admitted to the pediatric surgery department of Tongji Hospital in Wuhan, China, from January 1, 2003 to June 30, 2012. The children ranged in age from 1 to 12 years, with a mean age of 5.1 years. PARF was diagnosed based on the presence of sudden onset anuria for 24 hours or more, flank pain, pain on renal percussion, and elevated serum creatinine and/or serum urea nitrogen levels. None of the children had a history of urolithiasis or nephropathy.
The average time of ceftriaxone administration was 5.2 days overall; the average time from first ceftriaxone dose to the onset of anuria was 5.4 days. Dosages ranged from 70 to 100 mg/kg/d in the 13 cases with available dosing information. Anuria was present in all 31 cases. Renal ultrasonography results showed bilateral hydronephrosis in 6 children, unilateral hydronephrosis in 19 children, and normal results in 6 children. Calculi were discovered in 11 children. Of the 22 patients who had ultrasonography of their biliary tree, 4 had biliary pseudolithiasis.
Treatment of the children’s PARF included pharmacotherapy with an antispasmodic, an alkalinizing agent, antibiotics, albumin, and low-dose dexamethasone, along with tight control of liquid intake. Pharmacotherapy was aimed at dilating the ureters, relieving ureteral spasm, alleviating edema of the renal pelvis and ureter, and preventing acidosis and urinary tract infections.
Nine of the 31 patients responded to pharmacotherapy with complete resolution of acute renal failure; 21 were refractory to medication, with serum creatinine levels greater than 500 µmol/L, and required retrograde ureteral catheterization (RUC). One child failed pharmacotherapy and RUC and required hemodialysis. Normal urination was reestablished in that child after 3 hemodialysis sessions, equating to the successful treatment of all 31 children. Viable urinary calculi samples were obtained from 4 of the children, and all of the calculi later were confirmed to comprise mainly ceftriaxone.
While the authors note that it remains difficult to estimate the incidence of PARF in children treated with ceftriaxone, and they presume that this incidence is low, this study highlights the importance of closely monitoring children on pharmacologic regimens for adverse effects, even when using commonly administered medications.n
Chalanda Jones, MD, is a pediatrician at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Delaware.
Charles A. Pohl, MD—Series Editor, is professor of pediatrics and senior associate dean of student affairs and career counseling at Jefferson College in Philadelphia, Pennsylvania.
References
1. US Food and Drug Administration. Information for healthcare professionals: ceftriaxone (marketed as Rocephin and generics). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm084263.htm. Updated April 21, 2009. Accessed May 5, 2014.
2. Li N, Zhou X, Yuan J, Chen G, Jiang H, Zhang W. Ceftriaxone and acute renal failure in children [published online ahead of print March 24, 2014]. Pediatrics. 2014;133(4):e917-e922. doi:10.1542/peds.2013-2103.