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The review presents current data about cephalosporin-associated biliary sludge and cholelithiasis formation mechanism. Risks factors of pseudolithiasis development in children, who received cephalosporins, are analyzed and systematized. Moreover, the study provides information about the prevalence of pseudolithiasis in different periods of childhood. Not only main ways of ceftriaxone-induced cholelithiasis clinical course, but also the most common complications of pseudolithiasis have been described. The report characterizes typical clinical symptoms and sonographic features of pseudolithiasis in children. Furthermore, the research considers main methods of treatment that allow to avoid unnecessary cholecystectomy in children. For writing the review, we used such databases, as Scopus, Web of Science, MedLine, PubMed, Google Scholar, CyberLeninka, RSCI.

Background. One of the side effects of the third generation cephalosporins is the formation of cephalosporin-induced biliary pseudolithiasis (CIBPL). The purpose of the study was to establish the peculiarities of the formation of biliary sludge during the application of the third generation cephalosporins in the treatment of acute respiratory infections in children. Materials and methods. We examined 46 children aged 2 to 15 years with acute respiratory infections. Сephalosporins were administered intravenously in age doses. We evaluated the biochemical blood test and the echosonography (ultrasound) of the biliary tract before the treatment and after the end of antibiotic therapy of all children. Results. According to ultrasound data, in 10 patients (21.7 %) with acute respiratory infections, after a course of therapy with the third generation cephalosporins, heterogeneous contents were detected in the gallbladder lumen in the form of a hyperechoic suspension, which indicated the formation of CIBPL. The average age of patients with CIBPL was 9.05 ± 1.44 years and was within the range of 4 to 15 years. We found that in 60 % of the examined children, the formation of CIBPL proceeded subclinically. The results of a biochemical study of blood serum showed that in children with CIBPL, an increase in the activity of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase was observed. It was found that CIBPL is detected in 22.9 % of children against the background of ceftriaxone therapy, in 9 % of patients — ceftazidime. Biliary sludge was formed in 54.5 % of patients receiving ceftriaxone in high doses (100 mg/kg/day), and in 75 % of cases after 10 days of using this antibiotic. Conclusions. The obtained results showed that against the background of using third generation cephalosporins in the treatment of acute respiratory infections, 21.7 % of children had CIBPL. A particularly high risk of developing CIBPL is observed when using high doses of ceftriaxone and prolonged therapy with cephalosporins.

ObjectiveTo determine the safety of ceftriaxone in paediatric patients and systematically evaluate the categories and incidences of adverse drug reactions (ADRs) of ceftriaxone in paediatric patients.MethodsWe performed a systematic search in Medline, PubMed, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, International Pharmaceutical Abstracts and bibliographies of relevant articles up to December 2018 for all types of studies that assessed the safety of ceftriaxone in paediatric patients aged ≤18 years.Results112 studies met the inclusion criteria involving 5717 paediatric patients who received ceftriaxone and reported 1136 ADRs. The most frequent ADRs reported in prospective studies were gastrointestinal (GI) disorders (37.4 %, 292/780), followed by hepatobiliary disorders (24.6%, 192/780). Serious ADRs leading to withdrawal or discontinuation of ceftriaxone were reported in 86 paediatric patients. Immune haemolytic anaemia (34.9%, 30/86) and biliary pseudolithiasis (26.7%, 23/86) were the two major causes. Haemolytic anaemia following intravenous ceftriaxone led to death in 11 children whose primary disease was sickle cell disease. Almost all biliary pseudolithiasis are reversible. However, the incidence was high affecting one in five paediatric patients (20.7%).ConclusionsGI ADRs are the most common toxicity of ceftriaxone in paediatric patients. Immune haemolytic anaemia and biliary pseudolithiasis are the most serious ADRs and the major reasons for discontinuation of ceftriaxone. Immune haemolytic anaemia is more likely in children with sickle cell disease and may cause death. Ceftriaxone should be used with caution in children with sickle cell disease.Trial registration numberCRD42017055428

Ceftriaxone-associated biliary pseudolithiasis is common among children; however, there are only a few reports of pseudolithiasis in adult patients on HD. This retrospective cohort study included 278 adult patients on ceftriaxone therapy from 1 February 2016 to 1 September 2018. Pseudolithiasis was defined as a new development of sludge or stones in the gallbladder within 60 days of ceftriaxone therapy. After excluding patients with preexisting gallstones and a history of cholecystectomy, 113 patients on maintenance HD, and another 98 patients were enrolled as the HD and control group, respectively. Thirteen patients developed pseudolithiasis. Its incidence was significantly higher in the HD group than that in the control group. Multivariate logistic regression analyses showed that development of pseudolithiasis was significantly associated with HD and ceftriaxone dose. Therefore, HD in patients receiving ceftriaxone therapy appears to be associated with a risk of pseudolithiasis. These findings highlight the need for careful follow-up.

