Most medical myths arose decades ago, prior to the era of modern evidence-based medicine. When investigating the origin story of those myths, we wind up reading grainy old papers from the 1950s. Surely, we think, such myths wouldn’t arise today – not in our shiny, interconnected, science-based, hyper-argumentative medical world.
Unfortunately, new myths do continue to be born every year. When this occurs, it’s particularly interesting to see how these myths are derived and promoted. So, let’s take a few minutes and explore what happened with the myth that piperacillin-tazobactam is conditionally nephrotoxic in the presence of vancomycin.
Background – Simmering resentment against vancomycin/piperacillin-tazobactam.
Vancomycin plus piperacillin-tazobactam (aka vanc-zosyn or “vosyn”) is a popular broad-spectrum antibiotic regimen. Its versatility led to its overuse, which in turn caused some physicians to resent the combination. For example:
- Infectious Disease Consultant: “After reviewing the chart, taking a patient history that dates back to conception, and gazing upon the microbiology slides in the laboratory for an hour, I’m recommending a combination of linezolid, metronidazole, and ceftazidime.”
- Surgery: “That’s ok, we’ll just do vanc-zosyn.”
- Infectious Disease Consultant: Head explodes.
So, many practitioners have slowly come to loathe the combination of vancomycin and piperacillin-tazobactam. This primed them to be ready to believe any adverse effects from this combination…
Origin of the myth – Initial correlative studies
Starting around 2011, retrospective studies emerged showing that patients treated with vancomycin plus piperacillin-tazobactam had increased rates of acute kidney injury compared to patients treated with vancomycin plus other beta-lactams.
This generated the myth. While piperacillin-tazobactam may extremely rarely cause acute tubulointerstitial nephritis, this is an unusual, allergic reaction that can be seen with numerous antibiotics and many other medications. Thus, piperacillin-tazobactam is not generally regarded as being nephrotoxic.
The myth is that when used concurrently with vancomycin, piperacillin-tazobactam becomes nephrotoxic (despite piperacillin-tazobactam’s not being nephrotoxic on its own). To date, nobody has ever explained exactly why this would happen.
These studies were mostly published in obscure journals, so it took them a while to gain traction. Over time, additional studies were published, eventually receiving more attention…
Analysis of the myth origin in real time – It never made sense
I analyzed this issue in a 2016 blog post here. My findings at that point are summarized as follows:
- Piperacillin-tazobactam is a known pseudo-nephrotoxin. Piperacillin-tazobactam inhibits OAT1 and OAT3 (the organic anion transporters 1 and 3), leading to reduced secretion of creatinine into the urine. Thus, piperacillin-tazobactam causes an increase in serum creatinine. It does this without hurting the kidney or reducing the glomerular filtration rate.
- The fact that patients treated with piperacillin-tazobactam have higher creatinine levels is entirely predictable and fully explainable, since it is a proven pseudo-nephrotoxin.
- There is no laboratory data that piperacillin-tazobactam is nephrotoxic. In fact, blocking organic anion transporters has nephroprotective effects in some animal models (likely because this blocks the entry of nephrotoxins into renal tubule cells).
- There is no physiological mechanism whereby piperacillin-tazobactam would somehow conditionally act as a nephrotoxin solely in the presence of vancomycin. This is a very strange concept, with no defined biological basis.
- Clinical studies looking at vancomycin plus piperacillin-tazobactam have found higher creatinine levels (no surprise), but no increase in the need for hemodialysis.
In short, it was reasonably clear that the problem was how we were defining “kidney injury.” If you equate kidney injury with elevated creatinine levels, then anything artificially elevating the creatinine will cause “kidney injury.” There’s zero separation between wacky creatinine levels and an epidemic of “kidney injury.”
The Pile-On – Additional studies reinforce the myth
What happened from ~2016 to ~2022 is a bit odd. There was ongoing proliferation of more and more retrospective studies that correlated vancomycin plus piperacillin-tazobactam use with higher creatinine levels. These studies were mostly carbon copies of the initial studies discussed above.
These additional studies added little to the scientific literature, for the following reasons:
- The fact that piperacillin-tazobactam increases creatinine levels was already well established.
- The mechanism whereby piperacillin-tazobactam increases creatinine levels was already known at a molecular level (blockade of OAT-1 and OAT-3 transporters).
- These studies didn’t sort out the difference between elevated creatinine levels versus true kidney injury.
Roughly 50 studies were performed, but they all repeated the same flawed methodology. Fifty wrongs don’t make a right.
