|Year : 2016 | Volume
| Issue : 4 | Page : 210-216
Gallbladder sludge associated with ceftriaxone therapy for typhoid fever in Nigerian children: A case series
Hafsatu W Idris1, Lawal W Umar FWACP 1, Sakina Abdullahi1, Ahmed U Hamidu2
1 Department of Paediatrics, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
2 Department of Radiology, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
|Date of Web Publication||11-Jul-2017|
Lawal W Umar
Consultant Paediatrician, Department of Paediatrics, Ahmadu Bello University Teaching Hospital, Zaria
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.
Keywords: Biliary pseudolithiasis, ceftriaxone, children, gallbladder: precipitates, sludge, typhoid fever
|How to cite this article:|
Idris HW, Umar LW, Abdullahi S, Hamidu AU. Gallbladder sludge associated with ceftriaxone therapy for typhoid fever in Nigerian children: A case series. Sub-Saharan Afr J Med 2016;3:210-6
|How to cite this URL:|
Idris HW, Umar LW, Abdullahi S, Hamidu AU. Gallbladder sludge associated with ceftriaxone therapy for typhoid fever in Nigerian children: A case series. Sub-Saharan Afr J Med [serial online] 2016 [cited 2021 Dec 1];3:210-6. Available from: https://www.ssajm.org/text.asp?2016/3/4/210/210200
| Introduction|| |
Ceftriaxone is a third-generation cephalosporin with broad-spectrum activity against gram-positive, gram-negative, aerobic and some anaerobic bacteria. The activity of ceftriaxone against gram-negative bacteria is greater than that of its earlier generation counterparts. It is especially effective on infections due to multi-drug-resistant organisms (e.g. Enterobacteriaceae and Salmonella More Details typhi) and for sepsis syndrome and meningitis in children.,, Its long plasma half-life and ease of administration have contributed to its popularity and preference as the antibiotic of choice for several bacterial infections including typhoid fever.,,, The regular dose of ceftriaxone for mild-to-moderate infections is in the range of 50–75 mg/kg once daily (maximum 1–2 g). Some of the few indications when higher dosing was suitable included severe infections along with meningitis and septicaemia in children beyond neonatal age. Higher dosing of up to 100 mg/kg/24 h has been recommended for use in such conditions either once daily or in two divided doses twelve-hourly (maximum 2–4 g). Although it has a longer plasma half-life than other cephalosporins (which forms the basis for its use as a once-daily administered drug), in critically ill patients with severe sepsis and preserved renal function, inadequate plasma concentrations may result following daily bolus dosing due to its high rate of renal excretion (30–70% excreted unchanged in urine) and its volume of distribution. This explains the recommendation for twelve-hourly dosing in patients with severe sepsis and intact renal function. However, it is known to induce gallbladder and/or urinary precipitation that may mimic cholelithiasis or urolithiasis in all age groups.,,,, Although gallbladder lithiasis (stone formation) in children is commonly associated with haemolytic diseases, haemoglobinopathies, total parenteral nutrition, obesity and prior extensive bowel resection, pseudolithiasis (sludge accumulation) has been associated with oral restriction, surgery and ceftriaxone therapy that is either prolonged beyond 5 days or with doses above 2 g/day., Gallbladder sludge may be asymptomatic or result in significant morbidity; in addition, the diagnosis may be delayed or missed and may lead to unnecessary surgical intervention.,,,
Gallbladder sludge associated with ceftriaxone therapy has been considered to be the result of concentration of the drug in bile, which can range between 20 and 150 times higher than in serum.,,, The associated passive entry of Ca2+ ions in response to concentrated biliary secretion of ceftriaxone induces the formation of bile that is supersaturated in calcium ceftriaxone salt. Subsequently, precipitation occurs with increased flow/concentration of bile as well as prolonged biliary stasis within the gallbladder. Abnormalities of calcium or phosphate metabolism have not been identified as a risk factor for the development of gallbladder pseudolithiasis.
