Psychosomatics 39:540-542, December 1998
© 1998 The Academy of Psychosomatic Medine
Clarithromycin-Induced Delirium in a General Hospital
Hindi T. Mermelstein, M.D.
Received June 17, 1997; revised December 17, 1997; accepted January 8, 1998. From the Consultation Liaison Service, North Shore University Hospital, New York University School of Medicine, Manhasett, New York. Address reprint requests to Dr. Mermelstein, 73 Old Pond Road, Great Neck, NY 11023.
Key Words: Case Report • Delirium • Clarithromycin
Clarithromycin, a new macrolide antibiotic, is effective in the management of a wide range of clinical problems, including outpatient treatment of community-acquired pneumonia, shortening the course of peptic ulcer disease associated with Helicobacter pylori infection and curing previously resistant respiratory infections in immunocompromised patients.1–5 Clarithromycin is generally well tolerated, producing fewer gastrointestinal complaints than its parent compound, erythromycin. For these reasons, it is frequently prescribed in adult and pediatric settings.
Neurotoxic side effects, including seizures and delirium, have been reported with penicillin and other antibiotics but were not found in the preclinical and clinical trials of clarithromycin or erythromycin.6–9 Since then, there have been three brief case reports of alteration in mental status when clarithromycin was added to other medication regimens.10–12 Here I report four cases of clarithromycin-induced delirium in a general medical population.
Case Reports
Case 1: A 30-year-old man was in good health until about 4 days before admission, when he developed bronchitis. His doctor prescribed clarithromycin (500 mg bid). His cough subsided, but over the 24-hour period before admission, he began to have difficulty focusing and his speech became confused. When he started to sing about his special powers, he was referred for emergency evaluation. On examination, he was an ill-looking man, restless but afebrile, with no serum indication of metabolic abnormality or hypoxia or opacity on his chest X ray. On mental status examination, he was found to be disoriented and agitated, and to express paranoid and grandiose delusions. His thought process was characterized by tangentiality, and his judgment was impaired. He was admitted for presumed worsening pulmonary status and with a provisional diagnosis of delirium. His antibiotic was changed to cephalosporin, and haloperidol was ordered as needed. Within 2 days, his sensorium began to clear. Repeat laboratory tests remained within normal limits, all medications were discontinued, and the patient was discharged. At outpatient follow-up 3 weeks postdischarge, he said he felt like his old self, and there was no cognitive impairment or psychotic thinking on examination. No further treatment was planned.
Case 2: A 63-year-old man was brought to the hospital by the police after he was found crouched in a closet, "hiding from the Nazis." According to his wife, his only medical problem had been mild hypertension, which was well controlled on dyazide (25 mg hydrochlorothiazide and 37.5 mg triamterene qd), until the preceding week, when he was started on clarithromycin (250 mg bid) by his internist for an upper respiratory infection. In the emergency room, he was disoriented and screaming that the Nazis were coming to arrest him. He was hypersexual toward the psychiatric consultant and suspicious of the hospital staff. Metabolic, infectious, and neurological workups (including a computed tomography of his brain) were normal. Mania was considered but, in view of his age, the rapid onset of symptoms, the lack of behavioral prodromes, and the absence of a personal or family history for psychiatric illness, delirium became the working diagnosis. Early in his hospital stay, the patient remained significantly agitated in spite of sedation with haloperidol (1–2 mg q 6 hours, as needed). However, within 3 days after the clarithromycin course was completed, his psychiatric symptoms began to slowly resolve. He continued to improve and was discharged on dyazide only. When the patient was contacted by telephone at 1 and 4 weeks postdischarge, he reported that he felt fine and that he had resumed running his company without difficulty.
Case 3: A 52-year-old woman with bipolar illness, stable on lithium for over 15 years, was referred to the emergency room by her internist for increasing confusion and paranoid ideation. Three days before admission, her physician switched her prescription from penicillin to clarithromycin (loading dose of 500 mg, followed by 250 mg bid) for a persistent cough. The patient had no other significant medical history. Her physical examination and serum metabolic screening were within normal limits, except for mild dehydration; her lithium level was at 1.0 nmol/l, which by medical history was about her usual therapeutic level. On mental status examination, she was found to be lethargic, guarded, and hostile to the staff. She insisted that we were preventing her from marrying Jesus. Her husband added that, until the confusion began during the day or so before admission, she had been working without any noticeable change in mood or behavior. While on the medical service for a presumed delirium, her condition deteriorated in spite of neuroleptic medication. She now believed that she was Jesus, and she was disoriented to person, place, and time. She was transferred to inpatient psychiatry with a revised diagnosis of mania. Coincidentally, 5 days after the transfer, the course of antibiotic was completed. Her condition began to improve over the next 3 days, with no other change in her medications. She was discharged and continues to function well.
Case 4: A 71-year-old man with localized nonsmall-cell lung cancer was admitted to the hospital with fever and cough secondary to a presumed pneumonia. When his respiratory status improved, he was switched from intraveous ciprofloxacin to clarithromycin (250 mg bid) in anticipation of discharge. During morning rounds 2 days later, he complained to the oncologist that there was a conspiracy to kill him on the unit, and he was referred for psychiatric consultation. On mental status examination, he was found to be hypervigilant, tangential, and easily distracted. His mood was anxious, and he told the psychiatrist that a famous talk-show host had communicated a personal warning to him during the night. There was no recent shift in his metabolic state or respiratory status, and there was no sign of infection and no other change in medication. A diagnosis of delirium was made, and the patient empirically was switched to amoxicillin (500 mg tid). A small nightly dose of risperidol had been recommended by the consultant but never started. His sensorium began to clear within 4 days, and he was discharged home 10 days after the clarithromycin was discontinued.
Discussion
Common causes of delirium include infections, metabolic derangements, toxic agents, respiratory and cardiac disease, and for those who are most vulnerable, the stress of illness or a change in the environment. All of the persons I have described had a respiratory illness.13–16
Medications, particularly steroids, opiates such as hydromorphine, cardiac medications, and those with anticholinergic activity such as diphenhydramine, often cause delirium in the hospital setting, either by direct effects or via drug–drug interactions. Although the persons discussed here were either on no other medications, or on medications that are not known to interact with macrolide antibiotics via their effect on the P450 3A3/4 isoenzyme system (e.g., tetracyclic antidepressant, calcium channel blockers, cyclosporine, triazolobenzodiazepines, cisapride), drug interactions are an important potential cause of delirium and should be considered whenever a confusional state follows the addition of a macrolide antibiotic.17 Furthermore, in all four cases reported, the onset and resolution of the episodes were temporally related to the use of clarithromycin. Additionally, in the case of the woman with a history of bipolar disorder, the development of confusion before the delusional thinking, and the absence of any neurovegetative or behavioral prodrome, supports the diagnosis of delirium.
Clarithromycin is a relatively new medication in the medical setting. Though it is a safe and effective antibiotic for most people, the cases presented suggest that for some persons, it can induce delirium with almost manic-like symptoms. It remains unclear, however, what mechanism underlies the change in mental status. More research is needed to understand the pathophysiological process that occurs in delirium for more effective prevention and treatment of the syndrome.
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