Non Icteric Cholestasis and Cytolytic Hepatitis: Temocillin-Related?

• Published in: Drug safety Vol. 44; no. 12; p. 1430
• Main Authors: Dufosse, M, Boivin, P, Adrien, F, Gras, V, Masmoudi, K
• Format: Journal Article
• Language: English
• Published: Auckland Springer Nature B.V 01.12.2021
• Subjects: Acute lymphoblastic leukemia; Alcoholism; Anaphylaxis; Angioedema; Antibacterial agents; Arthralgia; Bilirubin; Biocompatibility; Biopsy; Bone marrow; Bone marrow transplantation; Cefotaxime; Cholestasis; Ciprofloxacin; Convulsions; Diarrhea; Drug abuse; E coli; Enzymes; Fever; Gallbladder diseases; Graft-versus-host reaction; Health services; Hemodynamics; Hepatitis; Hepatotoxicity; Leukemia; Literature reviews; Liver; Liver diseases; Neurological diseases; Patients; Pharmacokinetics; Renal failure; Toxicity; Trimethoprim
• ISSN: 0114-5916; 1179-1942

Background/Introduction: Temocillin, a forgotten antibacterial agent has been revived for its activity against Extended-Spectrum Beta-Lactamases (ESBL) and AmpC-producing Enterobacteriaceae [1]. To date, known adverse effects of temocillin are diarrhoea, urticarial or erythematous rash, fever, arthralgia, myalgia, angioedema, anaphylaxis, phlebitis, thrombophlebitis and neurological disorders with convulsions in patients suffering from renal failure [2]. Objective/Aim: We here report the case of a patient presenting with a suspected temocillin-induced acute cytolytic hepatitis. Methods: A 37-years-old male patient has been admitted in Intensive Care Unit (ICU) for coma, in a context of sepsis. His medical history includes an acute lymphoblastic leukaemia, treated by bone marrow transplant in 2006, causing a subcutaneous graft versus host disease. He had neither history of alcoholism nor any known underlying hepatic disease. He has been later diagnosed with pneumonia due to an ESBL Escherichia coli. His treatment consisted in cefotaxime and metronidazole during 6 days, then tigecycline and trimethoprim sulfamethoxazole during 14 days when a Streptomonas maltophilia was discovered in his broncho-alveolar lavage liquid. Finally, IV temocillin high dosage (6 g daily) was implemented. Before this treatment, his hepatic enzymes levels were normal, except for GGT level which was slightly above normal values (Table 1). Results: On day 5 of temocillin treatment, a routine biological check showed a severe non-icteric cytolytic hepatitis and a cholestasis with ASAT and ALAT, 22 times, GGT 46 times and ALP 88 times upper normal values (Table 1) without any clinical manifestation, as total bilirubin levels were normal. On day 7, temocillin is interrupted and replaced by ciprofloxacin. Hemodynamic, ischemic, infectious or auto-immune causes were excluded. Viral assessments and abdominal ultrasonography were also negative. A hepatic biopsy was performed, which aspect was compatible with a drug-induced hepatotoxicity. Two days after temocillin interruption, hepatic enzymes levels decreased dramatically (Table 1). A follow-up biological assessment performed 76 days after temocillin interruption found hepatic enzymes levels even lower. Conclusion: Beta lactams may be associated with idiosyncratic druginduced liver injury [3] but a literature review found no similar case of such liver toxicity associated with temocillin. Our clinical report suggests that temocillin have a role in inducing hepatotoxicology, in view of the adverse drug reaction chronology and its rapid regression after temocillin withdrawal. However, our patient was treated with tramadol, which is well known for hepatic toxicity, for weeks before enzymes levels elevation. Although this observation corresponds with temocillin pharmacokinetics (elimination half-life is approximately 5 h, and renal clearance takes about 24 h [4]), we cant exclude tramadols role.