An English-language search was conducted for relevant literature using Medline and Google Scholar for studies and reports related to use of ceftriaxone in children with typhoid fever and sepsis. The keywords used were ’Children; Ceftriaxone; Biliary Pseudolithiasis; Gallbladder: Precipitates; Sludge; Typhoid fever’. Out of many results identified, no such studies or case reports were from Nigeria nor sub-Saharan Africa. We present five cases of children with normal haemoglobin phenotypes, who developed ceftriaxone-associated gallbladder sludge while on treatment for typhoid fever. Consent for inclusion of each child’s medical information in publication for educational purposes but without disclosure of child’s personal identity was obtained from their respective caregivers.
| Case Reports|| |
Case number 1
H.I.H. was a 4-year-old girl who presented with fever and generalised abdominal pain for 9 and 4 days, respectively. She had no previous history suggestive of sickle cell disease and was never admitted to hospital. However, she had a history of ingestion of over-the-counter medications suggestive of antibiotics obtained from a patent medicine shop. Her father and three other siblings fell ill simultaneously, and two of the siblings were admitted at the same time in our facility (Cases 2 and 3). She was febrile (39.4°C), had normal anthropometric measurements and mild generalised abdominal tenderness with non-tender hepatomegaly at admission [Table 1]. Initial investigation results were normal except for hepatomegaly on ultrasound [Table 2]. Her urine, stool and blood cultures yielded no growth, while serial Widal tests revealed rising antibody titres to the ’H’ and ’O’ antigens of S. typhi [Table 2]. With a diagnosis of typhoid fever, she was placed on intravenous ceftriaxone 80 mg/kg/day given in two divided doses at every 12 h. Her temperature normalised on the 4th day, but she then developed mild jaundice with more severe but episodic generalised abdominal pain associated with prostration. Further examination did not reveal any features to suggest bowel perforation, but there was marked tenderness over the right hypochondrium. Her liver function tests were also normal, and hepatitis B surface antigen (HBsAg) was negative [Table 2]. Repeat ultrasound scan, however, showed dilated gallbladder with precipitates [Figure 1]. She was managed conservatively while the course of ceftriaxone was completed in 14 days and the child was discharged after 17 days of admission. She had no complaints, and a repeat abdominal ultrasound scan showed normal findings 2 weeks later.
|Figure 1: Ultrasound scans showing features of gallbladder sludge in Cases 1–4. Ultrasound on 4th day of ceftriaxone usage, using an ’Apogee Ultrasound machine, 1991 Model’ with a 5 MHz convex linear array transducer. The gallbladder, intra/extra-hepatic bile ducts and liver were examined methodically. Abnormal gallbladder sonographic findings were reported as biliary sludge accumulation (arrows in Cases 1 and 2) if there was low-amplitude echo within the lumen with no post-acoustic shadows|
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Case number 2
H.I.D. was a 9-year-old boy who presented with fever, generalised abdominal pain and melaena stools for 8 days. He had no history suggestive of renal, hepatic or haemolytic disease. His mother has administered paracetamol along with two other unidentified oral drugs from the 2nd day of onset of his illness without any improvement. Examination revealed pyrexia (38.4°C), moderate jaundice, moderate wasting and stunting. He had abdominal distension with tenderness and very scanty bowel sounds. He also had hepatosplenomegaly and irrational behaviour [Table 1]. A clinical impression of typhoid fever with suspected bowel perforation and psychosis was made. Full blood count (FBC) revealed severe anaemia, and serial Widal tests showed rising antibody titres (to ’H’ and ’O’ antigens). Stool microscopy showed numerous red blood cells and pus cells. Blood, stool and urine cultures were sterile. Serum chemistry and liver function tests were normal, and HBsAg was negative. Plain thoraco-abdominal X-ray and ultrasound were also normal [Table 2]. He was commenced on intravenous ceftriaxone at 80 mg/kg/day in two divided doses at every 12 h. By the 4th day of admission, his abdominal pain worsened, and examination then revealed an enlarged and tender gallbladder mass [Table 3]. Repeat ultrasound showed dilated gallbladder with precipitate formation [Figure 1]. The antibiotic was continued for up to 14 days along with other supportive management. His temperature subsided by the 9th day, and he was discharged on the 17th day after admission. His clinical condition and abdominal ultrasound findings became normal, and he had gained 2 kg at follow-up a fortnight later.
