Acute necrotizing cholecystitis: a rare complication of ceftriaxone-associated pseudolithiasis

Abstract

A 16-year-old male patient (59 kg) who presented to his primary care physician with a 3 week history of lethargy and myalgias. His physical examination was notable for a 5-cm bullseye lesion on his right foot, which was thought to be a spider bite. This resolved without treatment after 1 week. He developed a similar lesion on his left forearm, which also resolved on its own after 1 week. Four weeks after his symptoms began, he presented to our institution with a headache, jaw stiffness, and left-sided facial weakness (Bell's Palsy). He had a white blood cell count of 32,000 (normal 4,000-10,000). Lyme titers were positive. A lumbar puncture was performed and he was diagnosed with Lyme meningitis. He was treated with ceftriaxone 2 g intravenously twice a day for 4 weeks.The patient developed right upper quadrant pain 1 week after completing his treatment. The pain was intermittent and gradually became more severe over the next 2 weeks. He was seen again at our institution and an abdominal ultrasound was performed. It showed multiple gallstones with one gallstone in the gallbladder neck and mild gallbladder wall thickening (4 mm). There was no pericholecystic fluid and the common bile duct appeared normal. Due to his persistent and worsening symptoms, he underwent a laparoscopic cholecystectomy. He had a significant amount of inflammation around the gallbladder with indiscernible anatomy, and thus we converted to an open procedure.The pathological analysis showed acute necrotizing cholecystitis with surface erosions. The stone analysis by polarization microscopy and infrared spectroscopy revealed that the stone composition was 100% ceftriaxone (Laboratory for Stone Research, Newton, MA, USA). DiscussionCeftriaxone is a parenteral broad-spectrum, semi-synthetic third generation cephalosporin. A b-lactam antibiotic, it exerts its antibacterial activity through the inhibition of bacterial cell-wall synthesis. Its spectrum of activity includes many gram-positive aerobic bacteria, gram-negative aerobic bacteria and some anerobes. It is resistant to degradation by most bacterial b-lactamases [6]. Ceftriaxone's pharmacokinetic properties are nonlinear and all basic pharmacokinetic parameters (e.g. absorption and distribution), with the exception of the elimination half-life, are dose dependent. Its long halflife of elimination (i.e. 5.4 -10.9 h) allows for once or twice daily dosing.Although it is largely excreted in the urine, 10-40% is excreted unmetabolized in bile [5,7,17,22,29]. It is reversibly bound to albumin, and the binding decreases with the increase in concentration, e.g. from 95% binding at plasma concentrations less than 100 mg/l to 85% binding at 300 mg/l [17]. Due to the lower albumin content in interstitial fluid, the percentage of free drug in interstitial fluid is correspondingly higher than in plasma. As a result, the levels of ceftriaxone in the bile is 20-150 times greater than in serum [25]. As an anion, it binds to calcium and forms an insoluble calcium-ceftriaxone salt in a 1:1 molar ratio that is...

Cholecystectomy during ceftriaxone therapy. A translational study with a new rabbit model

“…Ceftriaxone exists in solution as a bivalent ion and may precipitate if the maximum amount dissolved in the bile exceeds the metastable zone under certain time and temperature conditions, as observed in this study with rabbits 20 . This behavior differs from that of other antibiotics excreted in the bile, which rarely become insoluble 10 . The authors of this study had the opportunity to follow one case of ceftriaxone treatment for Lyme disease, in a 56-yearold male adult, previously asymptomatic and with normal routine ultrasonography.…”

“…Likewise, when complains are present the general belief, even in adult's patients, is that the diagnosis of pseudolithiasis (sometimes denominated as sediment, sludge, precipitate) outlines a transient situation which disappears when the drug is discontinued [23][24][25][26] . However, a careful revision of the medical literature has showed a high incidence of symptomatology, ranging from 22% to 100% of the cases 7,10,11,12,21,22,27,28 . Ettestad et al 29 described 25 patients with Lyme disease diagnosis treated with ceftriaxone, of whom 14 underwent surgery with histopathological evidence of cholecystitis and 172 were diagnosed with biliary calculi.…”

“…It is noteworthy that microlithiasis formation in the gallbladder resulting from the use of ceftriaxone associated with serious adverse events is generally neglected, especially in adult population. In the medical literature, there are few but worrisome reports of acute biliary pancreatitis, acute cholecystitis including necrotizing type and choledocholithiasis followed by cholangitis during long-term ceftriaxone therapy [9][10][11][12][13] . The authors performed a translational study in an original rabbit model, aiming to study the reliable incidence of and cholecystitis due to intravenous ceftriaxone use, seldom described in the medical literature.…”

Ceftriaxone-associated Biliary Pseudolithiasis with Elderly Type 1 Diabetes Mellitus: Two Case Reports

“…Biliary pseudolithiasis is formed when the unaltered form of CTRX reaches a concentration in the bile of 20 to 150 times its blood concentration ( 8 ) and combines with calcium in the gallbladder to form stones. It has been reportedly associated with common bile duct lithiasis, pancreatitis, and gangrenous cholecystitis, which can lead to cholecystectomy ( 9 ).…”

Ceftriaxone Administration Associated with Lithiasis in Children: Guilty or Not? A Systematic Review

“…The high calciumbinding affinity of ceftriaxone has been suggested as the main pathogenetic factor of precipitation and formation of calcification and stones in the biliary tracts [7]. Occasionally, ceftriaxone-induced pseudolithiasis may cause severe complications, such as obstruction and infection [8,9]. Therefore, more interventions for the resolution of biliary lithiasis have occasionally been applied, such as the use of ursodeoxycholic acid [10].…”