Fluoroquinolones are commonly prescribed antimicrobials that have been implicated in alterations of glucose metabolism. We report a case of refractory fluoroquinolone-induced hypoglycemia in a patient with type-2 diabetes mellitus on glipizide that was successfully treated with octreotide. A patient was admitted with hypoglycemia after having been initiated on levofloxacin therapy. Despite treating the hypoglycemia supportively with multiple boluses of 25 g of dextrose, a continuous dextrose infusion, and glucagon, the patient experienced repeated episodes of rebound hypoglycemia. The persistent hypoglycemia was eventually reversed with the administration of subcutaneous octreotide. Clinicians should be cognizant of this adverse effect of fluoroquinolones, as well as predisposing risk factors, and consider octreotide as an adjunctive therapy for refractory hypoglycemia cases.
Fluoroquinolones are a commonly prescribed class of broad-spectrum antimicrobials used for a variety of bacterial infections given their excellent degree of tissue penetration and high oral bioavailability [
A 73-year-old Caucasian male with a past medical history of coronary artery disease, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, and type-2 diabetes mellitus was admitted after having a witnessed seizure at his nursing rehabilitation facility. When emergency medical services arrived, the patient was found to be hypoglycemic with blood glucose (BG) of 21 mg/dL. He was administered 25 g of dextrose 50% (D50) resulting in some improvement in his mental status. He was then transferred to our emergency department (ED).
In the ED, the patient was minimally responsive to both verbal and physical cues. The initial laboratory results were significant for hypokalemia with potassium of 2.9 mmol/L (normal 3.6-5.1 mmol/L), acute kidney injury with serum creatinine at 2.52 mg/dL (normal 0.7-1.3 mg/dL; baseline approximately 1.5 mg/dL), albumin of 2 g/dL (normal 3.5-5.7 g/dL), and hypoglycemia with a BG of 34 mg/dL (normal 70-105 mg/dL). Liver function tests (LFTs) were all within normal limits. The patient was immediately given 50 g of D50 resulting in a repeat BG of 134 mg/dL. Review of the patient’s home medication list identified that the patient was prescribed levofloxacin 750 mg daily for pneumonia on discharge from a hospitalization three days prior with no other medication changes. Chronic medications were inclusive of aspirin 81 mg daily, atorvastatin 80 mg daily, glipizide 10 mg daily, losartan 25 mg daily, mometasone 220 mcg/inhalation three times daily, spironolactone 25 mg daily, torsemide 100 mg daily, and warfarin. The patient required four additional boluses of D50 and a continuous dextrose 10% (D10) infusion to maintain euglycemia before transfer to the intensive care unit (ICU).
In the ICU, the patient continued to experience multiple episodes of severe rebound hypoglycemia despite an additional four boluses of D50, increasing the D10 infusion rate to 100 mL/hr (see Figure
Blood glucose values in response to D10 infusion, D50 boluses, glucagon, and octreotide. D10, dextrose 10%; D50, dextrose 50%.
Hypoglycemia is a rare but a known potential adverse effect of fluoroquinolone therapy. Several published case reports have specifically implicated levofloxacin as the causative agent of hypoglycemia with some resulting in fatal outcomes [
Several risk factors may predispose patients to hypoglycemia while being treated with fluoroquinolones including diabetes, concomitant use of sulfonylureas or insulin, renal insufficiency, and elderly which is conventionally defined as greater than 65 years old [
In a large population-based cohort study of over 78,000 diabetic patients newly prescribed a fluoroquinolone, the absolute risk of hypoglycemia per 1,000 people for moxifloxacin, levofloxacin, and ciprofloxacin was found to be 10.0, 9.3, and 7.9, respectively. This is in comparison to 3.7 for macrolides and 3.2 for cephalosporins [
The mechanisms by which fluoroquinolones induce hypoglycemia have not yet been fully elucidated. However, in vitro and animal model studies have provided evidence on proposed pharmacodynamic pathways that modulate insulin secretion. These studies in addition to the known pharmacokinetic profile of levofloxacin provide potential explanations for this clinical scenario.