Case number 3
H.I.B. was a 6-year-old boy who also presented with fever and abdominal pain for 8 days. He had no history of significant illness in the past, and was treated with native concoctions for the first 2 days of illness. In addition, two other syrup medications were administered twice daily from the 3rd day of illness till presentation. He was febrile (38.4°C), had mild jaundice, with hepatosplenomegaly, generalised abdominal tenderness and decreased bowel sounds [Table 1]. FBC showed moderate anaemia, with white blood cell (WBC) of 6.8 × 109/L, negative HBsAg and positive Widal test evidenced by elevated and rising ’O’ and ’H’ titres while on admission [Table 2]. Initial abdominal ultrasound scan showed hepatosplenomegaly, normal gallbladder and other abdominal organs [Table 3]. With a clinical impression of typhoid fever, he was placed on intravenous ceftriaxone 80 mg/kg/day in two divided doses at every 12 h and intramuscular gentamycin 2.5 mg/kg/dose at every 8 h along with other supportive management that included intravenous fluids and suspension of oral intake.
By the 6th day of admission, he was noticed to have a palpably enlarged gallbladder, and he later developed progressive abdominal distension with repeated episodes of vomiting [Table 3]. A repeat abdominal ultrasound showed evidence of intestinal perforation and gallbladder precipitate formation [Figure 1]. He had a wedge resection of the perforated bowel segment at an exploratory laparotomy, during which distension of the gallbladder was observed, but with free flow of bile along the main ducts and no features of stones, obstruction or inflammation. He was treated with gentamicin (for 5 days) and ceftrixone for a total of 14 days. His condition gradually improved, and he was subsequently discharged 33 days after admission. A repeat abdominal scan could not be performed because of financial constrains, but he remained clinically stable with no palpable gallbladder or other abdominal organs at subsequent follow-up visits.
Case number 4
I.A. was a 6-year-old boy who presented with fever and generalised abdominal pain for 3 weeks. He had no past history suggestive of haemoglobinopathy, cardiac, renal or liver disease and was never admitted to hospital. He also had native concoctions administered from the onset of illness combined with three syrup medications obtained at a pharmacy shop from the 2nd week onwards till presentation. He had an axillary temperature of 39.8°C, mild pallor and no jaundice. He had hepatomegaly and splenomegaly of 4 and 6 cm, respectively, and other abdominal findings were normal [Table 1]. He also had clinical features of bronchopneumonia. FBC showed moderate anaemia but no evidence of haemolysis, and he had normal haemoglobin genotype. Serial Widal test showed rising antibody titres (’O’ and ’H’ antigens), while urine, stool and blood cultures were sterile. Chest X-ray showed bilateral scattered opacities suggestive of bronchopneumonia [Table 2]. Plain abdominal X-ray showed dilated bowel and no evidence of perforation. Initial abdominal ultrasound showed hepatosplenomegaly with no gallbladder or other organ abnormality. With a diagnosis of typhoid fever, he was placed on intravenous ceftriaxone at 80 mg/kg/day in two divided doses at every 12 h and intramuscular gentamicin 2.5 mg/kg/dose at every 8 h. He had blood transfusion along with other supportive management that included intravenous fluids. His clinical condition improved, the abdominal pain subsided while his temperature normalised on the 3rd day. However, by the 4th day of admission, abdominal pain increased in severity and remained persistent. Examination then revealed a palpably enlarged gallbladder of 2 cm × 6 cm [Table 1] and [Table 3] with tenderness over the right hypochondrium, more marked over the gallbladder mass. Abdominal ultrasound scan showed a dilated gallbladder with precipitates on the dependent part [Figure 1]. The gallbladder was no longer palpable by the 10th day on ceftriaxone but he still had hepato-splenomegaly at the time of discharge from admission. He remained stable 3 weeks after discharge, but a repeat abdominal ultrasound could not be performed as the patient defaulted on his follow-up.
