GALLSTONE PANCREATITIS CAUSED BY CEFTRIAXONE

Abstract

Ceftriaxone is commonly used to treat serious infections in children. Complications of long term, large dosage therapy include biliary sludge and cholelithiasis.1-7 Patients who have biliary stasis, renal failure or fluid restriction are at increased risk for the development of cholelithiasis caused by ceftriaxone.2, 8 Although these complications of ceftriaxone therapy are widely appreciated, this broad spectrum antibiotic is not typically considered to be the cause of pancreatitis. We report the case of a 13-year-old boy with ceftriaxone-induced gallstone pancreatitis treated by cholecystectomy. Case report. A 13-year-old boy who weighed 55 kg was diagnosed with right frontal subdural empyema secondary to sinusitis. Two days after endoscopic surgery of the sinuses, a craniotomy with incision and drainage of the abscess was performed. Cultures of the cerebrospinal fluid and sinuses revealed multiple organisms including Enterobacter cloacae, enterococci, Corynebacterium spp., Streptococcus anginosus and staphylococci (both coagulase-negative and coagulase-positive). He received intravenous antibiotics consisting of metronidazole (500 mg every 6 h), gentamicin (140 mg every 8 h), vancomycin (875 mg every 12 h) and ceftriaxone (2 g every 12 h). Vancomycin and gentamicin serum concentrations were therapeutic, and the serum creatinine was normal. He did well after surgery and was transferred to a chronic care facility for completion of antibiotic therapy. Two weeks after transfer he was readmitted with emesis and an elevated creatinine of 1.6 mg/dl. Vancomycin and gentamicin serum concentrations were 56 and 18 μg/ml, respectively. The patient appeared to be mildly dehydrated. He received intravenous hydration and was not orally fed. Vancomycin, gentamicin and metronidazole were discontinued; ampicillin and nafcillin were added to the ceftriaxone. Renal ultrasound revealed enlarged kidneys with an area of increased echogenicity in the upper pole of the right kidney. Doppler studies showed findings compatible with renal parenchymal disease. Antibiotics were discontinued on the seventh hospital day after the patient had received 5 weeks of parenteral antibiotic therapy. He was no longer dehydrated, emesis ceased and the creatinine normalized. His diet was slowly advanced. On the eleventh hospital day he developed abdominal pain with bilious emesis. On physical examination bowel sounds were decreased and there was epigastric and right upper quadrant tenderness. The white blood cell count was 29 600/mm3 with 80% neutrophils, 4% band forms, 7% lymphocytes and 5% monocytes. Serum amylase was 1133 IU/l and lipase was 3528 IU/l. Serum transaminases were normal. Abdominal ultrasound examination showed cholelithiasis with no evidence of dilatation of the common bile duct. The patient had an uncomplicated cholecystectomy. Pathologic examination of the gallbladder was consistent with cholelithiasis and chronic cholecystitis. The gallbladder material was found to be 100% ceftriaxone by polarization microscopy and infrared spectroscopy (Laboratory for Stone Research, Newton, MA). The patient had complete resolution of symptoms 1 month after cholecystectomy. Discussion. Ceftriaxone is primarily excreted in the urine, and 30 to 60% of the drug is excreted in the bile.8 Prolonged administration of large dosages has been associated with transient formation of biliary sludge.1-3 In a prospective study by Schaad et al.1 37 children were treated with ceftriaxone for serious infections. Evaluation by abdominal ultrasound showed biliary concrements in 16 patients, 3 of whom were symptomatic. These patients were treated for 4 to 33 days (mean, 7) with 54 to 105 mg/kg/day (mean, 89). Clinical symptoms and abnormalities seen by ultrasound resolved after ceftriaxone was discontinued. There have been reports of gallbladder stones that developed during ceftriaxone therapy and required cholecystectomy.4 Gallstone pancreatitis has been shown to be associated with ceftriaxone therapy.5, 6 In the study by Lopez et al.5 pancreatitis was caused by gallstones, which were analyzed by infrared spectrophotometry. These stones consisted of 80% ceftriaxone and 20% bilirubin. To our knowledge there have been no reported cases of pancreatitis caused solely by ceftriaxone gallstones. Ceftriaxone is a divalent anion that is concentrated in canalicular bile. The concentration of ceftriaxone in ductular bile may exceed its saturation level.9 In rats it has been shown that secretion of ceftriaxone induces formation of an insoluble calcium-ceftriaxone complex.10 It has been extrapolated from known data that a dosage of >2 g/day may result in calcium-ceftriaxone precipitation.10 Our patient had several risk factors for the formation of calcium-ceftriaxone stones. He received a large dosage (4 g/day) of the antibiotic for several weeks which put him at risk for ceftriaxone-calcium precipitation. The therapeutic regimen included nephrotoxic drugs, which resulted in renal failure, thus increasing biliary excretion of ceftriaxone. In addition emesis and poor appetite led to dehydration and decreased gallbladder contraction. Patients receiving long term ceftriaxone therapy may potentially be at risk for cholelithiasis and pancreatitis. The risk increases in the setting of dehydration, starvation and decreased renal function. Ultrasound screening might be useful for monitoring such patients. Melinda C. Maranan, M.D. Susan I. Gerber, M.D. Grant G. Miller, M.D. Section of Pediatric Infectious Diseases; Department of Pediatrics; The University of Chicago Children's Hospital (MCM) Department of Microbiology/Immunology; Northwestern University Medical School (SIG) Chicago, IL Division of General Surgery; Department of Surgery; Royal University Hospital; University of Saskatchewan; Saskatoon, Canada (GGM)