Adenosine triphosphate-sensitive potassium (KATP) channels located in pancreatic
In addition to pharmacodynamics, a pharmacokinetic mechanism in our case should be explored. On admission, our patient was noted to be on concomitant therapy with glipizide for type-2 diabetes. Hence, the possibility of a combined drug-drug interaction between levofloxacin and glipizide should be considered as another mechanism to explain the refractory hypoglycemia. Glipizide is primarily metabolized by the cytochrome P-450 (CYP) system, specifically isoenzyme CYP2C9 [
Although supportive care therapies such as glucose and glucagon administration remain the cornerstone of treatment for hypoglycemia, complications have been reported. In this therapeutic approach, transient beneficial increases in serum glucose are offset by rebound hypoglycemia that can especially occur in patients taking medications affecting pancreatic KATP
Octreotide is a potent and long-acting synthetic analog of the inhibitory peptide hormone somatostatin [
The dosage and interval of octreotide therapy were based on published literature for insulin and sulfonylurea overdoses. In adults, doses of 50-100 mcg subcutaneously or intravenously every 6 to 12 hours have been reported [
To our knowledge, this is the second case report to describe the successful use of octreotide for treating life-threatening hypoglycemia caused by levofloxacin in combination with glipizide. The first case by Kelesidis and Canseco was similar to ours in that an elderly woman with type-2 diabetes mellitus treated with glipizide and chronic kidney disease experienced refractory hypoglycemia to supportive measures complicated by seizures after one dose of ciprofloxacin [
This case is limited by the fact that causation cannot unequivocally establish levofloxacin as the sole cause of hypoglycemia given other potential contributing factors, including the use of sulfonylureas where both pharmacodynamic and pharmacokinetic mechanisms may have contributed. Based on the Naranjo score of 4, it is possible the hypoglycemia was attributed to levofloxacin [
It should also be noted that the patient was initiated on high calorie, high fiber enteral nutrition (EN) at 50 mL/hr at the time octreotide was initiated. However, the carbohydrates provided by EN in addition to that provided by the D10 infusion at 100 mL/hr only supplied the patient with 20.8 g of carbohydrates per hour. This amount of carbohydrates is less than that provided by each bolus of D50 (25 g) and thus, unlikely to account for the sudden maintenance of euglycemia.
Our case and review of the literature highlight the safety concern of potential hypoglycemia with the use of levofloxacin in patients with identified risk factors and support the use of octreotide to reverse this phenomenon. Early recognition of this potential complication and subsequent treatment are necessary to prevent increased morbidity and mortality. Clinicians should exercise caution when prescribing fluoroquinolones by evaluating patients for known risk factors for hypoglycemia especially when unavoidable drug-drug interactions are possible. In patients unresponsive to standard supportive care therapies, the early adjunctive use of octreotide appears to be a reasonable off-label treatment option for fluoroquinolone-induced hypoglycemia.
Severe hypoglycemia is a known adverse effect of fluoroquinolones. However, until the recent updates in safety labeling, general awareness of this adverse effect was lacking. Clinicians should be aware of the risk factors and increase monitoring or choose alternative therapy when appropriate. It is essential clinicians are cognizant of these lesser-known adverse effects and drug-drug interactions to ensure prompt recognition and treatment using appropriate adjuncts. Octreotide may represent a novel reversal agent in addition to supportive care therapies for patients presenting with refractory, fluoroquinolone-induced hypoglycemia. To the best of the authors’ knowledge, this is the second case report to describe the successful use of octreotide to treat severe and refractory hypoglycemia caused by levofloxacin in a patient with type-2 diabetes mellitus receiving glipizide.
Abstract was presented at the Society of Critical Care Medicine Annual Congress meeting in San Diego, February 17th, 2019.
The authors declare that they have no conflicts of interest.
Watson and Ward were responsible for drafting of the manuscript. Watson, Ward, Prabhakar, Fiza, and Moll were responsible for critical revision of the manuscript for important intellectual content. Moll was responsible for study supervision.