My elderly hospitalized patient with pneumonia has developed hypoglycemia within days of initiating piperacillin/tazobactam (Zosyn). Is there a connection between piperacillin/tazobactam and hypoglycemia?

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!

My elderly hospitalized patient with pneumonia has developed hypoglycemia within days of initiating piperacillin/tazobactam (Zosyn). Is there a connection between piperacillin/tazobactam and hypoglycemia?

What changes should I consider in my treatment of hospitalized patients with community-acquired pneumonia (CAP) in light of the 2019 guidelines of the American Thoracic society (ATS) and Infectious Diseases Society of America (IDSA)?

Compared to 2007,1 the 2019 ATS/IDSA guidelines2 propose changes in at least 4 major areas of CAP treatment in inpatients, with 2 “Do’s” and 2 “Dont’s”:

  • Do select empiric antibiotics based on severity of CAP and risk factors for methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (see related pearl on P4P)
  • Do routinely treat CAP patients who test positive for influenza with standard CAP antibiotics
  • Don’t routinely provide anaerobic coverage in aspiration pneumonia (limit it to empyema and lung abscess) (see related pearl on P4P)
  • Don’t routinely treat CAP with adjunctive corticosteroids in the absence of refractory shock

β-lactam plus macrolide is recommended for both non-severe and severe CAP.  β-lactam plus respiratory fluoroquinolone is an alternative regime in severe CAP, though not endorsed as strongly as β-lactam plus macrolide therapy (low quality of evidence).  Management per CAP severity summarized below:

  • Non-severe CAP
    • β-lactam (eg, ceftriaxone, cefotaxime, ampicillin-sulbactam and newly-added ceftaroline) plus macrolide (eg, azithromycin, clarithromycin) OR respiratory fluoroquinolone (eg, levofloxacin, moxifloxacin)
    • In patients at risk of MRSA or P. aeruginosa infection (eg, prior isolation of respective pathogens, hospitalization and parenteral antibiotics in the last 90 days or locally validated risk factors—HCAP has been retired), obtain cultures/PCR
    • Hold off on MRSA or P. aeruginosa coverage unless culture/PCR results return positive.
  • Severe CAP
    • β-lactam plus macrolide OR β-lactam plus respiratory fluoroquinolone (see above)
    • In patients at risk of MRSA or P. aeruginosa infection (see above), obtain cultures/PCR
    • Add MRSA coverage (eg, vancomycin or linezolid) and/or P. aeruginosa coverage (eg, cefepime, ceftazidime, piperacillin-tazobactam, meropenem, imipenem) if deemed at risk (see above) while waiting for culture/PCR results

Duration of antibiotics is for a minimum of 5 days for commonly-targeted pathogens and a minimum of 7 days for MRSA or P. aeruginosa infections, irrespective of severity or rapidity in achieving clinical stability.

For patients who test positive for influenza and have CAP, standard antibacterial regimen should be routinely added to antiinfluenza treatment.

For patients suspected of aspiration pneumonia, anaerobic coverage (eg, clindamycin, ampicillin-sulbactam, piperacillin-tazobactam) is NOT routinely recommended in the absence of lung abscess or empyema.

Corticosteroids are NOT routinely recommended for non-severe (high quality of evidence) or severe (moderate quality of evidence) CAP in the absence of refractory septic shock.

Related pearls on P4P:

2019 CAP guidelines on diagnostics:                                        https://pearls4peers.com/2020/02/14/what-changes-should-i-consider-in-my-diagnostic-approach-to-hospitalized-patients-with-community-acquired-pneumonia-cap-in-light-of-the-2019-guidelines-of-the-american-thoracic-society-ats-and-inf/ 

Anerobic coverage of aspiration pneumonia: https://pearls4peers.com/2019/07/31/should-i-routinely-select-antibiotics-with-activity-against-anaerobes-in-my-patients-with-presumed-aspiration-pneumonia/

References

  1. Mandell LA, Wunderink RG, Anzueto A. Infectious Disease Society of America/American Thoracic Society Consensus Guidelines on the Management guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44:S27-72. https://www.ncbi.nlm.nih.gov/pubmed/17278083
  2. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. Am J Respir Crit Care Med 2019;200:e45-e67. https://www.ncbi.nlm.nih.gov/pubmed/31573350

 

What changes should I consider in my treatment of hospitalized patients with community-acquired pneumonia (CAP) in light of the 2019 guidelines of the American Thoracic society (ATS) and Infectious Diseases Society of America (IDSA)?

Is meropenem a good choice of antibiotic for treatment of my patient’s intraabdominal infection involving enterococci?

Although meropenem is a broad spectrum antibiotic that covers many gram-negative and gram-positive organisms as well as anaerobes, its activity against enterococci is generally poor and leaves much to be desired.

