Journal of Toxicology CLINICAL TOXICOLOGY Vol. 42, No. 3, pp.

295297, 2004

CASE REPORT

Refractory Hypoglycemia from Ciprofloxacin and Glyburide Interaction

George Lin, M.D., Daniel P. Hays, Pharm.D., and Linda Spillane, M.D.*
Department of Emergency Medicine, University of Rochester, Rochester, New York, USA

ABSTRACT
Patients taking multiple medications may suffer from unpredictable and complex drug drug interactions resulting in significant morbidity and mortality. There are few reports in the literature of hypoglycemia with concurrent administration of an oral hyperglycemic agent and a fluoroquinolone antibiotic. We present a case of a diabetic patient taking glyburide who was prescribed ciprofloxacin and developed prolonged hypoglycemia, which persisted for over 24 hours. The mechanisms by which these agents interact to produce prolonged hypoglycemia are complex and probably multifactorial. Patients stabilized on glyburide who are started on a fluoroquinolone should have their glucose levels monitored closely. Key Words: Refractory hypoglycemia; Ciprofloxacin; Glyburide; Glyburide interaction; Ciprofloxacin interaction.

INTRODUCTION Patients with multiple medical problems taking multiple medications are at increased risk of drug drug interactions as new medications are added to their drug regimen (1,2). These interactions are complex and may be difficult to predict despite an understanding of drug metabolism and mechanisms of action. There are few reports in the literature of hypoglycemia with concurrent administration of an oral hyperglyce-

mic agent and a fluoroquinolone antibiotic (3 5). We present a case of a diabetic patient taking glyburide who was prescribed ciprofloxacin and developed prolonged hypoglycemia.

CASE PRESENTATION A 68-year-old man with a history of coronary artery disease, atrial fibrillation, and Type II diabetes

*Correspondence: Linda Spillane, M.D., Department of Emergency Medicine, University of Rochester, Box 655, 601 Elmwood Ave., Rochester, NY 14642, USA; E-mail: Linda_Spillane@urmc.rochester.edu. 295
DOI: 10.1081/CLT-120037431 Copyright D 2004 by Marcel Dekker, Inc. 0731-3810 (Print); 1097-9875 (Online) www.dekker.com

296 Table 1. Time 17:50 19:00 20:50 23:30 00:45 03:30 06:30 09:00 09:15 09:35 11:30 12:30 13:35 15:00 16:00 17:00 19:00 21:20 23:30 Blood glucose mg/dl 20 28 (BG) 24 (Serum) 109 50 37 52 50 45 25 158 50 195 145 57 65 53 91 71 165 Chronological blood glucose levels. Food and juice Juice and meal

Lin, Hays, and Spillane

Intravenous dextrose 25 g D50 given by EMS 25 g D50; D10 NS at 100 cc./hr. started 25 50 50 25 g g g g D50 D50 D50 D50

25 g D50 Breakfast Juice and meal Sandwich Meal 25 g D50 25 g D50 IV changed to D5 NS

*Over the next 24 h glucose levels were checked every 4 h and ranged from 140 to 206 mg/dl.

mellitus presented to the emergency department (ED) with sudden onset of confusion, tremors, diaphoresis, and weakness. The day prior to admission he was started on ciprofloxacin 250 mg twice a day for an uncomplicated urinary tract infection. His wife reported that the afternoon of admission the patient was confused, diaphoretic, and tremulous. His mental status progressively declined until he became unresponsive. Upon EMS arrival, his finger stick blood glucose (FSBG) was 20 mg/dl. The patient was given one ampoule (50 mL) of 50% dextrose (D50) with some improvement in his mental status. The patients past medical history was significant for noninsulin-dependent diabetes mellitus, coronary artery disease, atrial fibrillation, hypertension, and renal insufficiency (serum creatinine 2.3 mg/dl). Current medications included twice daily glyburide 1.25 mg and furosemide 40 mg and once daily warfarin 3 mg, fosinopril 10 mg, clopidogrel 75 mg, lovastatin 40 mg and metoprolol XL 50 mg. He had received only one dose of ciprofloxacin 250 mg. The patient later denied any past episodes of hypoglycemia or recent changes in medications except for the addition of ciprofloxacin. At baseline the patient was coherent, ambulatory, and fully functional. On ED arrival, the patient was alert and oriented to time, person, and place. The initial vital signs were temperature 35.1C, respiratory rate 18/min, heart rate