This study aimed to characterize the computed tomography (CT) findings of pseudolithiasis and investigate the outcomes and natural history in adult patients receiving CTRX therapy. A total of 17 patients were diagnosed with CTRX-associated biliary pseudolithiasis on CT between April 2013 and March 2017. The medical records, characteristics, complications, treatment options, and outcomes of these patients were examined. Serial CT images and the form, density, and location of pseudolithiasis were reviewed by two radiologists. Of the 17 patients with CTRX-associated pseudolithiasis, seven were men and ten were women. The median patient age was 78 years (range 31–88 years). The median interval from CTRX administration to the diagnosis of pseudolithiasis was 10 days (range 4–32 days). The CT findings of pseudolithiasis included a sludge pattern (11 patients [64.7%]), stone pattern (two patients [11.8%]), and stone plus sludge pattern (four patients [23.5%]). Seven patients (41.2%) showed gall bladder enlargement along with a common bile duct (CBD) stone. Two patients with CBD stones underwent endoscopic CBD stone removal. The median time to pseudolithiasis resolution after CTRX cessation was 69 days. The high-density sludge pattern is the most common typical CT finding of CTRX-associated pseudolithiasis in adults.

Ceftriaxone is an antibiotic agent frequently used in paediatric hospital practice for the treatment of severe bacterial infections. The use of this agent can result in cholelithiasis and/or biliary sludge, more commonly in children than in adults. This systematic review was aimed at analysing available literature concerning ceftriaxone-associated biliary pseudolithiasis in paediatric patients, with a special emphasis on the clinical aspects. A literature analysis was performed using Medline and Embase electronic databases (articles published in English up to December 2019), with the search terms and combinations as follows:'ceftriaxone', 'cholelithiasis', 'biliary sludge' 'gallstones' 'neonates' 'children' 'clinical aspects' 'management'. Several case reports, case series and prospective/retrospective studies have documented a relationship between ceftriaxone treatment and biliary pseudolithiasis in the paediatric population, even though literature data regarding neonates and infants are scarce. Ceftriaxone-associated biliary pseudolithiasis is dose-dependent and usually asymptomatic but, sometimes, it may present with abdominal pain, nausea and emesis. Abdominal ultrasonography should be performed when this complication is suspected. Generally, ceftriaxone-associated cholelithiasis resolves over a variable period of time (days to months) after cessation of therapy. Therefore, a conservative approach to this condition is advocated, but a prolonged follow-up may be necessary. A personalized assessment of factors predisposing to ceftriaxone-associated biliary pseudolithiasis before prescribing the drug can allow to minimize the risk of developing it, with significant advantages in terms of human and economic costs.

Introduction: Ceftriaxone is a frequently used antibiotic in inpatients treated for a number of bacterial infections. Biliary calculi formation called pseudolithiasis is a well-known asymptomatic and reversible complication of this drug. However, a percentage of patients do present with new onset of abdominal symptoms which can be attributable to presence of pseudoliths. Aim: To evaluate incidence of pseudolithiasis in inpatients treated with parenteral Ceftriaxone, to assess resolution of pseudoliths and development of abdominal symptoms attributable to pseudolithiasis on long term follow-up over one year. Materials and Methods: A prospective observational cohort study including all patients admitted at our centre and started on Ceftriaxone. These patients were subjected to sonographic examination on day 1 and day 7 of treatment. Patients who developed pseudolithiasis were prospectively followed-up at one month, three months, six months and one year to assess for resolution or whenever they presented with symptoms. Incidence of pseudolithiasis and complications in patients who developed pseudolithiasis was calculated using standard formulae. Descriptive statistics in terms of numbers and percentages were used. Results: A total of 1490 patients were included in the study from August 2016 till July 2017 and followed for a period of one year (June 2018). The incidence of pseudolithiasis in inpatients treated with parenteral ceftriaxone was 8.7% (131 patients) as observed on Sonographic examination performed on day 7 of therapy. Ten (7.6%) patients had pseudoliths at one month and 1 (0.76%) patient out of these had persistent pseudoliths at all subsequent reviews till one year after diagnosis of the condition. Eleven (8.3%) patients who developed pseudolithiasis during therapy with Ceftriaxone had presented with upper abdominal symptoms suggestive of biliary colic before resolution of pseudolithiasis. Conclusion: Biliary pseudolithiasis is a common side effect of ceftriaxone therapy, occurring in approximately 10% of patients. Biliary colic, cholecystitis and pancreatitis may also result due to these pseudoliths complicating the course of primary illness. Further consultations and interventions like cholecystectomy can be reserved not only to symptomatic individuals but also for those with persistent pseudoliths.

International audience; BACKGROUND: Ceftriaxone is widely used to treat community-acquired CNS bacterial infections. French guidelines for meningitis in adults promote 75-100\,mg/kg/day ceftriaxone without an upper limit for dosage, yet little is known about the pharmacology and tolerability of such regimens. PATIENTS AND METHODS: A multicentre prospective cohort study was conducted in adult patients to assess the adverse drug reactions (ADRs) of high-dose ceftriaxone (i.e. daily dosage ≥q4\,g or ≥q75\,mg/kg) in CNS infections and to analyse their related factors. Drug causality was systematically assessed by an expert committee who reviewed the medical charts of all included patients. RESULTS: A total of 196 patients were enrolled over a 31\,month period. Median dosage and duration of ceftriaxone were 96.4\,mg/kg/day (7\,g/day) and 8\,days, respectively. Nineteen ceftriaxone-related ADRs (mainly neurological) occurred in 17 patients (8.7%), with only one case of treatment discontinuation (biliary pseudolithiasis). In univariate analysis, older age, male gender, renal impairment and high trough ceftriaxone plasma concentration were associated with ceftriaxone-related ADRs. CONCLUSIONS: High-dose ceftriaxone for CNS infection administered as recommended by French guidelines in adults was well tolerated overall, suggesting these recommendations could be applied and generalized. In patients with advanced age or renal insufficiency, prescription should be done with caution and therapeutic drug monitoring could be useful.

