Clarithromycin monotherapy-induced delirium

Abstract

Sir, An 87-year-old male patient receiving clarithromycin treatment, 500 mg daily, for upper respiratory infection (sore throat without fever) was referred to the emergency room on the third day of drug treatment with a clinical picture of delirium. Physical examination results were normal. After neuropsychiatric evaluation, he was found to have lost orientation to person, space and time. His concentration and attention were impaired. He was agitated and experiencing visual hallucinations of naked people around him, as well as paranoid (that ‘his relatives were trying to poison him’), grandiose (that ‘he was a prophet’) and nihilistic (that ‘the world has come to an end’) delusions. Routine laboratory tests including complete blood count, erythrocyte sedimentation rate, electrolytes, hepatic and renal function tests, arterial blood gas levels, thyroid function tests, chest X-ray, vitamin B12 and folic acid levels as well as cultures, electrocardiogram, echocardiography and electroencephalogram, and computerized tomography results were normal. Cranial magnetic resonance imaging (MRI) showed cortical atrophy consistent with ageing. The patient didn’t use additional drugs, nor was there any history of previous drug reaction and previous psychiatric disorder. He was admitted to the neurology intensive care unit, monitored for cardiac and neurological functions and electrolyte balance was supported by parenteral feeding. Even before 24 h had elapsed after discontinuation of clarithromycin administration, the clinical picture ameliorated dramatically with no need for an antipsychotic or other type of medication. Neuropsychiatric evaluation repeated 48 h later was found to be normal. Since the patient’s psychical examination, blood tests, electrocardiogram, echocardiography, electroencephalogram, computed tomography and cranial MRI did not show any other organic causes for his delirium, and there was no other pharmacological agent in his treatment, the main cause of delirium in this case seemed to be the administration of clarithromycin. This hypothesis is further supported by the fact that as soon as clarithromycin was stopped, the clinical picture of delirium disappeared. There have been numerous case reports of delirium following antibiotic treatment, especially penicillins, cephalosporins and quinolones. Risk factors were defined as: prior psychiatric illness, severe medical illness, slow acetylator status, advanced age, renal impairment, increased permeability of blood–brain barrier, high antibiotic dosage, and intrathecal or intravenous administration. Clarithromycin is a macrolide antibiotic commonly used as monotherapy in upper respiratory tract infections and as polypharmacy in Helicobacter pylori eradication. The most common adverse effects of clarithromycin involve the digestive tract; it is much less frequently associated with hepatic cholestasis, skin rashes, ototoxicity with tinnitus and transitory deafness. Reports of neurological alterations during Phases I, II and III of the clinical trials with clarithromycin are very few. We believe this case to be of interest, since there is only one other report concerning delirium due to clarithromycin monotherapy in the literature and other cases involved polypharmacy. – 5 The most frequently reported psychiatric adverse effect associated with clarithromycin is mania. The clinical picture of mania caused by antimicrobial drugs has been termed ‘antibiomania’. There are 21 case reports of ‘antibiomania’ in the literature, together with unpublished cases from the World Health Organization and the Food and Drug Administration, six of which were with clarithromycin. Mechanisms of CNS toxicity of clarithromycin are as yet unclear, but drug interactions, a direct toxic effect of the lipid-soluble active metabolite of clarithromycin (14-hydroxyclarithromycin) on the CNS, alterations of cortisol and prostaglandin metabolism as well as interactions with glutaminergic and g-aminobutyric acid pathways have been considered. For this particular case, the mechanism that underlies the cause of delirium remains unclear, yet the fact that clarithromycin was administered as a monotherapy excludes the possibility of any drug interaction. Though clarithromycin treatment is relatively safe and effective, this case suggests that the neuropsychiatric status of patients receiving clarithromycin should be cautiously monitored during treatment.