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

Abstract Purpose: To evaluate the actual incidence of both microlithiasis and acute cholecystitis during treatment with intravenous ceftriaxone in a new rabbit model. Methods: New Zealand rabbits were treated with intravenous ceftriaxone or saline for 21 days. Ultrasound monitoring of the gallbladder was performed every seven days until the 21st day when histopathology, immunohistochemistry for proliferating cell nuclear antigen (PCNA), pro-caspase-3 and CD68, liver enzyme biochemistry, and chromatography analysis of the bile and sediments were also performed. Results: All animals treated with ceftriaxone developed acute cholecystitis, confirmed by histopathology (P<0.05) and biliary microlithiasis, except one that exhibited sediment precipitation. In the group treated with ceftriaxone there was an increase in pro-caspase-3, gamma-glutamyl transpeptidase concentration, PCNA expression and in the number of cells positive for anti-CD68 (P<0.05). In the ceftriaxone group, the cholesterol and lecithin concentrations increased in the bile and a high concentration of ceftriaxone was found in the microlithiasis. Conclusion: Ceftriaxone administered intravenously at therapeutic doses causes a high predisposition for lithogenic bile formation and the development of acute lithiasic cholecystitis.

Litiasis biliar asociada a ceftriaxona en pediatría: reporte de dos casos y revisión de la literatura / Biliary lithiasis due to ceftriaxone treatment in pediatric: report of two cases and literature review

Introducción: La ceftriaxona es una cefalosporina de tercera generación, bactericida, de amplio espectro de acción y de una vida media larga, por lo que es utilizada ampliamente en pediatría. Un efecto colateral poco conocido de este fármaco es la formación de precipitaciones biliares. Objetivo: Presentar 2 casos clínicos de pacientes de 9 y 14 años que cursaron con litiasis vesicular asintomática durante el tratamiento con ceftriaxona, y que tuvieron una resolución espontánea antes de 30 días. La revisión de la literatura muestra que la detección de precipitaciones biliares ocurre en un 14-47 por ciento de los pacientes tratados con ceftriaxona, los factores de riesgo de desarrollarlas es una mayor edad, tratamiento prolongado y dosis alta. Su resolución es espontánea y precoz. Conclusión: La formación de precipitaciones biliares si bien es frecuente, la mayoría de las veces es asintomática y de resolución espontánea, por lo que ceftriaxona sigue siendo un antibiótico seguro.

Introduction: Ceftriaxone is a third-generation cephalosporin, with a wide spectrum of action and a prolonged half-life time. These properties have contributed to its widespread use in pediatric patients.An infrequent collateral effect is the development of biliary pseudolithiasis. The aim is to present two cases of 9 and 14 years old, with asymptomatic gallstones during treatment with ceftriaxone, andresolved spontaneously before 30 days. Material and methods: Literature review shows that biliary pseudolithiasis occurs between 14 percent to 47 percent of patients treated with ceftriaxone. Risk factors are older age, long treatment, and high doses. Its resolution is early and spontaneous. Conclusion: Formation of biliary pseudolithiasis although frequent, most of the times is asymptomatic and resolves spontaneously, therefore ceftriaxone remains as safe antibiotic.

Relationship between use of hydroxyurea and cholelithiasis in patients with major and intermediate beta-thalassemia