In a study of ampicillin-sensitive E. faecalis isolates from hospitalized patients, only 36% of isolates were considered susceptible (MIC≤4 mg/L); activity against E. faecium isolates was similarly poor.1 Several other studies have reported the suboptimal activity of meropenem against both E. faecalis and E. faecium, 2-4 with susceptibility rates as low as 8.6% depending on the MIC break point used.3

A popular textbook and a handbook on infectious diseases also do not recommend the use of meropenem for treatment of enterococcal infections. 5,6

Of interest, the package insert states that meropenem is indicated for complicated skin and soft tissue infections due to a variety of organisms, including E. faecalis (vancomycin-susceptible isolates only), but not for complicated intra-abdominal infections or meningitis due this organism.7

In our patient with intraabdominal infection,  we may consider piperacillin-tazobactam instead.  Piperacillin-tazobactam is a broad spectrum antibiotic with excellent coverage against anaerobes and ampicillin-susceptible E. faecalis.1,8  

 

References

  1. Endtz HP, van Dijk WC, Verbrugh HA, et al. Comparative in-vitro activity of meropenem against selected pathogens from hospitalized patients in the Netherlands. J Antimicrob Chemother 1997;39:149-56. https://www.ncbi.nlm.nih.gov/pubmed/9069534
  2. Pfaller MA, Jones RN. A review of the in vitro activity of meropenem and comparative antimicrobial agents tested against 30,254 aerobic and anaerobic pathogens isolated world wide. Diag Microbiol Infect Dis 1997;28:157-63. https://www.ncbi.nlm.nih.gov/pubmed/9327242
  3. Hallgren A, Abednazari H, Ekdahl C, et al. Antimicrobial susceptibility patterns of enterococci in intensive care units in Sweden evaluated by different MIC breakpoint systems. J Antimicrob Chemother 2001;48:53-62. https://www.ncbi.nlm.nih.gov/pubmed/11418512
  4. Hoban DJ, Jones RN, Yamane N, et al. In vitro activity of three carbapenem antibiotics comparative studies with biapenem (L-627), imipenem, and meropenem against aerobic pathogens isolated worldwide. Diag Microbiol Infect Dis 993;17:299-305.https://www.ncbi.nlm.nih.gov/pubmed/8112045
  5. Chambers HF. Carbapenem and monobactams. In Mandell GL et al. eds. Principles and practice of infectious diseases. 2010, pp 341-45.
  6. Cunha CB, Cunha BA. Antibiotic essentials. 2017, pp 689-91.
  7. Meropenem.http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7253?searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dmeropenem%26t%3Dname
  8. Perry CM, Markham A. Piperacillin/tazobactam. Drugs 1999;57:805-43. https://link.springer.com/article/10.2165%2F00003495-199957050-00017

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Is meropenem a good choice of antibiotic for treatment of my patient’s intraabdominal infection involving enterococci?

Should I be concerned about piperacillin-tazobactam nephrotoxicity in the absence of vancomycin?

Nephrotoxicity associated with piperacillin-tazobactam (PT) combined with vancomycin (V) has been increasingly reported1,2,  with  some recommending that an alternative to V be used when PT is also on board 2. However, there are several reasons why the nephrotoxic potential of PT either alone or with antibiotics other than V also deserves further study before such recommendations can be widely embraced3.

First, most studies of VPT combination do not include comparative V or PT alone arms making it difficult to assess the relative contribution of these 2 antibiotics to kidney injury when used in combination. A small study that did include a PT-only  arm reported a similar rate of acute kidney injury (AKI) in PT and VPT arms ( 15.4% and 18.8% , respectively), both significantly higher that than of  V-only group (4%).4

 Other reasons not to readily dismiss PT as a cause of nephrotoxicity include the  lack of association between higher V trough levels and AKI in patients receiving VPT2, the association of PT with lower rates of renal function recovery in critically ill patients when compared to other selected β-lactams5,  and higher magnesium and potassium renal tubular loss with the use of PT compared to selected cephalosporins and ciprofloxacin6.  As with other penicillins, PT-associated acute interstitial nephritis may also occur7-8.

In short, even in the absence of V, nephrotoxic potential of PT should not be automatically dismissed.

Update: Since the original posting of this pearl, an in-depth article on the subject was published in 2021 (https://www.karger.com/Article/Pdf/513742)

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References

  1. Hammond DA, Smith MN, Chenghui Li, et al. Systematic review and meta-analysis of acute kidney injury associated with concomitant vancomycin and piperacillin/tazobactam. Clin Infect Dis 2017;64:666-74.
  2. Navalkele B, Pogue JM, Karino S, et al. Risk of acute kidney injury in patients on concomitant vancomycin and piperacillin-tazobactam compared to those on vancomycin and cefepime. Clin Infect Dis 2017;64:116-123.
  3. Manian FA. Should we revisit the nephrotoxic potential of piperacillin-tazobactam as well? Clin Infect Dis 2017; https://doi.org/10.1093/cid/cix321
  4. Kim T, Kandiah S, Patel M, et al. Risk factors for kidney injury during vancomycin and piperacillin/tazobactam administration, including increased odds of injury with combination therapy. BMC Res Notes 2015;8:579.
  5. Jensen J-U S, 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 randomized trial. BMJ Open 2012;2:e000635. http://bmjopen.bmj.com/content/2/2/e000635
  6. Polderman KH, Girbes ARJ. Piperacillin-induced magnesium and potassium loss in intensive care unit patients. Intensive Care Med 2002;28:530-522.
  7. Muriithi AK, Leung N, Valeri AM, et al. Clinical characteristics, causes and outcomes of acute interstitial nephritis in the elderly. Kidney International 2015;87:458-464.
  8. Soto J, Bosch JM, Alsar Ortiz MJ, et al. Piperacillin-induced acute interstitial nephritis. Nephron 1993;65:154-155. 

Disclosures: Ref 3 was authored by the creator of http://www.Pearls4Peers.com. 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!

Should I be concerned about piperacillin-tazobactam nephrotoxicity in the absence of vancomycin?