Nonetheless, this torrent of literature about the purported dangers of vancomycin plus piperacillin-tazobactam was highly effective in changing public opinion. When repeatedly exposed to the concept that vancomycin plus piperacillin-tazobactam is nephrotoxic, most practitioners eventually accepted this as being valid. This is an illustration of the illusory truth effect, a phenomenon whereby repeated information is perceived as more truthful than new information.
Review articles during this period continued to openly admit that there was no concrete evidence that vancomycin plus piperacillin-tazobactam actually cause harm. Regardless, there was a gradual and broad acceptance of the concept that vancomycin plus piperacillin-tazobactam is nephrotoxic.
Many hospitals shifted their preferred antibiotic algorithms to favor cefepime, rather than piperacillin-tazobactam.1,2 These misguided attempts at antibiotic stewardship provided intensivists and neurologists with a crash course in the diagnosis and management of cefepime neurotoxicity.
Deconstruction – Newer data disproves the myth
We are finally starting to see sufficient data emerge to disprove this myth, including three lines of evidence:
(#1/3) Laboratory studies
Three laboratories have independently investigated whether the addition of piperacillin-tazobactam to vancomycin increases the nephrotoxicity of vancomycin.3–5 Models utilized to test this hypothesis included:
- Sprague-Dawley rats (two studies).
- Mice (one study).
- Cell culture of rat NRK-52E kidney cells (one study).
The results of the three studies by different laboratories using various models are consistent:
- Vancomycin alone is nephrotoxic.
- The addition of piperacillin-tazobactam to vancomycin caused less nephrotoxicity than vancomycin alone. Thus, piperacillin-tazobactam was nephroprotective!
The fact that piperacillin-tazobactam is nephroprotective shouldn’t be surprising. Prior animal studies have also found that piperacillin is nephroprotective in various situations.6,7 The mechanism whereby piperacillin is nephroprotective appears to be inhibition of OAT1 and OAT3 (organic anion transporters-1 and -3) on the basolateral membrane of renal tubule cells. Inhibition of these transporters may block the entry of various nephrotoxic substances into renal tubule cells, possibly including vancomycin.8,9
(#2/3) Evaluation of patient-centered outcomes (e.g., hemodialysis)
Kidney function is generally closely linked with clinical outcomes (e.g., mortality and length of hospital stay). A true nephrotoxin should therefore be expected to affect patient-centered outcomes (e.g., hemodialysis, hospital length of stay, and mortality). Of course, a pseudo-nephrotoxin will not.
Studies have almost universally found that the combination of vancomycin plus piperacillin-tazobactam causes elevated creatinine levels. However, these same studies have failed to demonstrate an increase in hemodialysis.10,11
One illustration of this dissociation is a meta-analysis of studies comparing vancomycin plus meropenem versus vancomycin plus piperacillin-tazobactam (including a total of 14,511 patients).12 Despite a robust increase in “acute kidney injury” among patients treated with piperacillin-tazobactam, there was no increase in mortality or hemodialysis (figure below). Thus, elevated creatinine levels are dissociated from patient-centered outcomes.
(#3/3) Miano et al. – Biomarkers & urea refute the myth’s original basis
The entire genesis of the myth was a pile of studies correlating piperacillin-tazobactam use with elevated creatinine levels. These studies are severely limited by their myopic focus on creatinine, while ignoring other endpoints. Finally, after nearly a decade, a study has emerged that evaluates other endpoints besides creatinine.
This study is part of a prospective observational project evaluating patients with sepsis at the University of Pennsylvania, including the measurement of renal biomarkers. 192 patients were identified who were treated either with vancomycin plus cefepime or with vancomycin plus piperacillin-tazobactam.
- Piperacillin-tazobactam was associated with higher levels of creatinine and thus higher levels of “acute kidney injury” as defined by elevated creatinine.
- Piperacillin-tazobactam was associated with a trend towards lower levels of cystatin C (a renal biomarker that measures kidney injury).
- Piperacillin-tazobactam was associated with a trend towards lower rates of dialysis (RR 0.63; 95% confidence interval 0.3-1.3).
- There were no mortality differences (RR = 1.05; 95% confidence interval 0.79-1.41).
- Blood urea nitrogen levels were similar between groups. The ratio of blood urea nitrogen divided by creatinine (BUN/creatinine) was lower in patients receiving piperacillin-tazobactam.