Ceftriaxone (CTRX) is a third-generation cephalosporin widely used for the treatment of bacterial infections in patients with renal disease because of its excretion by both renal and hepatic mechanisms. Biliary pseudolithiasis is a known CTRX-associated complication; however, there have been no studies of this adverse event in adult patients receiving maintenance hemodialysis. Here we report the case of a 79-year-old Japanese woman with end-stage renal disease (ESRD) receiving maintenance hemodialysis who developed CTRX-induced pseudolithiasis. The patient received CTRX for bronchial pneumonia. Fifteen days following CTRX initiation, the patient presented with stomachache. Because of the presence of one gallstone and increased gallbladder wall thickness on computed tomography scans, not detected at the onset of pneumonia, the patient was diagnosed with CTRX-induced gallbladder pseudolithiasis. CTRX was discontinued immediately. At 48 days following CTRX withdrawal, the gallstone and thickening of the gallbladder wall had completely resolved. ESRD may be a risk factor for CTRX-induced pseudolithiasis as hepatic excretion of CTRX is the predominant clearance mechanism in patients with ESRD. More attention should be paid to CTRX-induced pseudolithiasis following the use of CTRX in ESRD patients.

Background Cholelithiasis is one of the side-effects of ceftriaxone (CTRX). Reportedly, the cholelithiasis resolves relatively soon after cessation of CTRX, hence, it is called pseudolithiasis. Previous reports have suggested that biliary pseudolithiasis can cause not only gallstone attacks, but also severe adverse events, such as cholecystitis and pancreatitis. The purpose of this study was to prospectively elucidate the risk factors and clinical features of CTRX-associated pseudolithiasis in pediatric patients. Methods We prospectively examined the incidence and clinical outcome of CTRX-associated biliary pseudolithiasis. Subjects included infants and children who were admitted to hospital with acute disease. Ultrasonography was used to confirm the absence of stones and sludge in the gallbladder before CTRX therapy, and in assessment of pseudolithiasis on days 3, 5, 7 and 10 after initiation of CTRX in all subjects. The pseudolithiasis group was then compared with the non-pseudolithiasis group in terms of age, sex, CTRX dose, CTRX duration, duration of fever, fasting period, period of bed rest, and blood test results. Results Sixty patients were enrolled in the study. Eleven of them had biliary pseudolithiasis on ultrasonography (18.3%). Formation of biliary pseudolithiasis was prevalent in the fasting and bed rest groups, appearing relatively early in these groups. Conclusions Special attention should be paid to the degree of oral intake and patient activity when CTRX is prescribed. We recommend regular ultrasonographic follow up of patients receiving CTRX, to evaluate the formation of biliary pseudolithiasis.