54 beats/min, and blood pressure 124/78 mmHg. His physical examination was normal except for tremulousness, diaphoresis, and an irregular heart rhythm. The patient was given a second ampoule of D50 and started on 10% dextrose in half normal saline (D10 1 /2 NS) at 100 cc/hr. His mental status improved and a small meal was provided. Laboratory test results included a white cell count (WBC) 11,600 per mm3, (84.3% neutrophils) and a hematocrit of 29%. Serum electrolyte values were sodium 138 mmol/l, potassium 4.4 mmol/l, chloride 98 mmol/l, carbon dioxide 32 mmol/l; serum urea nitrogen 24 mg/dl, creatinine 1.8 mg/dl, glucose 24 mg/dl (FSBG 28 mg/dl), and INR 3.5. These initial blood glucose levels were drawn prior to the patient receiving D50 or being started on a D10 NS infusion. Serum troponin was not elevated. Urinalysis showed specific gravity of 1.010, 2+ leukocyte esterase, 3+ hemoglobin, 69 RBC/HPF, and 60 WBC/HPF. Urine culture grew Pseudomonas and Klebsiella species. There was no occult blood in his stool. The ciprofloxacin was replaced by a cephalosporin based on urine culture susceptibility. The patient displayed refractory hypoglycemia (Table 1) that persisted over 24 h, resolving after multiple doses of D50, regular meals, and a D10 1/2 NS infusion. His lethargy and mental status waxed and waned in relation to his blood glucose, and he returned to baseline with resolution of his hypoglycemia.

Refractory Hypoglycemia from Ciprofloxacin and Glyburide Interaction

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DISCUSSION We report a case of prolonged hypoglycemia apparently due to an interaction between the broadspectrum fluoroquinolone (ciprofloxacin) and a secondgeneration sulfonylurea hypoglycemic agent (glyburide). Because glyburide has a long duration of action (24 h) and its active metabolites are renally excreted, one could postulate that worsening renal insufficiency might have caused prolonged hypoglycemia. However, our patient was not clinically dehydrated, had a stable creatinine (compared to previously recorded laboratory values), and had been on his current medications for at least 6 months. Our hypothesis that the hypoglycemia was caused by a drug drug interaction is supported by a case reported in the literature in which the authors measured elevated levels of serum glyburide in a patient also taking ciprofloxacin (5). The cellular mechanisms by which glyburide and ciprofloxacin interact to produce hypoglycemia are poorly described but likely to be complex and multifactorial. Mechanisms might include interactions at one or more of the P450 isoenzymes (5 8) or ciprofloxacin-related blockage of ATP-potassium channels that are responsible for insulin control (10). In the report by Roberge et al, the patient developed hypoglycemia after treatment with ciprofloxacin for 1 week (5). Our patient developed significant hypoglycemia after one dose. Although we cannot prove with certainty that the hypoglycemia was caused by the addition of ciprofloxacin, a search for other possible etiologies was not successful. The patient did not have an infection or worsening renal failure and was not started on other new medications.

fluoroquinolone should have their glucose levels monitored closely.

REFERENCES Hogan DB. Revisiting the O complex: urinary incontinence, delirium and polypharmacy in elderly patients. Can Med Assoc J 1997; 157(8):1071 1077. 2. Chung MK, Bartfield JM. Knowledge of prescription medications among elderly emergency department patients. Ann Emerg Med 2002; 39(6). 3. Baker SE, Hangii MC. Possible gatifloxacininduced hypoglycemia. Ann Pharmacother 2002; 36(11):1722 1726. 4. Menzies DJ, Dorsainvil PA, Cunha BA, Johnson DH. Severe and persistent hypoglycemia due to gatifloxacin interaction with oral hypoglycemic agents. Am J Med 2002; 113(3):232 234. 5. Roberge RJ, Kaplan R, Frank R, Fore C. Glyburide-Ciprofloxacin interaction with resistant hypoglycemia. Ann Emerg Med 2000; 36(2):160 163. 6. Ciprofloxacin. West Haven, Connecticut: Bayer Pharmaceuticals, 2000. [package insert]. 7. Kim K, Park JY. Inhibitory effect of glyburide on cytochrome P450 isoforms in human liver microsomes. Drug Metab Dispos 2003; 31(9):1090 1092. 8. Michalets EL. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 1998; 18(1):84 112. 9. Kirchheiner J, Brockmoller J, Meineke I, Bauer S, Rohde W, Meisel C, Roots I. Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. Clin Pharmacol Ther Apr. 2002; 71(4):286 296. 10. Maeda N, Tamagawa T, Niki I, Miura H, Ozawa K, Watanabe G, Nonogaki K, Uemura K, Iguchi A. Increase in insulin release from rat pancreatic islets by quinolone antibiotics. Br J Pharmacol 1996; 117:372 376. 1.

CONCLUSIONS The concurrent administration of ciprofloxacin and glyburide can result in prolonged hypoglycemia. Patients stabilized on glyburide who are started on a Submitted July 24, 2003 Accepted January 28, 2004