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      Is Ceftriaxone-Induced Biliary Pseudolithiasis Influenced by UDP-Glucuronosyltransferase 1A1 Gene Polymorphisms?

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          Abstract

          Ceftriaxone (cfx), a third-generation cephalosporin antibiotic, leads to transient cholelithiasis in some children, also known as pseudolithiasis. However, the underlying pathogenetic mechanism of this adverse effect has not yet been elucidated. We describe 3 children with ceftriaxone-induced pseudolithiasis, who were also carriers of the A(TA) 7TAA polymorphism of the UGT1A1 gene, implying that a cause and effect relation may exist.

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          Ceftriaxone. A review of its antibacterial activity, pharmacological properties and therapeutic use.

          Ceftriaxone is a new 'third generation' semisynthetic cephalosporin with a long half-life which has resulted in a recommended once daily administration schedule. It is administered intravenously or intramuscularly and has a broad spectrum of activity against Gram-positive and Gram-negative aerobic, and some anaerobic, bacteria. The activity of ceftriaxone is generally greater than that of the 'first' and 'second generation' cephalosporins against Gram-negative bacteria, but less than that of the earlier generations of cephalosporins against many Gram-positive bacteria. Although ceftriaxone has some activity against Pseudomonas aeruginosa, on the basis of present evidence it cannot be recommended as sole antibiotic therapy in pseudomonal infections. Ceftriaxone has been effective in treating infections due to other 'difficult' organisms such as multidrug-resistant Enterobacteriaceae. Ceftriaxone was effective in complicated and uncomplicated urinary tract infections, lower respiratory tract infections, skin, soft tissue, bone and joint infections, bacteraemia/septicaemia, and paediatric meningitis due to susceptible organisms. In most of these types of infections once-daily administration appears efficacious. Results were also encouraging in a few patients with ear, nose and throat, intra-abdominal, obstetric and gynaecological infections, and adult meningitis, but conclusions are not yet possible as to the efficacy of the drug in these indications due to limited experience. A single intramuscular dose of ceftriaxone has been compared with standard therapy for gonorrhoea due to non-penicillinase-producing and penicillinase-producing strains of Neisseria gonorrhoeae and shown to be highly effective. In a few small trials the comparative efficacy of ceftriaxone and other antibacterials has been assessed in other types of infections and in perioperative prophylaxis in patients undergoing surgery. Few significant differences in response rates were found between therapeutic groups in these comparative studies, but larger well-designed studies are needed to more clearly assess the comparative efficacy of ceftriaxone and other antimicrobials, especially the aminoglycosides and other 'third generation' cephalosporins, and to confirm the apparent lack of serious side effects with ceftriaxone. If more widespread use confirms the safety and efficacy of ceftriaxone, it will offer an important alternative, particularly for the treatment of serious infections due to multidrug-resistant Gram-negative bacteria and in situations where the long half-life of the drug could result in worthwhile convenience and cost benefits.
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            Pathogenesis of ceftriaxone-associated biliary sludge. In vitro studies of calcium-ceftriaxone binding and solubility.

            Ceftriaxone, a semisynthetic third-generation cephalosporin, has recently been associated with biliary sludge formation. Analysis of the biliary concretions induced by this agent shows a calcium salt of ceftriaxone. The present in vitro studies were undertaken to provide insight into the pathogenesis of ceftriaxone-associated biliary sludge formation by evaluating possible interactions that may exist between calcium, bile salts, and ceftriaxone. Ceftriaxone possessed high calcium-binding affinity. The formation constant for the calcium ceftriaxone salt at 37 degrees C was about 157.3 L/mol; stoichiometry of the salt was 1:1, i.e., calcium ceftriaxone. The calcium-binding property of ceftriaxone was observed to be additive to that of taurocholate in mixed taurocholate-ceftriaxone solutions. Although the solubility product constant for calcium ceftriaxone was only 1.62 x 10(-6) mol/L2, marked metastability was observed; neither visible nor microscopic precipitates developed until the [Ca2+] x [ceftriaxone] ion product exceeded the solubility product constant by a factor of 10.4. Metastability of the calcium ceftriaxone salt was also observed in human gallbladder bile in vitro. Estimates of human biliary calcium ceftriaxone solubility in vivo were than calculated from previously-reported values for biliary [Ca2+], [ceftriaxone], and from the solubility product constant as defined in this study. Calculated saturation indices for calcium-ceftriaxone in human bile generally increased (corresponding to a decrease in solubility) with increasing ceftriaxone dose. At doses less than or equal to 1 g, saturation index was well within the metastable range of this calcium-salt. However, at doses greater than or equal to 2 g, the saturation index surpassed the metastable limit. Under these conditions, precipitation of ceftriaxone could occur. It was concluded that the development of ceftriaxone-induced biliary sludge is a solubility problem that occurs in patients receiving high-dose treatment (greater than or equal to 2 g). This study proposes that the risk of developing ceftriaxone-associated biliary "pseudolithiasis" increases with increasing ceftriaxone dose and in patients with impaired gallbladder emptying.
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              Reversible ceftriaxone-associated biliary pseudolithiasis in children.

              Serial abdominal ultrasonography was performed in 37 children being treated with ceftriaxone for serious infections. Biliary concrements developed in 16 patients, causing symptoms in 3, one of whom also had urolithiasis with renal colic and obstructive ureteropyelectasia. After cessation of ceftriaxone treatment, ultrasound abnormalities and symptoms gradually disappeared, with complete sonographic resolution after 2 to 63 days.
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                Author and article information

                Journal
                Case Report Med
                CRIM
                Case Reports in Medicine
                Hindawi Publishing Corporation
                1687-9627
                1687-9635
                2011
                26 October 2011
                : 2011
                : 730250
                Affiliations
                1Third Department of Pediatrics, “Attikon” General University Hospital, 1 Rimini Street, Haidari, 124 62 Athens, Greece
                2Laboratory of Hematology, “Aghia Sophia” Children's Hospital, Thivon and Papadiamantopoulou Street, Goudi, 115 27 Athens, Greece
                Author notes
                *Andrew Fretzayas: afretz@ 123456med.uoa.gr

                Academic Editor: Hermann E. Wasmuth

                Article
                10.1155/2011/730250
                3205720
                22110515
                98afe931-5182-4aac-97c3-e4f23a67079b
                Copyright © 2011 Andrew Fretzayas et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 June 2011
                : 22 August 2011
                Categories
                Case Report

                Medicine
                Medicine

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