Update on Quinolone-Induced Changes in Glycemic Control
Special feature
By Thao Tran, Jocelyn Walton, Christine Maddox, and Jessica C. Song, Thao Tran, Jocelyn Walton, and Christine Maddox are PharmD Candidates, University of the Pacific, and Jessica C. Song, MA, PharmD, is Pharmacy Residency Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.
Thao Tran, Jocelyn Walton, and Jessica C. Song report no financial relationships relevant to this field of study.
Within the past few months, gatifloxacin (Tequin®) has received some attention in the medical community due to reports of serious hypoglycemia and hyperglycemia.1 Gatifloxacin is an 8-methoxyfluoroquinolone that exhibits in vitro activity against numerous Gram-positive and Gram-negative aerobes, as well as anaerobes and some atypical organisms.2 To date, over 20 published cases of dysglycemia (hypoglycemia or hyperglycemia) have been reported with gatifloxacin.3 Because of these events, Bristol-Myers Squibb has ceased production of this antibiotic.4 A few months prior to its discontinuation, the prescribing information added a new contraindication in patients with diabetes mellitus, as well as updated warnings and precautions to identify other risk factors for dysglycemia, such as concomitant antidiabetic medications, renal insufficiency, and older age.5
Pathophysiology for Quinolone-Induced Dysglycemia
While gatifloxacin is known to cause both hypoglycemia and hyperglycemia, hypoglycemic events appear to be more commonly associated with use of this agent.6-10 Much of the available evidence explaining the pathophysiology of gatifloxacin-induced hypoglycemia has been extrapolated from in vitro studies performed on mouse pancreatic islet cells.6 Chimeric pancreatic islets were isolated and placed in buffers containing different concentrations of glucose, as well as one of the following quinolones: gatifloxacin, levofloxacin, or temafloxacin. KATP (adenosine triphosphate-sensitive potassium channel) currents regulating insulin secretion were recorded. Inhibitory effects on these ATP-dependent K+ channels depolarize pancreatic cells, which allow for the opening of voltage-gated calcium channels. The entrance of calcium into the cell promotes insulin secretion, leading to the adverse side effects associated with hypoglycemia.6,7
The 3 tested quinolones exhibited varying degrees of effects on insulin release. Astunori and colleagues observed that gatifloxacin and temafloxacin stimulated insulin secretion, whereas levofloxacin caused no significant effects. Increasing doses of gatifloxacin also increased insulin secretion, thereby suggesting a dose- dependent augmentation of insulin secretion.6
The exact pathogenesis of gatifloxacin-associated hyperglycemia has yet to be fully elucidated, but it is hypothesized that it may trigger the vacuolation of pancreatic beta cells, which decreases insulin levels.7 Of note, a recently published case report highlighted the development of diabetes after gatifloxacin therapy.10 A 57-year-old man developed new-onset diabetes 3 weeks after receiving a 10-day course of gatifloxacin. His fasting blood glucose concentrations from the previous years ranged from 103 to 116 mg/dL. Bhasin and colleagues noted a temporal relationship between the administration of gatifloxacin and the onset of diabetes, as the patient's blood glucose concentration was 992 mg/dL within 3 weeks of completing gatifloxacin therapy. In addition, Bhasin et al stated that the usual onset of type 2 diabetes is a more gradual process than the one displayed by their patient.
Hypoglycemia Associated with Gatifloxacin and Other Quinolones
Although the incidence of serious dysglycemia during gatifloxacin therapy is rare, the possibility of life-threatening effects on the central nervous system raises concern.9 The updated product labeling (prior to discontinuation) warned of decreased serum glucose usually occurring within 3 days of initiating the medication, while hyperglycemia was noted to occur after the third day of administration.2,7 Serious complications have included seizures, hypoglycemic coma, altered level of consciousness, and hyperosmolar non-ketotic hyperglycemic coma. Most of these events were reversible (within 1-2 days), but a few resulted in fatal outcomes.5 Patients without a history of diabetes nor on glucose-altering medications may also be at risk, as one study found no significant difference in the risk of experiencing dysglycemia between diabetic patients receiving treatment and patients not taking diabetic medications.7
Hypoglycemia appears to be more common in older patients and those with renal insufficiency. Both populations have decreased renal function, which may reduce the clearance of the medication. Gatifloxacin is primarily excreted through the kidneys, of which 80% is eliminated unchanged in the urine.8 Patients with impaired renal function will subsequently have increased exposure to gatifloxacin, possibly leading to hypoglycemia.
