Skip to main content
SpringerLink
Log in

Hypoglycemia Associated with Antibiotics Alone and in Combination with Sulfonylureas and Meglitinides: An Epidemiologic Surveillance Study of the FDA Adverse Event Reporting System (FAERS)

  • Original Research Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Introduction

Fluoroquinolones, clarithromycin, linezolid, tigecycline, cefditoren, doxycycline, and trimethoprim–sulfamethoxazole are known to be associated with hypoglycemia, but few studies have considered concomitant glucose-lowering medications.

Objective

The objective of this study was to evaluate the association between hypoglycemia and antibiotics using the US Food and Drug Administration Adverse Event Reporting System (FAERS), while accounting for concomitant glucose-lowering medications including sulfonylureas and meglitinides.

Methods

FAERS reports from 1 January 2004 to 31 December 2017 were included in the study. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs) for the association between antibiotics and hypoglycemia were calculated. An association was considered to be statistically significant when the lower limit of the 95% CI was > 1.0.

Results

A total of 2,334,959 reports (including 18,466 hypoglycemia reports) were considered, after inclusion criteria were applied. Statistically significant hypoglycemia RORs (95% CI) for antibiotics were: cefditoren 14.03 (8.93–22.03), tigecycline 3.32 (1.95–5.65), clarithromycin 2.41 (1.89–3.08), ertapenem 2.07 (1.14–3.75), moxifloxacin 2.06 (1.59–2.65), levofloxacin 1.66 (1.37–2.01), and linezolid 1.54 (1.07–2.20). After adjusting for concomitant sulfonylureas and meglitinides, the following antibiotics were still significantly associated with hypoglycemia: cefditoren 14.25 (9.08–22.39), tigecycline 3.34 (1.96–5.68), ertapenem 1.93 (1.03–3.60), and clarithromycin 1.56 (1.15–2.11).

Conclusion

In many patients, antibiotics, including fluoroquinolones, are associated with hypoglycemia when they are also taking sulfonylureas or meglitinides. Cefditoren, tigecycline, ertapenem, and clarithromycin are associated with hypoglycemia even if not taken with sulfonylureas or meglitinides. The association between ertapenem and hypoglycemia has not been previously reported.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data-sharing statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Food and Drug Administration. FDA updates warnings for fluoroquinolone antibiotics on risks of mental health and low blood sugar adverse reactions. https://www.fda.gov/news-events/press-announcements/fda-updates-warnings-fluoroquinolone-antibiotics-risks-mental-health-and-low-blood-sugar-adverse. Accessed 5 Nov 2019.

  2. Frier BM. Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications. Nat Rev Endocrinol. 2014;10:711–22.

    Article  CAS  Google Scholar 

  3. Viswanathan P, Iarikov D, Wassel R, Davidson A, Nambiar S. Hypoglycemia in patients treated with linezolid. Clin Infect Dis. 2014;59:e93–5.

    Article  CAS  Google Scholar 

  4. Kadoyama K, Sakaeda T, Tamon A, Okuno Y. Adverse event profile of tigecycline: data mining of the public version of the U.S. Food and Drug Administration Adverse Event Reporting System. Biol Pharm Bull. 2012;35:967–70.

    Article  CAS  Google Scholar 

  5. Chou HW, Wang JL, Chang CH, Lee JJ, Shau WY, Lai MS. Risk of severe dysglycemia among diabetic patients receiving levofloxacin, ciprofloxacin, or moxifloxacin in Taiwan. Clin Infect Dis. 2013;57:971–80.

    Article  CAS  Google Scholar 

  6. Mohr JF, McKinnon PS, Peymann PJ, Kenton I, Septimus E, Okhuysen PC. A retrospective, comparative evaluation of dysglycemias in hospitalized patients receiving gatifloxacin, levofloxacin, ciprofloxacin, or ceftriaxone. Pharmacotherapy. 2005;25:1303–9.

    Article  CAS  Google Scholar 

  7. Eshraghian A, Omrani GR. Cotrimoxazole-induced hypoglycemia in outpatient setting. Nutrition. 2014;30:959.

    Article  CAS  Google Scholar 

  8. Lee AJ, Maddix DS. Trimethoprim/sulfamethoxazole-induced hypoglycemia in a patient with acute renal failure. Ann Pharmacother. 1997;31:727–32.