Актуальність. Одним із побічних ефектів дії цефалоспоринів ІІІ покоління є формування цефалоспориніндукованого біліарного псевдолітіазу (ЦІБПЛ). Мета. Вивчити особливості формування біліарного сладжа при застосуванні цефалоспоринів ІІІ покоління в терапії гострих респіраторних інфекційних захворювань у дітей. Матеріали та методи. Обстежено 46 дітей віком від 2 до 15 років з гострими респіраторними інфекційними захворюваннями, які отримували в терапії цефалоспорини ІІІ покоління парентеральним шляхом введення у вікових дозах. У всіх дітей до початку лікування і після закінчення антибіотикотерапії оцінювали показники біохімічного дослідження крові і дані ехосонографії (ультразвукове дослідження) біліарного тракту. Результати. За даними УЗД у 10 пацієнтів (21,7 %) з гострими респіраторними інфекційними захворюваннями після проведеного курсу терапії цефалоспоринами ІІІ покоління виявлено неоднорідний вміст у просвіті жовчного міхура у вигляді гіперехогенного субстрату, що свідчило про формування ЦІБПЛ. Середній вік пацієнтів із ЦІБПЛ становив 9,05 ± 1,44 року і перебував у межах від 4 до 15 років. Встановлено, що у 60 % обстежених дітей формування ЦІБПЛ протікало субклінічно. Результати біохімічного дослідження сироватки крові показали, що у дітей із ЦІБПЛ спостерігалося підвищення активності аланінамінотрансферази, аспартатамінотрансферази і лужної фосфатази. Було встановлено, що ЦІБПЛ відзначається у 22,9 % дітей на тлі терапії цефтріаксоном, у 9 % пацієнтів — цефтазидимом. Біліарний сладж формувався у 54,5 % хворих, які отримували цефтріаксон у високих дозах (100 мг/кг/добу), і в 75 % випадків — після 10-денного застосування даного антибіотика. Висновки. Отримані результати показали, що на тлі застосування цефалоспоринів ІІІ покоління при терапії гострих респіраторних інфекційних захворювань у 21,7 % хворих дітей відбувається формування ЦІБПЛ. Особливо високий ризик розвитку ЦІБПЛ відзначається при використанні високих доз цефтріаксону і пролонгованої терапії цефалоспоринами., Актуальность. Одним из побочных эффектов действия цефалоспоринов ІІІ поколения является формирование цефалоспорининдуцированного билиарного псевдолитиаза (ЦИБПЛ). Цель. Изучить особенности формирования билиарного сладжа при применении цефалоспоринов ІІІ поколения в терапии острых респираторных инфекционных заболеваний у детей. Материалы и методы. Обследовано 46 детей возрастом от 2 до 15 лет с острыми респираторными инфекционными заболеваниями, которые получали в терапии цефалоспорины ІІІ поколения парентеральным путем введения в возрастных дозировках. У всех детей до начала лечения и после окончания антибиотикотерапии оценивали показатели биохимического исследования крови и данные эхосонографии (ультразвуковое исследование) билиарного тракта. Результаты. По данным УЗИ у 10 пациентов (21,7 %) с острыми респираторными инфекционными заболеваниями после проведенного курса терапии цефалоспоринами ІІІ поколения выявлено неоднородное содержимое в просвете желчного пузыря в виде гиперэхогенной взвеси, что свидетельствовало о формировании ЦИБПЛ. Средний возраст пациентов с ЦИБПЛ составлял 9,05 ± 1,44 года и находился в границах от 4 до 15 лет. Установлено, что у 60 % обследуемых детей формирование ЦИБПЛ протекало субклинически. Результаты биохимического исследования сыворотки крови показали, что у детей с ЦИБПЛ наблюдалось повышение активности аланинаминотрансферазы, аспартатаминотрансферазы и щелочной фосфатазы. Было установлено, что ЦИБПЛ отмечается у 22,9 % детей на фоне терапии цефтриаксоном, у 9 % пациентов — цефтазидимом. Билиарный сладж формировался у 54,5 % больных, получавших цефтриаксон в высоких дозах (100 мг/кг/сут), и в 75 % случаев — после 10-дневного применения данного антибиотика. Выводы. Полученные результаты показали, что на фоне применения цефалоспоринов ІІІ поколения при терапии острых респираторных инфекционных заболеваний у 21,7 % больных детей происходит формирование ЦИБПЛ. Особенно высокий риск развития ЦИБПЛ отмечается при использовании высоких доз цефтриаксона и пролонгированной терапии цефалоспоринами., Background. One of the side effects of the third generation cephalosporins is the formation of cephalosporin-induced biliary pseudolithiasis (CIBPL). The purpose of the study was to establish the peculiarities of the formation of biliary sludge during the application of the third generation cephalosporins in the treatment of acute respiratory infections in children. Materials and methods. We examined 46 children aged 2 to 15 years with acute respiratory infections. Сephalosporins were administered intravenously in age doses. We evaluated the biochemical blood test and the echosonography (ultrasound) of the biliary tract before the treatment and after the end of antibiotic therapy of all children. Results. According to ultrasound data, in 10 patients (21.7 %) with acute respiratory infections, after a course of therapy with the third generation cephalosporins, heterogeneous contents were detected in the gallbladder lumen in the form of a hyperechoic suspension, which indicated the formation of CIBPL. The average age of patients with CIBPL was 9.05 ± 1.44 years and was within the range of 4 to 15 years. We found that in 60 % of the examined children, the formation of CIBPL proceeded subclinically. The results of a biochemical study of blood serum showed that in children with CIBPL, an increase in the activity of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase was observed. It was found that CIBPL is detected in 22.9 % of children against the background of ceftriaxone therapy, in 9 % of patients — ceftazidime. Biliary sludge was formed in 54.5 % of patients receiving ceftriaxone in high doses (100 mg/kg/day), and in 75 % of cases after 10 days of using this antibiotic. Conclusions. The obtained results showed that against the background of using third generation cephalosporins in the treatment of acute respiratory infections, 21.7 % of children had CIBPL. A particularly high risk of developing CIBPL is observed when using high doses of ceftriaxone and prolonged therapy with cephalosporins.

Ceftriaxone (CTRX) is a known cause of biliary pseudolithiasis (BPL) mainly in children. Biliary elimination of CTRX increases in patients with renal dysfunction. However, the influence of renal dysfunction on the incidence of CTRX-associated BPL has not been well investigated. The aim of this study was to investigate the cumulative incidence of CTRX-associated BPL in adults and to assess if renal dysfunction is a risk factor. We retrospectively analyzed the medical records of 478 patients treated with CTRX to assess the incidence and risk factors of CTRX-associated BPL. We examined age, sex, body weight, dosage, and duration of CTRX therapy, and the concentrations of serum creatinine, estimated glomerular filtration rate (eGFR), albumin, and serum calcium in all the patients. The cumulative incidence of BPL was calculated using a competing risk model. The multivariate analysis of each variable for the development of BPL was assessed by a Cox proportional hazards model. A total of 362 patients (75.7%) had renal dysfunction (eGFR

Prior literature suggests that ceftriaxone causes formation of gallbladder stones at a relatively high frequency, and when abdominal symptoms occur, prompt investigation of the gallbladder is required with institution of appropriate treatment. Aging, malnutrition, renal impairment, and sepsis are risk factors for pseudolithiasis, and prevention of these is important to suppress gallstone development.