This study demonstrates that piperacillin-tazobactam elevated creatinine without causing true kidney injury or affecting blood urea nitrogen levels. This indicates that piperacillin-tazobactam is behaving as a pseudo-nephrotoxin that merely causes an artificial elevation of creatinine levels. There might even be some weak signals that piperacillin-tazobactam is nephroprotective. Although this is only one study, its methodology is superior to the dozens of studies that solely evaluated creatinine levels.
Prevention of antibiotic-induced nephrotoxicity needs to focus on a real culprit: vancomycin
Antibiotics can cause nephrotoxicity. This is a real clinical problem which we need to avoid. To take a scientific, evidence-based approach to this problem we must focus on limiting antibiotics which are actually nephrotoxic (e.g., vancomycin, aminoglycosides, acyclovir).
One detrimental side effect of the myth of piperacillin-tazobactam nephrotoxicity is that it led practitioners into a misguided strategy to prevent renal failure. In many cases, due to concern for impending renal failure, practitioners continued vancomycin while discontinuing piperacillin-tazobactam! This is exactly the wrong thing to do.
Vancomycin is a nephrotoxin. Vancomycin exposure should be limited as able, to avoid renal failure. Strategies to limit vancomycin exposure include the following:
- Don’t use vancomycin in situations where MRSA isn’t known to be a pathogen (e.g., community-acquired urosepsis, community-acquired intra-abdominal infections, nonpurulent cellulitis).
- Vancomycin should only be used selectively for pneumonia (more on this here).
- When vancomycin is started empirically, strongly consider discontinuing it within 24-48 hours if there isn’t laboratory evidence that the patient has MRSA (e.g., positive MRSA nares PCR, culture positive for MRSA).
- Vancomycin should be dosed carefully with monitoring of levels. Especially pay close attention to vancomycin levels in patients who are developing renal failure – vancomycin levels may progressively rise, causing an exacerbation of renal failure in a vicious spiral.
- For patients at high risk of nephrotoxicity, consider using an antibiotic that isn’t nephrotoxic (e.g., linezolid or daptomycin). Additionally, linezolid is arguably superior to vancomycin for MRSA pneumonia.
- Piperacillin-tazobactam alone has negligible nephrotoxicity. There are rare cases of idiosyncratic tubulointerstitial nephritis, but overall piperacillin-tazobactam is not regarded as a nephrotoxin.
- Piperacillin-tazobactam is a pseudo-nephrotoxin, due to its effect of reducing renal secretion of creatinine. Thus, piperacillin-tazobactam will elevate the creatinine level, but this doesn’t reflect actual kidney damage.
- There is no physiological mechanism whereby piperacillin-tazobactam should selectively exert nephrotoxicity, solely in the presence of vancomycin.
- Meta-analyses likewise show that vancomycin plus piperacillin-tazobactam elevates creatinine levels, but this doesn’t translate into an increase in any patient-centered adverse outcomes (e.g., hemodialysis, mortality).
- Animal models show that the addition of piperacillin-tazobactam to vancomycin actually exerts a nephroprotective effect.
- A new study by Miano et al. demonstrates that although vancomycin plus piperacillin-tazobactam increases creatinine levels, patients don’t experience changes in renal biomarkers nor in blood urea nitrogen levels.
- Overall there is no evidence in humans or animals that piperacillin-tazobactam, when added on top of vancomycin, causes true kidney injury or clinical harm.
- The concept that piperacillin-tazobactam exerts some sort of weird, selective nephrotoxicity solely in the presence of vancomycin is a myth.
Related:
- 2022 Miano et al. Association of vancomycin plus piperacillin–tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study. Open Access in Intensive Care Medicine.
- 2016 PulmCrit Wee – Is piperacillin-tazobactam nephrotoxic?