Cholelithiasis is a common problem among patients with homozygous major and intermediate beta-thalassemia due to chronic hemolysis, ineffective erythropoesis and other factors that causes variety of side effects. Hydroxyurea [HU] decreases hemolysis by increasing HbF production in homozygous beta-thalassemia patients. Up to now, there have not been evidences about relationship between use of Hydroxyurea and cholelithiasis in the patients. The aim of this study was to determine the relationship between use of HU and incidence of cholelithiasis in patients with major and intermediate beta-thalassemia referred to thalassemia research center of Mazandaran University of medical sciences at Boo-Ali Sina hospital of Sari, IRAN. This historical cohort study was performed in 2006. Study population was major and intermediate beta-thalassemia patients referred to Boo-Ali Sina Hospital of Sari, IRAN. The patients were divided to two groups: case and control groups. The case group [36 patients] was consisted of major or intermediate beta -thalassemia patients using hydroxyurea at least for one year, and the control group were: non-hydroxyurea user patients or beginning to use the drug less than 3 months. The groups were matched on order to age, gender and severity of the disease. Severity of the disease was determined according to grading, clinical and laboratory characteristics of the patients. Data about demographic information, severity of the disease and results of hepatobiliary ultrasound were recorded in a questionnaire. The data was analyzed using SPSS [11] software and t-test, Chi-square test and fisher exact test. Thirty-six [20 women [55.6%]] patients in case group and 36 [19 women [52.8%]] patients in control group were studied. The mean duration of use of hydroxyurea was 67.9 +/- 25.5 months with maximum 108 months [9 year]. The mean dosage of the drug was 14.9 +/- 5.9 mg/kg with maximum dosage 34 mg/kg. Thirteen [48.1%] patients in control group [12 cholelithiasis, 1 sludge] and 6 [19.4%] patients in case group [5 cholelithiasis, 1 sludge] had abnormal hepatobiliary sonography. The difference between two groups was significant statistically [P<0.02]. Among the different variables, a significant relationship was detected between gender of the patients and effect of HU on cholelithiasis. This study showed that the incidence of cholelithiasis in major and intermediate beta-thalassemia patients using hydroxyurea was less than non-hydroxyurea user patients did. As a result, it seems that there was a preventive effect of hydroxyurea in incidence of cholelithiasis in major and intermediate beta-thalassemia patients

Colelitíase associada ao uso de ceftriaxona / Cholelithiasis associated with the use of ceftriaxone

Crianca de sete anos recebeu ceftriaxona para o tratamento de meningite, evoluindo com dor em hipocôndrio direito associada a cálculo na vesícula biliar. Após três meses, a ultrassonografia abdominal foi normal. O conhecimento de que a ceftriaxona pode levar ao surgimento de colelitíase pode evitar intervencões cirúrgicas desnecessárias.

Gallstone formation and gallbladder mucosal changes in mice fed a lithogenic diet

To investigate the pathologic change of gallbladder mucosa related to gallstone formation, 52 mice were fed a lithogenic diet containing 1% cholesterol and 0.5% cholic acid and we evaluated the sequential morphologic changes in the gallbladder from two days to 40 weeks. Cholesterol gallstones began to appear after two weeks and all the mice had gallstones after eight weeks. At two days, the mitotic index was at its highest. The gallbladder mucosa showed progressive hyperplastic change with earlier papillary projection of the folds and later inward proliferation. At the same time of stone formation, mucous cells forming glands appeared. Their histochemical profile of mucin was different from that of normal epithelium. Numbers of mucous cells increased gradually until 24 weeks but slightly decreased afterward. These results suggest hyperplasia and metaplasia are closely related to the gallstone formation. Hyperplasia is probably reactive to irritating effect of lithogenic bile or stone. Metaplasia and cholesterol gallstone may develop simultaneously, and act synergistically.

Pigment cholelithiasis induced by vitamin A and its prevencion by butylated hydroxytoluene

We previously reported on the induction by vitamin A of gallstones, rich in calcium and phosphate, in hamsters. On the other hand, it has been reported that the phenolic antioxidant butylate hydroxytoluene (BHT) potentiates the hepatotoxicity of vitamin A. In the present work we have tested the effect of BHT on the lithogenicity of vitamin A and on bile composition. The urinary excretion of calcium and phosphate was determined to assess a possible asymptomatic bone resorptin due to vitamin A toxicity, and/or an effect of BHT on the homeostasis of calcium and phosphate. Theree groups of 18 male hamsters were fed with the following diets for 70 days: Group 1, Purina Nutricubes (DB); Group 2, DB + 25,000 IU percent retinol acetate (DL); group 3, DL + 500 mg percent BHT. Vitamin A (group 2) induced gallstones in 78 percent of the animals, increased bile flow and biliary phosphate and calcium concentrations, and reduced those of bili salt, cholesterol and phospholipid. BHT (Group 3) reduced gallstone frequency to 5.5 percent, and decreased biliary phosphate, calcium and lipids toward more normal concentrations. Vitamin A alone or with BHT did not significantly affect food intake or urinary excretion of calcium and phosphate