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Delirium induced by clarithromycin in a patient with community-acquired pneumonia

¹ Internal Medicine, and ³ Pneumology Section, University Hospital Arnau de Vilanova, and ² CAP Ferran, Lleida, Spain.

To the Editors:

We would like to describe the case of a patient who was treated with clarithromycin for community-acquired pneumonia (CAP). She presented with an episode of agitation and delirium while taking the clarithromycin, but this disappeared when the clarithromycin was stopped. This case is interesting because of the low frequency of symptoms of the central nervous system during the treatment.

The patient was a 63-yr-old female, with pathological history of arterial hypertension. She was treated with angiotensin-converting enzyme inhibitor and a pacemarker for atrial block and had no previous psychiatric history. The patient went to the emergency department in a poor general state; she had had a fever for 7 days and developed chills. Once at home, she was treated with paracetamol. A physical examination revealed a fever (39°C), blood pressure of 120/60 mmHg and heart frequency of 70 beats·min^-1. She had crepitations at the left hemithorax and cardiac arrhythmic tones without left ventricular failure. The abdomen was not painful and neurological examination was normal. The right thorax showed an alveolar pattern of the superior lobe in the left lung. The analytical results were as follows: glucose 104 mg·dL^-1; creatinin 0.91 mg·dL^-1; aspartate aminotransferase 118 UI·L^-1; sodium 140 mEq·L^-1; potassium 4.6 mEq·L^-1; leukocytes 6,200·µL^-1; haemoglobin 10.9 g·dL¹; and platelets 265,000·µL^-1. The arterial blood gas results were: pH 7.57; carbon dioxide tension 4.38 kPa; partial pressure of oxygen 10.37 kPa; and HCO₃ 24 mEq·L^-1.

The ECG showed an atrial fibrillation. The diagnosis was severe CAP and the patient was treated with 2 g intravascular ceftriaxone every 24 h and 500 mg intravascular clarithromycin every 12 h. The patient also received sodium heparin for the atrial fibrillation. On the third day of treatment, the patient presented with an acute episode of agitation and delirium, which required administration of antipsychotics (haloperidol). A cranial computed tomography (CT) scan was carried out, which didn't show any alterations. The current authors suspected that the delirium was induced by clarithromycin as when treatment with the drug ceased the symptoms disappeared. The patient was observed by the psychiatric service and was diagnosed with delirium induced by clarithromycin in resolution phase. The patient presented with good evolution of CAP and outside hospital control she was asymptomatic.

Clarithromycin is an antibiotic belonging to the macrolide family with a structural ring of 14 atoms. The bacterial effect of the macrolides is due to the inhibition of protein synthesis, and the ability to administer it orally and intravascularly. Clarithromycin is metabolised by hepatic metabolism and the majority is eliminated biliary, in fomites and in a smaller portion in urine. It is active against Gram-positive cocci, Legionella and Chlamydia and is indicated in the treatment of severe CAP associated with cephalosporin (cefotaxime or ceftriaxone) 1.

Adverse effects of clarithromycin in the central nervous system include dizziness, ototoxicity and headaches, but delirium is very uncommon with few cases being reported in previous literature. In our case, it is obvious that there is a relationship between delirium and clarithromycin as the patient did not have any psychiatric history and delirium disappeared completely when the drug was removed. Other delirium causes were also excluded as the neurological exploration did not find any focus, the cranial CT scan was normal, and the patient was observed by the psychiatric service who diagnosed the case as delirium in resolution phase induced by clarithromycin, and delirium disappeared when the drug was removed.

In previous literature, some cases of hallucinations have been described in patients receiving clarithromycin with renal failure because of the possibility of the accumulating effect of the drug 2, but in the present patient the renal function was normal.

In other cases, effects in the central nervous system caused by clarithromycin appeared when the patient was taking fluoxetine at the same time. There is a possible interaction of the macrolide with the cytochrome P450 3, which increases levels of fluoxetine, although other studies have attributed the appearance of delirium in these patients to the direct effect of clarithromycin only.

Clarithromycin, used in the treatment of the Mycobacterium avium complex (1,000 mg·day^-1), was responsible for the appearance of mania in two patients with AIDS 4 and in a group of elderly patients without HIV 5 who presented with confusion and insomnia. In all cases, the symptoms disappeared when treatment with the drug ceased.

Delirium induced by clarithromycin is an extremely uncommon adverse effect, but doctors have to know about this if they use this drug, because the delirium disappears when clarithromycin is removed from treatment.

REFERENCES

1. Niederman MS, Mandell LA, Anzuelto A, et al. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001;163:1730–1754.[Free Full Text]
2. Steinman MA, Steinman TI. Clarithromycin-associated visual hallucinations in a patient with chronic renal failure on continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1996;27:143–146.[Web of Science][Medline] [Order article via Infotrieve]
3. Pollak PT, Sketris IS, Mackenzie SL, Hewlett TJ. Delirium probably induced by clarithromycin in a patient receiving fluoxetine. Ann Pharmacother 1995;29:486–488.[Abstract]
4. Nightingale SA, Koster FT, Mertz GJ, Loss SD. Clarithromycin-induced mania in two patients with AIDS. Clin Infect Dis 1995;20:1563–1564.[Web of Science][Medline] [Order article via Infotrieve]
5. Wallace RJ, Brown BA, Griffith DE. Drug intolerance to high-dose clarithromycin among elderly patients. Diagn Microbiol Infect Dis 1993;16:215–221.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

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