Probable fatal interaction between ciprofloxacin and theophylline.

Dr R HOLDEN (Edinburgh) writes: Thomson et al recently reported theophylline toxicity in an elderly patient concurrently taking ciprofloxacin. ' The Committee on Safety of Medicines has been notified of several other cases (R D Mann, personal communication). We report a further probable interaction with a fatal outcome. A 65 year old woman with a history of a left hemiplegia, atrial fibrillation, congestive cardiac failure, and inoperable carcinoma of the breast was admitted after collapsing. Five days before admission she had been prescribed ciprofloxacin 250 mg twice daily and slow release theophylline (Uniphyllin Continus) 600 mg daily for a chest infection. Her condition had been stable until the time of collapse. She had been taking digoxin 0 25 mg, bumetanide 1 mg, and tamoxifen 40 mg daily for more than a year. On examination she was conscious but unable to communicate and had frequent epileptic seizures, involving the non-hemiplegic side. She had developed fast atrial fibrillation with a ventricular rate of 160 beats/minute and blood pressure of 120/60 mm Hg, but cardiovascular examination gave otherwise unremarkable results. Neurological examination showed features of a previous left hemiplegia and an equivocal right plantar response. Radiography of the chest showed slight cardiomegaly, and electrocardiography showed atrial fibrillation with a heart rate of 160 beats/minute and widespread ST segment depression. Plasma concentrations of sodium were 133 mmol/l, potassium 2-8 mmolIl, and urea 4-1 mmol/l. Liver function was substantially altered: serum aspartate transaminase activity was 319 IU/l (normal range 12-42 IU/1) and alanine transferase activity was 660 IU/I (normal range 10-50 IU/A); alkaline phosphatase activity was 493 IU/l (normal range 90-300 IU/1); and serum total bilirubin concentration was 59 p.molIl (normal range < 17 imol/l) and albumin concentration 32 g/l (normal range 36-52 g/l). Haemoglobin concentration was 118 g/l and white cell count 17 6x 109/l with moderate neutrophilia. Serum concentration of digoxin was 1-3 nmol/l (reference range 1-3-2-5 nmol/l) and theophylline 188 [smol/l (55-110 tmol/l). The patient was treated with intravenous digoxin 0-5 mg and subcutaneous diazepam 10 mg, but one hour later her heart rate was still the same, she continued to have frequent seizures, and she had become unconscious. Phenytoin 250 mg was given intravenously, abolishing the seizures. Over the next six hours the patient remained deeply unconscious, her heart rate remaining between 140 and 150 beats/ minute, and she died seven hours after admission. Permission to perform a necropsy was not obtained. In this case abnormal liver function due to metastatic disease could have contributed to theophylline toxicity. Alternatively, the hepatic abnormalities may have been due to uncontrolled atrial fibrillation with hepatic congestion induced by theophylline. Ciprofloxacin has been shown experimentally to have a minor effect on theophylline metabolism in normal subjects.2 The effect may be clinically important in the elderly34 and those with acute and chronic disturbance of liver function. Wijnands et al have shown that full body clearance of theophylline is reduced by 30% and that plasma theophylline concentration is increased by 23% in patients with chronic obstructive airways disease taking ciprofloxacin 500 mg twice daily and suggested that the 4-oxo metabolite common to several quinolones was responsible for the interaction. ' This potentially common combination should be avoided in the elderly and in acutely ill patients, and the dosage of theophylline should be monitored carefully in hospital whenever the combination is used.