Case number 5
P.P. was a 9-year-old girl who presented with a week’s history of fever, peri-umbilical abdominal pain, progressive weight loss and lethargy. She had no previous history suggestive of any systemic disease or haemoglobinopathy but was treated for the presenting illness with oral amoxicillin and chloramphenicol among other medications administered at home with no improvement. She was severely pale, pyrexic (39.2°C), underweight, with abdominal distension, tenderness, guarding and reduced bowel sounds. Her haemoglobin was 4 g/dl, WBC was 4.3 × 109/L and other laboratory findings were normal [Table 2], except for rising Widal antibody titres and dilated bowel loops on abdominal ultrasound and X-ray. With a clinical impression of typhoid fever complicated by intestinal perforation, she was placed on ceftriaxone 80 mg/kg/day in two divided doses at every 12 h, transfused with fresh whole blood and given other supportive management, including intravenous fluids and suspension of oral intake in anticipation for surgical intervention. By the 4th day of admission, the abdominal distension had persisted, and she started passing bloodstained stools and talking irrationally. Repeat abdominal ultrasound showed a dilated gallbladder with sludge in the dependent part. Abdominal X-ray showed evidence of intestinal perforation. She had exploratory laparotomy and wedge resection of affected multiple bowel segments on the 5th day of admission. Intraoperative findings included a dilated gallbladder but with no obvious features of inflammation. Her condition deteriorated rapidly, and she was transferred to the intensive care unit wherein she developed multiple organ dysfunction and subsequently died of septic shock.
| Discussion|| |
The emergence of suggestive clinical features and ultrasound findings of biliary precipitate in our patients from the 4th day of therapy with ceftriaxone and their spontaneous resolution within two weeks of completion of the antibiotic therapy does suggest a ceftriaxone-associated effect. The use of ceftriaxone is known to be associated with reversible sonographic gallbladder and sometimes urinary bladder precipitation that could mimic cholelithiasis or urolithiasis in some children and adults being treated for systemic bacterial infections.,,,,
In our patients, gallbladder precipitate appeared after a dose of 80 mg/kg/day within the first 4–6 days of initiating treatment with ceftriaxone. The risk factors for biliary pseudolithiasis in children include high dose (above 100 mg/day/24 h) or prolonged use of ceftriaxone., However, all the patients presented in this study received just 80 mg/kg/day of the drug, which is less than the reported limit for dosing associated with gallbladder precipitate formation. The concurrence of other risk factors for precipitate formation may explain why the condition still developed despite use of a drug dosage below 100 mg/kg/day. Although all the children were maintained on adequate intravenous fluid replacement as part of supportive care, a possible risk factor for biliary precipitation common to all was the reduced oral feeding due to associated anorexia and total suspension of oral feeding in the 3rd and 5th cases preparatory to surgical exploration. This may have contributed to biliary accumulation and stasis in the gallbladder, which in the presence of high concentrations of un-metabolised ceftriaxone predisposed them to formation of ceftriaxone precipitate in bile. Fasting is known to lead to increase in bile flow, which in the presence of high concentrations of un-metabolised ceftriaxone predisposes to formation of precipitate of calcium ceftriaxone salt.,
It is also noteworthy that none of these children had sickle cell disease, a condition associated with gallstone formation, even as three were siblings from the same family. The possibility that either a common environmental exposure to an unidentified potential trigger or some other genetic/familial trait may still have played some role in the occurrence of gallbladder pseudolithiasis amongst the three siblings cannot be ruled out. It has been argued in a previous study that because not all patients treated with the same dosage of ceftriaxone develop pseudolithiasis, individual predisposition and genetic profile might play some role. Fratzayas et al. demonstrated the evolution of pseudolithiasis in the gallbladder of three under-five children treated with ceftriaxone at doses of 100 mg/kg/day. These children on further evaluation were discovered to be carriers of a specific polymorphism of the gene encoding for uridine diphosphate-glucuronosyltransferase, the enzyme involved in glucuronidation of bilirubin. The concurrence of gallbladder pseudolithiasis in the three related children in our study may suggest the possibility of some genetic predisposition in Nigerian children as a strong familial risk factor.