Background:Biliary lithiasis, or sludge, and nephrolithiasis have been reported as a possible complication of ceftriaxone therapy. However, no study related to cefotaxime-induced biliary pseudolithiasis or nephrolithiasis was observed in the literature. Therefore, we investigated the comparative formation of biliary pseudolithiasis and nephrolithiasis after cefotaxime and ceftriaxone therapies.Methods:The patients treated with ceftriaxone or cefotaxime were enrolled during the study period. Ultrasound imaging of the biliary and urinary tract was performed in all patients before and after the treatment. The patients with a positive sonographic finding at the end of treatment were followed up with monthly ultrasonography for 3 months.Results:The present study showed that abnormal biliary sonographic findings were demonstrated in 18 children (20.9%) treated with ceftriaxone, 13 (15.1%) had biliary lithiasis, 5 (5.8%) had biliary sludge and 1 (1.2%) had nephrolithiasis. Abnormal biliary sonographic findings were demonstrated in only four (5.9%) children treated with cefotaxime who had biliary sludge and only one (1.5%) had nephrolithiasis. It was observed that older age was at significantly higher risk of developing biliary sludge or stone formation. Receiver operating characteristic analysis was performed to determine the residual risk and analysis found that 4.5 years was the cut-off value for age.Conclusions:The present study is unique in the literature for reporting for the first time gall bladder sludge and nephrolithiasis associated with cefotaxime use. Therefore, patients treated with cefotaxime should be monitored for serious complications like patients treated with ceftriaxone. Nevertheless, if third-generation cephalosporin is used, cefotaxime is recommended to be used rather than ceftriaxone.

Ceftriaxone is known to cause biliary pseudolithiasis and, rarely, nephrolithiasis mainly in children. However, we reported the development of bilateral distal ureteral ceftriaxone-associated lithiasis in 7 adults, which suggests that the risk of ureterolithiasis impaction should be considered when treating patients with ceftriaxone, even in adults. To avoid strengthening greater renal damage, ureteroscopic insertion of double J stents may be an alternative management for patients with ureteral ceftriaxone-associated lithiasis.

In this randomized, single-blind, case-controlled, prospective study, the incidence and outcome of ceftriaxone-associated biliary pseudolithiasis in Chinese children was evaluated via ultrasonography. A total of 108 children diagnosed with hepatobiliary infection or pneumonia were randomized to receive ceftriaxone or ceftazidime. Serial gallbladder sonograms were obtained on days 1, 5 − 7 and 10 − 14 of therapy. Gallstones were detected in 43.10% of patients in the ceftriaxone-treated group and in 2.00% of the ceftazidime-treated group. The incidence of pseudolithiasis was significantly higher in the ceftriaxone-treated than the ceftazidime-treated group. Biliary precipitation abnormalities appeared after 2 − 7 days of treatment. After gallstones were found, the drug was stopped and symptoms resolved within 1 − 2 days. This study suggests that the risk of ceftriaxone-associated biliary pseudolithiasis should be considered when treating Chinese children.

Ceftriaxone is a commonly used third-generation cephalosporin that has antimicrobial activity against many gram-positive and gram-negative organisms. Generally, ceftriaxone is a safe antibiotic; however, symptomatic biliary sludge has been reported in rare instances, most of which have involved children. It is uncommon for ceftriaxone to cause increases in laboratory indexes, such as bilirubin levels. We describe the case of a 53-year-old man who was treated with intravenous ceftriaxone 2 g every 12 hours. After 7 days of therapy, the patient's liver function test results, including total, direct, and indirect bilirubin levels, increased significantly from baseline, and the patient became jaundiced. A right upper quadrant ultrasound examination revealed biliary sludge and cholelithiasis without sonographic evidence of cholecystitis. Ceftriaxone was thought to be the responsible agent, and it was discontinued. The patient's jaundice subsided, and his liver function test results improved, returning to baseline within 14 days. Clinicians need to be aware of the association of ceftriaxone and biliary pseudolithiasis and hyperbilirubinemia, and monitor accordingly.