    Article  CAS  Google Scholar 

  9. Johnson JA, Kappel JE, Sharif MN. Hypoglycemia secondary to trimethoprim/sulfamethoxazole administration in a renal transplant patient. Ann Pharmacother. 1993;27:304–6.

    Article  CAS  Google Scholar 

  10. Tan CH, Shelley C, Harman KE. Doxycycline-induced hypoglycaemia. Clin Exp Dermatol. 2016;41:43–4.

    Article  CAS  Google Scholar 

  11. Odeh M, Oliven A. Doxycycline-induced hypoglycemia. J Clin Pharmacol. 2000;40:1173–4.

    CAS  PubMed  Google Scholar 

  12. Basaria S, Braga M, Moore WT. Doxycycline-induced hypoglycemia in a nondiabetic young man. South Med J. 2002;95:1353–4.

    Article  Google Scholar 

  13. Ito M, Fukuda M, Suzuki Y, Wakamoto H, Ishii E. Carnitine-related hypoglycemia caused by 3 days of pivalate antibiotic therapy in a patient with severe muscular dystrophy: a case report. BMC Pediatr. 2017;17:73.

    Article  Google Scholar 

  14. Makino Y, Sugiura T, Ito T, Sugiyama N, Koyama N. Carnitine-associated encephalopathy caused by long-term treatment with an antibiotic containing pivalic acid. Pediatrics. 2007;120:e739–41.

    Article  Google Scholar 

  15. Parekh TM, Raji M, Lin YL, Tan A, Kuo YF, Goodwin JS. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas. JAMA Intern Med. 2014;174:1605–12.

    Article  Google Scholar 

  16. Khamaisi M, Leitersdorf E. Severe hypoglycemia from clarithromycin-repaglinide drug interaction. Pharmacotherapy. 2008;28:682–4.

    Article  CAS  Google Scholar 

  17. Clarithromycin [package insert]. North Chicago: Abbott Laboratories; 2000. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050662s044s050,50698s026s030,050775s015s019lbl.pdf. Accessed 5 Nov 2019.

  18. Food and Drug Administration. FDA Adverse Event Reporting System (FAERS). https://www.fda.gov/drugs/surveillance/fda-adverse-event-reporting-system-faers. Accessed 5 Nov 2019.

  19. Food and Drug Administration. Drugs@FDA: FDA-approved drugs. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed 5 Nov 2019.

  20. Evoy KE, Teng C, Encarnacion VG, et al. Comparison of quetiapine abuse and misuse reports to the FDA Adverse Event Reporting System with other second-generation antipsychotics. Subst Abuse. 2019;13:1–8.

    Google Scholar 

  21. Teng C, Reveles KR, Obodozie-Ofoegbu OO, Frei CR. Clostridium difficile infection risk with important antibiotic classes: an analysis of the FDA Adverse Event Reporting System. Int J Med Sci. 2019;16(5):630–5.

    Article  CAS  Google Scholar 

  22. Teng C, Walter EA, Gaspar DK, Obodozie-Ofoegbu OO, Frei CR. Torsades de pointes and QT prolongation associations with antibiotics: a pharmacovigilance study of the FDA Adverse Event Reporting System. Int J Med Sci. 2019;16(7):1018–22.

    Article  CAS  Google Scholar 

  23. Teng C, Baus C, Wilson JP, Frei CR. Rhabdomyolysis associations with antibiotics: a pharmacovigilance study of the FDA Adverse Event Reporting System (FAERS). Int J Med Sci. 2019;16(11):1504–9.

    Article  Google Scholar 

  24. Patek TM, Teng C, Kennedy KE, Alvarez CA, Frei CR. Comparing acute kidney injury reports among antibiotics: a pharmacovigilance study of the FDA Adverse Event Reporting System (FAERS). Drug Saf. 2019. https://doi.org/10.1007/s40264-019-00873-8.

    Article  PubMed  Google Scholar 

  25. McConeghy KW, Soriano MM, Danziger LH. A quantitative analysis of FDA adverse event reports with oral bisphosphonates and Clostridium difficile. Pharmacotherapy. 2016;36:1095–101.