The true incidence of gatifloxacin-related dysglycemia is difficult to estimate, as the FDA's process for monitoring adverse events (Adverse Events Reporting System) is limited by under-reporting.7 The package labeling referred to 2 earlier studies in which no clinically significant changes in glucose tolerance and homeostasis were found in non-insulin dependent patients controlled with diet and exercise. Only transient, modest increases in serum insulin, and decreases in glucose concentrations, were reported after the first dose of gatifloxacin. Additionally, it was found that patients on glyburide experienced clinically insignificant decreases in serum insulin.2
Park-Wyllie and colleagues analyzed data from the National Ambulatory Medical Care Survey and from the National Hospital Ambulatory Medical Care Survey (1995-2002), in order to conduct 2 separate nested case-control studies to assess the odds of gatifloxacin-associated hypo- and hyperglycemia.7 Park-Wyllie et al examined dysglycemic events necessitating hospitalization within 30 days of administration of quinolones (ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin), macrolides, and second-generation cephalosporins (cefaclor, cefuroxime axetil) in a population of approximately 1.4 million Ontario, Canada residents over the age of 65. The percentages of diabetic patients were 92% and 62%, respectively, in the hypo- and hyperglycemia nested case-control studies.
The adjusted odds ratio for hypoglycemia in the gatifloxacin group as compared to macrolide-treated patients was 4.3 (95% CI, 2.9 to 6.3). Levofloxacin use was also shown to increase the risk of hypoglycemia relative to macrolides (adjusted odds ratio 1.5, 95% CI, 1.2 to 2.0), though to a lesser degree than observed with gatifloxacin. Of note, no increased odds of hypoglycemia were reported after treatment with either ciprofloxacin or moxifloxacin. Interestingly, aside from gatifloxacin (adjusted odds ratio 16.7, 95% CI, 10.4 to 26.8), there were no statistically significant differences in the odds of hyperglycemia for the other quinolones or second-generation cephalosporins (compared to macrolides).7
The results from a retrospective study conducted by Frothingham and colleagues3 support the observations reported in the Canadian nested, case-control studies. Frothingham et al analyzed spontaneous adverse event reports associated with the use of ciprofloxacin, gatifloxacin, levofloxacin, and moxifloxacin in the United States during the time from November 1997 to September 2003. Of 568 dysglycemic events, 80% were attributed to gatifloxacin. Furthermore, 68% of the fatal dysglycemic events were associated with gatifloxacin treatment.
Conclusion
Recent reports have suggested that the use of gatifloxacin, especially in elderly and diabetic patients, may lead to severe hypoglycemia or hyperglycemia, warranting in-hospital treatment. Ciprofloxacin and moxifloxacin appear to be safe for diabetic patients, whereas levofloxacin use may be associated with a slightly higher risk of hypoglycemia. At present, no cases of dysglycemia have been attributed to gemifloxacin, one of the newer quinolones available in the United States. Quinolones have become the most commonly prescribed class of antibiotics, with nearly half prescribed for non-approved diagnoses.11 Consequently, since there may be a slightly higher risk of hypoglycemia associated with levofloxacin use, compared with other quinolones on the US market, healthcare providers should discuss how to detect changes in blood glucose with patients who may be at risk for dysglycemic events.
References
- Petition to the FDA to Immediately Ban the Antibiotic Gatifloxacin (Tequin). Health Research Group Publication #1768. Website accessed on June 4, 2006. www.citizen.org/publications/release.cfm?ID=7430
- Bristol-Myers Squibb Company. Tequin (Gatifloxacin) Package Insert. Princeton, NJ: January 2006.
- Frothingham R. Glucose Homeostasis Abnormalities Associated with Use of Gatifloxacin. Clin Infect Dis. 2005;41:1269-1276.
- Bristol-Myers Squibb Discontinues Tequin. Drug Store News. Website Accessed on June 4, 2006. www.retailnet.com/story.cfm?ID=28434
- Bristol-Myers Squibb Company. Dear Healthcare Provider Letter. Princeton, NJ: February 15, 2006.
- Saraya A, et al. Effects of Fluoroquinolones on Insulin Secretion and b-cell ATP-Sensitive K+ Channels. Eur J Pharmacol. 2004;497:111-117.
- Park-Wyllie LY, et al. Outpatient Gatifloxacin Therapy and Dysglycemia in Older Adults. N Engl J Med. 2006;354:1352-1361.
- Stading JA, et al. Development of Diabetes after Gatifloxacin Therapy. Am J Health Syst Pharm. 2005;62:2293-2295.
- Tailor S, et al. Analysis of Spontaneous Reports of Hypoglycemia and Hyperglycemia Associated with Marketed Systemic Fluoroquinolones Made to the Canadian Adverse Drug Reaction Monitoring Program. Can J Hosp Pharm. 2004;57:12-17.
- Bhasin R, et al. Hypoglycemia Associated with the Use of Gatifloxacin. Am J Med Sci. 2005;330:250-253.
- Linder JA, et al. Fluoroquinolone Prescribing in the United States: 1995 to 2002. Am J Med. 2005;118:259-268.
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