WOS: 000227997400013, PubMed ID: 15737522, It is well known that ceftriaxone leads to pseudolithiasis in some patients. Clinical and experimental studies also suggest that situations causing gallbladder dysfunction, such as fasting, may have a role for the development of pseudolithiasis. In this study, we prospectively evaluated the incidence and clinical importance of pseudolithiasis in paediatric surgical patients receiving ceftriaxone treatment, who often had to fast in the post-operative period. Fifty children who were given ceftriaxone were evaluated by serial abdominal sonograms. Of those, 13 (26%) developed biliary pathology. Comparison of the patients with or without pseudolithiasis revealed no significant difference with respect to age, sex, duration of the treatment and starvation variables. After cessation of the treatment, pseudolithiasis resolved spontaneously within a short period. The incidence of pseudolithiasis is not affected by fasting. (C) 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Background: Background: Ceftriaxone, a third generation cephalosporin, is widely used for treating infection during childhood. The kidneys eliminate approximately 33–67% of this agent, and the remainder is eliminated via the biliary system. Ceftriaxone may bind with calcium ions and form insoluble precipitate leading to biliary pseudolithiasis. The aim of this study was to assess whether ceftriaxone associated nephrolithiasis develops by the same mechanism, and whether this condition is dose related. Methods: The study involved 51 children with various infections. Of these, 24 were hospitalized with severe infection and received 100 mg/kg/day ceftriaxone divided into two equal intravenous doses. The other 27 patients received a single daily intramuscular injection of 50 mg/kg/day. Serum and urine parameters were evaluated before and after treatment, and abdominal ultrasonographic examinations were also carried out before and after treatment. Results: Serum urea, creatinine, and calcium levels were normal in all patients before and after treatment. Post-treatment ultrasound identified nephrolithiasis in four (7.8%) of the 51 subjects. The stones were all of small size (2 mm). Comparison of the groups with and without nephrolithiasis revealed no significant differences with respect to age, sex distribution, duration of treatment, or dose/route of administration of ceftriaxone. The renal stones disappeared spontaneously in three of the four cases, but were still present in one patient 7 months after ceftriaxone treatment. Conclusions: Conclusions: The study showed that children taking a 7 day course of normal or high dose ceftriaxone may develop small sized asymptomatic renal stones. The overall incidence of nephrolithiasis in this study was 7.8%.

Cholelithiasis is a pathology that can be confidently diagnosed by sonographic examination. The following case presents sonographic findings consistent with cholelithiasis in a child being treated with the antibiotic Rocephin. A follow-up preoperative sonographic examination of the gallbladder displayed no evidence of cholelithiasis. This is a classic example of Rocephin-induced “biliary pseudolithiasis.”

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 theUGT1A1gene, implying that a cause and effect relation may exist.

Ceftriaxone has been associated with development of pseudolithiasis. In our institution, it is used for treatment of perforated appendicitis in children. This study evaluated the occurrence of ceftriaxone-related pseudolithiasis in this population. After obtaining IRB approval, we performed a retrospective chart review over 51 months. We included patients undergoing laparoscopic appendectomy for perforated appendicitis. All patients were treated with ceftriaxone post-operatively. Patients without initial or post-treatment gallbladder imaging available for review were excluded. There were 71 patients who met inclusion criteria with a mean (±SD) age of 10.8 ± 3.8 years. Of these, 14 % (n = 10) developed stones or sludge in the gallbladder. The mean duration of ceftriaxone therapy was 8.7 ± 3.8 days. The average time to post-antibiotic imaging was 11.5 ± 10.3 days from initiation of antibiotics. There was no significant difference in duration of ceftriaxone therapy in the children that developed pseudolithiasis or sludge (10.0 ± 4.9 days) compared to those that did not (8.5 ± 3.6, p = 0.26). One child (10 %) with pseudolithiasis went on to become symptomatic, requiring a laparoscopic cholecystectomy. In our experience, ceftriaxone use for perforated appendicitis is associated with a significant incidence of biliary pseudolithiasis, and is unrelated to duration of ceftriaxone therapy.

The prolonged biological half-life of Ceftriaxone, allowing once-daily dosing, has contributed to the large diffusion of this third-generation cephalosporin in children. Ceftriaxone is known to induce reversible precipitates in the gallbladder of adults and children. A prospective study was conducted during 1997 in 34 children admitted for the treatment of acute pyelonephritis. Ceftriaxone (intravenous daily single-dose of 50 mg/kg under 2g/day) was initially used. A first gallbladder sonogram, performed before the first or second injection, was normal in all cases. A second evaluation was performed before the fifth and last injection. On this second evaluation the presence of one (n = 3) or two gallstones was recorded in 5 children (15%) on a sonogram made after 3 (n = 4) or 5 (n = 1) injections. Their median age was 7 years (range 4 months to 11 years). All five children remained symptom-free and the normalization of the sonographic patterns was constant on the last sonogram performed 2 (n = 1), 3 (n = 2) and 5 months (n = 2) after discontinuation of Ceftriaxone. This study confirms the possibility of precocious biliary lithiasis under Ceftriaxone therapy in childhood and their spontaneous dissolution after discontinuation of the drug. They seem unpredictable and independent of the age, sex in a cohort homogeneous for the nature of the infection, modality of a short- and low-dose therapy. Clinicians and radiologists should be aware of this complication as an etiology of a so-called primary cholelithiasis and to prevent anxiety or unnecessary cholecystectomy. The antibacterial and pharmacokinetic benefits of Ceftriaxone outweigh the problem of reversible biliary pseudolithiasis with this drug.