Although the presenting abdominal pain had remained persistent in two children (Cases 3 and 5), in the three others the presenting abdominal pain subsided within the first 3–4 days of commencing ceftriaxone therapy. However, the severity of pain increased thereafter. The examination findings of either tenderness over the right hypochondrium (Case 1) or tender mass over the right hypochondrium (Cases 2 and 4) suggest the possibility of a gallbladder abnormality. Having been on treatment with ceftriaxone, a known risk factor for precipitate formation in bile, coupled with the suggestive ultrasound imaging, it is reasonable to presume that gallbladder sludge accumulation was responsible for the subsequent examination findings. Three of the children had jaundice, while four children were shown to have dilated gallbladder sonographically, and it is clear that the constellation of features of the condition could vary between patients. Biliary precipitation of ceftriaxone has been reported to be asymptomatic in some patients, but it could also present with severe symptoms that could lead to a consideration for surgical intervention., Soysal et al. reported that of the 35 children among 114 (30.7%) who developed sonographically demonstrable gallbladder precipitate, none were symptomatic. Acun et al. on the other hand, reported two symptomatic children out of five with sonographically demonstrable pseudolithiasis, which appeared after 4–9 days of ceftriaxone therapy and resolved by 7–19 days after end of treatment. Although ceftriaxone has been documented to also predispose to urinary bladder precipitate, none of our patients developed this condition.
The four surviving children had spontaneous resolution of features of gallbladder precipitation by the 14th day after cessation of ceftriaxone and had maintained good health at subsequent follow-up visits; however, the fifth child died of severe complications of typhoid sepsis. An important differential diagnosis to consider in these cases is acute acalculous cholecystitis. This condition has been reported to occur in up to 8% of children during treatment for typhoid fever with ciprofloxacin and typically manifests with a thickened gallbladder wall and peri-colic collection with neither gallstone nor sludge formation, none of which were found in our series. We could not isolate any organisms from the cultured specimens of all the cases; this we attribute to the use of over-the-counter medication prior to presentation in all the children, which may have reduced the extent of bacteraemia, even though the medication was not enough to cure tissue invasion. The rampant use of over-the-counter antibiotics prior to hospital presentation was observed in most patients that presented to our facility, and as such, the yield of cultures was very low in an earlier study. However, a presumptive diagnosis of probable typhoid fever was made based on the suggestive clinical features supported by significant Widal test titres in all the children.
In conclusion, this study is presented to create awareness of the possibility of a transient development of gallbladder precipitate that may or may not be symptomatic in children treated with ceftriaxone. In patients with typhoid fever and other intra-abdominal infections, a recurrence or worsening of abdominal pain associated with gallbladder enlargement may give a false impression of poor response or deterioration and development of grave surgical complications. Knowledge of this condition for consideration as a differential diagnosis could help physicians avoid extensive diagnostic and therapeutic interventions that may not be of much benefit to the management and outcome of patients. In patients being considered for treatment with ceftriaxone, it may be useful to include serial abdominal ultrasonography as part of the evaluation and monitoring of their clinical response to intervention. A larger prospective study is needed to determine the true incidence of this drug-related complication in Nigerian children.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms signed by their respective parents. In the form, the parents of the patients has/have given their consent for their child’s images and other clinical information to be reported in the journal. The parents of the patients understand that their children’s names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]