This transcript has been edited for clarity.
Is piperacillin-tazobactam (Zosyn) nephrotoxic? It's a question that has come up repeatedly during my past 2 weeks on our infectious disease consultation service in the hospital, especially among house staff and advanced-level practitioners.
Here's the back story. Over a decade ago, the FDA placed warnings in the prescribing information for piperacillin-tazobactam that in critically ill patients, it can affect renal function, and they suggested using alternative agents. They also warned about combining piperacillin-tazobactam with vancomycin because of the risk for increased acute kidney injury. Some of this was based on a 1200-patient trial, indicating about a 70% increased risk for renal failure with piperacillin/tazobactam compared with other beta-lactam drugs.
So, what's happened in the ensuing decade, especially for more ill patients or those with some baseline renal abnormalities is that cefepime (a cephalosporin) became the favored drug when you need gram-negative coverage, and use of piperacillin/tazobactam declined.
However, I would say the warning has always been a bit controversial because before that study was performed, piperacillin, like any beta-lactam, can rarely cause acute interstitial nephritis, but it is rare and the drug generally wasn't considered nephrotoxic. But a whole bunch of me-too studies that were often observational or retrospective seemed to confirm this problem and helped to reinforce the point of view that piperacillin-tazobactam could be nephrotoxic
However, there's really no biological basis for this, and investigations in recent years have found that when piperacillin-tazobactam hits the kidney, it tends to impact and use OAT3. This is an organic ion transporter in the proximal tubule and it uses OAT3 much more than other hydrophilic beta-lactams such as carbapenems or cephalosporins do. This can cause some extra stress to those cells and therefore we often see some competition with serum creatinine and a rise in serum levels. But studies hadn't generally found that there were any worse outcomes with this, such as increased need for dialysis. So the thought was perhaps this just means that piperacillin is competing with creatinine for transportation through this OAT3 and doesn't reflect any real renal injury.
A paper last year looked at 700-plus ICU patients who either got vancomycin and piperacillin-tazobactam or vancomycin and cefepime, and found that the group that got the vancomycin and piperacillin-tazobactam had what was called a creatinine-defined acute kidney injury but had no change in associated alternative kidney biomarkers such as cystatin C, which is actually more accurate. Also, there was no increased risk for mortality or dialysis. This all supports the hypothesis that the effect of piperacillin-tazobactam on creatinine reflects pseudotoxicity.
Just recently in JAMA, the ACORN trial tried to address, in a prospective randomized fashion, whether piperacillin-tazobactam injures the kidney. They looked at more than 2500 patients who received piperacillin-tazobactam or needed it within 12 hours of hitting the emergency room or needing ICU care. And this was randomized between piperacillin-tazobactam and cefepime. They found that at day 14, there was no difference in the primary outcome of kidney injury or death. However, there are a number of limitations to this study. It was unblinded, there was no knowledge of premorbid creatinine levels, 20% of people got other drugs such as vancomycin, and actually, the patients only received on average of 3 days of either drug, suggesting that perhaps they weren't very ill or they had alternative explanations for their illness. Also, piperacillin-tazobactam was given by extended infusion. All this is to say that the ACORN study is perhaps not the definitive trial to help answer this question.
But regardless, what I've been trying to explain to our infectious disease fellows, house staff, medical students and advanced practitioners is that with piperacillin-tazobactam, if there is a rise in creatinine, it is unlikely to have any clear impact on a patient. Of course, vancomycin is known to cause interstitial renal disease and certainly can cause problems with higher doses. So if using in combination, you might see somewhat higher serum creatinine levels than you would when using vancomycin alone. But again, this doesn't influence my decision to use piperacillin-tazobactam or not.
In conclusion, I hope that instead of always reaching for cefepime (which has its own problems especially in the older population with encephalopathy) you still might write for piperacillin-tazobactam when it's appropriate for your patients. Of course, until this warning is removed, it will remain ingrained in our patient care.
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Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: Zosyn: Why I Don't Worry About Nephrotoxicity - Medscape - Dec 11, 2023.
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