Ceftriaxone is a third-generation cephalosporin with a wide spectrum of activity against both gram-negative and gram-positive organisms. Ceftriaxone has proven efficacy against severe and difficult-to-treat community-acquired infections including typhoid fever and other sepsis syndromes caused by multi-drug resistant organisms. Several studies including prospective studies exist in the literature that described the accumulation of sonographically demonstrable sludge (or precipitates) in the gallbladder and sometimes in the urinary tract. The accumulation of sludge occurs during therapy for severe infections in some children identified with certain predisposing factors. The condition is often asymptomatic but might be associated with clinical features that could mimic disease progression in patients with intra-abdominal manifestations of infection such as typhoid fever. Five Nigerian children aged between 4 and 11 years developed demonstrable gallbladder sludge (precipitate) while on treatment for typhoid fever with ceftriaxone. Three of the children manifested clinical features suggestive of gallbladder precipitate accumulation following commencement of the antibiotic, while the other two did not. Ceftriaxone therapy was continued to completion in all the cases along with conservative management. Four of the children recovered and had resolution of the sludge, while the fifth died of multi-organ failure after surgery for intestinal perforation. Although several studies exist in the literature regarding this condition, our search using Medline and Google Scholar did not identify such reports from children in Nigeria or sub-Saharan Africa. The cases are presented to create awareness on the possibility of occurrence of a drug-induced biliary precipitate formation in children.

It is known that ceftriaxone administration is associated with biliary pseudolithiasis, although the development of urolithiasis has been rarely reported. We encountered a young male with bacterial meningitis complicated by urinary precipitates composed of ceftriaxonecalcium salt which is confirmed by high-performance liquid chromatography. This patient suggested that ceftriaxone significantly increased urinary excretion of calcium, which may be linked to ceftriaxone-related urolithiasis or sludge. It is therefore worthwhile to monitor the levels of urinary calcium to creatinine ratio in patients on ceftriaxone, as they may be at greater risk for developing large stones and renal damage.

The administration of ceftriaxone is known to be associated with biliary pseudolithiasis, although the development of urolithiasis has only rarely been reported. We treated a young male with bacterial meningitis complicated by urinary precipitates composed of ceftriaxone-calcium salt, which prompted us to study whether ceftriaxone administration predisposes children to the formation of urinary precipitates. The case-control study reported here included 83 children with bacterial pneumonia aged from 3 months to 8.9 years. The children were divided into one group of 43 children who received ceftriaxone (group A) and a second group of 40 children who received amoxicillin (group B). Paired samples of serum and urine before and after treatment were obtained from the patients in each group. There were no significant differences in demographic characteristics and blood biochemistry between the groups. However, the mean urinary calcium to creatinine ratio (uCa/Cr; mg/mg) was significantly higher in group A patients than in group B patients after treatment (0.19 vs. 0.09, respectively; p 0.001), and analysis of the paired urine samples revealed that the uCa/Cr significantly increased after treatment only in group A patients(p 0.001). There was a weak but non-significant relationship between the dose of ceftriaxone and the uCa/Cr in group A (p = 0.10, r = 0.24). Our results are the first to demonstrate that ceftriaxone has the potential to significantly increase urinary excretion of calcium, which may be linked to ceftriaxone-related urolithiasis or sludge. We therefore suggest that it is worthwhile monitoring the uCa/Cr levels in patients on ceftriaxone as they may be at greater risk for developing large stones and renal damage.

Purpose Ceftriaxone is a widely used third-generation cephalosporin. In this prospective study, we used sonography to investigate the incidence and outcome of biliary complications in children receiving ceftriaxone therapy. Methods Ceftriaxone was administered intravenously at a dosage of 100 mg/kg/day for 1–3 weeks to 118 children hospitalized for severe infection. Serial gallbladder sonograms were obtained on days 1, 5–7, and 10–14 of therapy and the day after therapy ended if it had lasted more than 2 weeks. When sonographic abnormalities were found, additional sonograms were obtained every 3 days until the abnormalities had completely resolved. Results Twenty patients (17%), all asymptomatic, demonstrated sonographic abnormalities: 8 had gallbladder sludge, defined as echogenic material without associated acoustic shadowing, and 12 had pseudolithiasis, defined as echogenic material with acoustic shadowing. These abnormalities spontaneously resolved within 2 weeks of stopping the ceftriaxone (mean time to disappearance, 8.2 ± 3.4 days). No significant differences were found between patients with normal versus abnormal sonographic findings in sex, age, duration of treatment, or other risk factors for drug precipitation. Conclusions Ceftriaxone-associated biliary pseudolithiasis is usually asymptomatic and was rapidly reversible after cessation of therapy in this group of Turkish children. © 2000 John Wiley & Sons, Inc. J Clin Ultrasound 28:166–168, 2000.