References
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1.Kimball J, Deri C, Nesbitt W, Nelson G, Staub M. Development of the Three Antimicrobial Stewardship E’s (TASE) Framework and Association Between Stewardship Interventions and Intended Results Analysis to Identify Key Facility-Specific Interventions and Strategies for Successful Antimicrobial Stewardship. Clin Infect Dis. 2021;73(8):1397-1403. doi:10.1093/cid/ciab430
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2.Watkins R, Deresinski S. Increasing Evidence of the Nephrotoxicity of Piperacillin/Tazobactam and Vancomycin Combination Therapy-What Is the Clinician to Do? Clin Infect Dis. 2017;65(12):2137-2143. doi:10.1093/cid/cix675
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3.He M, Souza E, Matvekas A, Crass R, Pai M. Alteration in Acute Kidney Injury Potential with the Combination of Vancomycin and Imipenem-Cilastatin/Relebactam or Piperacillin/Tazobactam in a Preclinical Model. Antimicrob Agents Chemother. 2021;65(4). doi:10.1128/AAC.02141-20
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4.Chang J, Pais G, Valdez K, Marianski S, Barreto E, Scheetz M. Glomerular Function and Urinary Biomarker Changes between Vancomycin and Vancomycin plus Piperacillin-Tazobactam in a Translational Rat Model. Antimicrob Agents Chemother. 2022;66(3):e0213221. doi:10.1128/aac.02132-21
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5.Pais G, Liu J, Avedissian S, et al. Lack of synergistic nephrotoxicity between vancomycin and piperacillin/tazobactam in a rat model and a confirmatory cellular model. J Antimicrob Chemother. 2020;75(5):1228-1236. doi:10.1093/jac/dkz563
-
6.Hayashi T, Watanabe Y, Kumano K, et al. Protective effect of piperacillin against nephrotoxicity of cephaloridine and gentamicin in animals. Antimicrob Agents Chemother. 1988;32(6):912-918. doi:10.1128/AAC.32.6.912
-
7.Hayashi T, Watanabe Y, Kumano K, et al. Protective effect of piperacillin against the nephrotoxicity of cisplatin in rats. Antimicrob Agents Chemother. 1989;33(4):513-518. doi:10.1128/AAC.33.4.513
-
8.Li H, Yang Q, Gui M, et al. Changes of renal transporters in the kinetic process of VCM-induced nephrotoxicity in mice. Toxicol Res (Camb). 2021;10(4):687-695. doi:10.1093/toxres/tfab048
-
9.Shimada I, Iwata C, Taga S, et al. Enhanced renal clearance of vancomycin in rats with carcinogen-induced osteosarcoma. Anticancer Res. 2012;32(3):823-829. https://www.ncbi.nlm.nih.gov/pubmed/22399600
-
10.Bellos I, Karageorgiou V, Pergialiotis V, Perrea D. Acute kidney injury following the concurrent administration of antipseudomonal β-lactams and vancomycin: a network meta-analysis. Clin Microbiol Infect. 2020;26(6):696-705. doi:10.1016/j.cmi.2020.03.019
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11.Blair M, Côté J, Cotter A, Lynch B, Redahan L, Murray P. Nephrotoxicity from Vancomycin Combined with Piperacillin-Tazobactam: A Comprehensive Review. Am J Nephrol. 2021;52(2):85-97. doi:10.1159/000513742
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12.Alshehri A, Alzahrani M, Abujamal M, et al. Comparative Risk of Acute Kidney Injury Following Concurrent Administration of Vancomycin with Piperacillin/Tazobactam or Meropenem: A Systematic Review and Meta-Analysis of Observational Studies. Antibiotics (Basel). 2022;11(4). doi:10.3390/antibiotics11040526
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Great summary of recent science dispelling this myth. I’ve been beating this drum for years…always made a point of teaching my trainees that eventually people would wake up and stop the nonsense. It just never made sense from the get-go, and there was decades-old evidence to explain the Scr increase. Can’t believe the FDA actually went so far as to put a warning in the P/T product insert about it.
This is so important review. Now I can argue with which I am somewhat skeptical about the real nephrotoxicity of this combination when all my colleagues get alarmed by rising in creatinine and everyone across the board conclude as AKI.
Your article is excellently explains everything and provides an avenue to analyze our data.
There is actually little evidence of nephrotoxicity of vancomycin beyond theoretical considerations. That pertains to modern formulations and careful dosing anyway. Please entertain us all with some good literature if you think I am wrong.
A great article otherwise. Thanks.
In critically ill patients, anti-anaerobic antibiotics increase risk of adverse clinical outcomes (ersjournals.com)
Should we be using zosyn though?
HUGE fan of your work! I feel that the main thrust of the argument here – focusing on debunking the postulate that pip-tazo becomes a nephrotoxin in the presence of vancomycin – is a bit of a strawman. Does pip-tazo become nephrotoxic in the presence of vancomycin? Does pip-tazo potentiate vanc nephrotoxicity? Are there excipients in the two bags that have some yet-to-be-uncovered interaction that causes AKI? I’m content to let researchers ask and answer those questions. What clinicians really need to know is whether “vosyn” is relatively more nephrotoxic (to humans) than vanc/cefepime or other combinations that might be… Read more »