    Article  CAS  Google Scholar 

  26. Evans SJ, Waller PC, Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf. 2001;10:483–6.

    Article  CAS  Google Scholar 

  27. MedDRA MSSO. Introductory guide for Standardised MedDRA Queries (SMQs) version 21.0. http://www.meddra.org/sites/default/files/guidance/file/smq_intguide_21_0_english.pdf. Accessed 5 Nov 2019.

  28. Bate A, Evans SJ. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf. 2009;18:427–36.

    Article  CAS  Google Scholar 

  29. Aspinall SL, Good CB, Jiang R, McCarren M, Dong D, Cunningham FE. Severe dysglycemia with the fluoroquinolones: a class effect? Clin Infect Dis. 2009;49:402–8.

    Article  CAS  Google Scholar 

  30. Food and Drug Administration (9/9/2008). Determination that TEQUIN (gatifloxacin) was withdrawn from sale for reasons of safety or effectiveness. https://www.federalregister.gov/documents/2008/09/09/E8-20938/determination-that-tequin-gatifloxacin-was-withdrawn-from-sale-for-reasons-of-safety-or. Accessed 5 Nov 2019.

  31. Bito M, Tomita T, Komori M, Taogoshi T, Kimura Y, Kihira K. The mechanisms of insulin secretion and calcium signaling in pancreatic beta-cells exposed to fluoroquinolones. Biol Pharm Bull. 2013;36:31–5.

    Article  CAS  Google Scholar 

  32. Saraya A, Yokokura M, Gonoi T, Seino S. Effects of fluoroquinolones on insulin secretion and beta-cell ATP-sensitive K+ channels. Eur J Pharmacol. 2004;497:111–7.

    Article  CAS  Google Scholar 

  33. Ashcroft FM. Mechanisms of the glycaemic effects of sulfonylureas. Horm Metab Res. 1996;28:456–63.

    Article  CAS  Google Scholar 

  34. Niemi M, Neuvonen PJ, Kivisto KT. The cytochrome P4503A4 inhibitor clarithromycin increases the plasma concentrations and effects of repaglinide. Clin Pharmacol Ther. 2001;70:58–65.

    Article  CAS  Google Scholar 

  35. Eberl S, Renner B, Neubert A, et al. Role of p-glycoprotein inhibition for drug interactions: evidence from in vitro and pharmacoepidemiological studies. Clin Pharmacokinet. 2007;46:1039–49.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs, the National Institutes of Health, or the authors’ affiliated institutions.

Author information

Authors and Affiliations

  1. Pharmacotherapy Division, College of Pharmacy, The University of Texas at Austin, San Antonio, TX, USA

    Kaitlin E. Kennedy, Chengwen Teng, Taylor M. Patek & Christopher R. Frei

  2. Pharmacotherapy Education and Research Center, Long School of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., MSC-6220, San Antonio, TX, 78229, USA

    Kaitlin E. Kennedy, Chengwen Teng, Taylor M. Patek & Christopher R. Frei

  3. South Texas Veterans Health Care System, San Antonio, TX, USA

    Christopher R. Frei

  4. University Health System, San Antonio, TX, USA

    Christopher R. Frei

Authors
  1. Kaitlin E. Kennedy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chengwen Teng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taylor M. Patek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christopher R. Frei
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Study concept and design: CT and CRF. Statistical analysis: CT. Interpretation of data: all authors. Drafting of the manuscript: KEK, CRF, and CT. Critical revision of the manuscript for important intellectual content: all authors. Study supervision: CRF.

Corresponding author

Correspondence to Christopher R. Frei.

Ethics declarations

Funding

No funding was sought for this research study. Dr. Frei was supported, in part, by a National Institutes of Health (NIH) Clinical and Translational Science Award (National Center for Advancing Translational Sciences, UL1 TR001120, UL1 TR002645, and TL1 TR002647) while the study was being conducted. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Conflict of interest

Kaitlin E. Kennedy, Chengwen Teng, Taylor M. Patek, and Christopher R. Frei have no conflicts of interest that are directly relevant to the content of this study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kennedy, K.E., Teng, C., Patek, T.M. et al. Hypoglycemia Associated with Antibiotics Alone and in Combination with Sulfonylureas and Meglitinides: An Epidemiologic Surveillance Study of the FDA Adverse Event Reporting System (FAERS). Drug Saf 43, 363–369 (2020). https://doi.org/10.1007/s40264-019-00901-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-019-00901-7

Search

Navigation