Hypoglycemia is a rare (<1%) reported side effect of piperacillin/tazobactam (P/T) [1].  While the exact mechanism is unclear, hypoglycemia in this setting may be related to the adverse impact of P/T on renal function or possibly competitive inhibition of renal organic anion transporter 3 (OAT3).

The association of P/T with acute kidney injury (AKI) is well known. In a retrospective cohort analysis of 11,650 patients, P/T was associated with AKI in 7.8% of patients [2]. Of interest, compared to other antibiotics, P/T has also been shown to delay renal recovery in critically ill patients [3].  Decline in renal function may in turn reduce clearance of insulin and lead to hypoglycemia, particularly in patients who already have risk factors for hypoglycemia, such as malnutrition [4]. This is not surprising because renal clearance accounts for 25% of insulin clearance (rest is hepatic).  

Another plausible mechanism is the impact of P/T on glucose metabolism through competitive inhibition of OAT3 [5]. OAT3 is important in reabsorption of gluconeogenic precursors as well as excretion of uremic metabolites [6], which may further dysregulate hepatic gluconeogenesis and precipitate hypoglycemia. Fascinating!

Bonus pearl: Did you know that elderly patients may be at risk of reactive (post-prandial) hypoglycemia particularly in the setting of pre-diabetes or diabetes due to loss of coordination between glucose load and insulin secretion [7]? 

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Contributed by Michael Nance, MD, PhD, Department of Medicine, Mercy Hospital-St. Louis, St. Louis, Missouri

References:

1. Wyeth Pharmaceutical Inc. Zosyn (piperacillin/tazobactam) [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/050684s88s89s90_050750s37s38s39lbl.pdf. Revised May 2017. Accessed January 16, 2021.
2. Rutter WC, Burgess DR, Talbert JC, Burgess DS. Acute kidney injury in patients treated with vancomycin and piperacillin-tazobactam: A retrospective cohort analysis. J Hosp Med. 2017 Feb;12(2):77-82. doi: 10.12788/jhm.2684. PMID: 28182801; PMCID: PMC5573255. https://pubmed.ncbi.nlm.nih.gov/28182801/
3. Jensen JS, Hein L, Lundgren B, et al. Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial. BMJ Open 2012;2:doi: 10.1136/bmjopen-2011-000635  https://bmjopen.bmj.com/content/2/2/e000635
4. Leibovitz E, Adler H, Giryes S, Ditch M, Burg NF, Boaz M. Malnutrition risk is associated with hypoglycemia among general population admitted to internal medicine units. Results from the MENU study. Eur J Clin Nutr. 2018 Jun;72(6):888-893. doi: 10.1038/s41430-018-0143-9. Epub 2018 Mar 27. PMID: 29588529. https://pubmed.ncbi.nlm.nih.gov/29588529/
5. Wen S, Wang C, Duan Y, Huo X, Meng Q, Liu Z, Yang S, Zhu Y, Sun H, Ma X, Yang S, Liu K. OAT1 and OAT3 also mediate the drug-drug interaction between piperacillin and tazobactam. Int J Pharm. 2018 Feb 15;537(1-2):172-182. doi: 10.1016/j.ijpharm.2017.12.037. Epub 2017 Dec 23. PMID: 29277663. https://pubmed.ncbi.nlm.nih.gov/29277663/
6. Wu, W., Bush, K.T. & Nigam, S.K. Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivoHandling of Uremic Toxins and Solutes. Sci Rep 7, 4939 (2017). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504054/
7. Tamura Y, Araki A, Chiba Y, Horiuchi T, Mori S, Hosoi T. Postprandial reactive hypoglycemia in an oldest-old patient effectively treated with low-dose acarbose. Endocr J. 2006 Dec;53(6):767-71. doi: 10.1507/endocrj.k05-140. Epub 2006 Sep 12. PMID: 16966825. https://pubmed.ncbi.nlm.nih.gov/16966825/ 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!