Ceftriaxone, a third-generation cephalosporin, is partially excreted into bile. With its clinical use, the formation of gallbladder sludge detected by ultrasonography has been reported. Four surgical specimens were examined and no gallstones were found. Instead, fine precipitates of 20-250 microns were present. Microscopically, there was a small number of cholesterol monohydrate crystals and bilirubin granules among an abundant amount of granular-crystalline material that was not morphologically cholesterol monohydrate crystals. The chemical composition of the precipitates (n = 4) was determined. There was a small amount of cholesterol (1.7% +/- 0.8%) and bilirubin (13.9% +/- 0.74%). The major component of the precipitate was a residue. On further analysis using thin-layer chromatography, high-performance liquid chromatography, and electron microprobe analysis, the residue was identified as a calcium salt of ceftriaxone. The residue also had identical crystal morphology and chromatographic elution profile as authentic calcium-ceftriaxone standards. It is concluded that ceftriaxone, after excretion and being concentrated in the gallbladder bile, can form a precipitate. The major constituent has been identified as a ceftriaxone-calcium salt.

La lithiase biliaire est exceptionnelle dans l'enfance et associee habituellement avec quelques facteurs predisposant comme une anomalie congenitale du tractus biliaire, une maladie hemolytique, l'administration de TPN et des maladies de l'ileon terminal. Des etudes recentes ont demontre que la Ceftriaxone entrainait des precipitations reversibles dans la vesicule biliaire qui ressemblaient a une lithiase choledochienne. Cette complication est denommee «pseudo-lithiase biliaire» ou «cholelithiase reversible». Dans cette communication, nous decrivons un patient qui a developpe une pseudo-lithiase biliaire apres un traitement de 6 jours par Ceftriaxone; la guerison complete est survenue 11 jours apres la fin de traitement. Les indications de la cholecystectomie sont discutees.

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.

The hepatic transport of ceftriaxone, a third-generation cephalosporin, was characterized in the rat and hamster; its effect on bile flow and bile acid-induced biliary lipid secretion was also measured. In anesthetized rats with biliary fistulae, the Tmax was about 5 mumol.min-1.kg-1, and in the hamster the Tmax was about 1 mumol.min-1.kg-1. The compound was not biotransformed. At high secretion rates, the concentration of cephalosporin in bile increased to 27 mmol/L, a concentration far exceeding the solubility product of its calcium salt [2 x 10(-6) (mol/L)2], which precipitated from bile. In the rat, ceftriaxone induced choleresis (22 microL/mumol ceftriaxone, the expected value for a dianionic compound). In the isolated perfused rat liver, ceftriaxone had a fractional hepatic extraction rate averaging 3%; the compound was concentratively secreted into bile, the bile-perfusate ratio ranging from 35-250. Ceftriaxone inhibited phospholipid and cholesterol secretion induced by endogenous or exogenous bile acids; the rate of inhibition was linearly proportional to the canalicular secretion rate of ceftriaxone. Hepatic transport of ceftriaxone had no influence on hepatic secretion of ursodeoxycholyltaurine. In contrast, the net hepatic transport of ursodeoxycholic acid, ursodeoxycholyltaurine, or cholyltaurine inhibited ceftriaxone transport in a dose-dependent manner. It is concluded that ceftriaxone and bile acids share a common mechanism for hepatic transport in the rat and also interact in the processes involved in biliary lipid secretion. Biliary secretion of unbiotransformed ceftriaxone occurs at high concentrations; secondary Ca2+ entry results in the formation of supersaturated canalicular bile and subsequent precipitation as a calcium salt in the biliary tract. These data explain the formation of biliary sludge that occurs in patients undergoing high-dose ceftriaxone therapy.

A 5-year-old boy who had pneumonia was treated in a neighboring hospital. Ceftriaxone was administrated 2 g/day divided into two equal intravenous doses. After 1 week of ceftriaxone therapy, the patient developed abdominal pain. In our hospital, an abdominal sonogram showed a hyperechoic band with postacoustic shadow within the collapsed gallbladder. He was diagnosed with ceftriaxone-associated biliary pseudolithiasis, and ceftriaxone therapy was ceased. On the 8th our hospital day, he again complained of right abdominal pain after supper. A sonogram revealed high-amplitude echoes within the gallbladder neck and common bile duct. Furthermore, bile duct dilatation was observed. He was managed conservatively, after which the symptoms were resolved. On the 11th day, a sonogram showed only sludge within the gallbladder, and on the 13th day, he was discharged from our hospital. It is important for sonographers to recognize the possible occurrence of biliary pseudolithiasis in ceftriaxone-treated patients, especially when a high dose is used in children.

The debate as to whether to administer ceftriaxone to neonates is likely to continue. Ceftriaxone has numerous advantages for critically ill pediatric patients. However, it is also known to contribute substantially to the development of biliary pseudolithiasis. Although pediatric patients rarely develop gallbladder disorders, this complication may lead to adverse events in high-risk patients with predisposing factors, particularly in neonates and infants treated with ceftriaxone. In this paper we present an interesting case report of a 28-day-old neonate with spontaneous severe epidural hematoma who developed biliary pseudolithiasis related to the use of ceftriaxone. We also discuss the efficacy of ceftriaxone in neonates and infants. Neonatologists and pediatric intensivists should be aware of the higher risk of co-existence of hyperbilirubinemia and gallbladder disorders while using ceftriaxone in pediatric settings.