Rounding in the intensive care unit (ICU), you’re three patients deep with 20-plus to go. Already you’re bobbing in a vancomycin-piperacillin-tazobactam (vanc-PT) sea, your mouth salty from the carrier. Every patient is on both, and you suspect the nurses and therapists are too. The intern appears to have red man syndrome, and you begin to wonder about your own vancomycin level. Is it therapeutic? Has it affected your kidneys?

Rather than outsource 100% of your thought processes to house staff and hospital culture, you pause to reflect. Empirical coverage with broad-spectrum antibiotics in the ICU is common and consistent with guidelines. Sepsis is more frequent than a Detroit Pistons loss, and time to coverage drives outcomes. But doesn’t vanc-Zosyn come at a cost? Doesn’t it damage the kidneys?

Vancomycin’s effects on the kidney border on urban legend. I’ve been told it doesn’t cause kidney injury since they changed from the Mississippi mud formulation — or was that term just used for the title of an editorial? Another gadfly might tell you that the levels required to cause harm are above the therapeutic range and we need not worry. There’s some truth to both legends, given that formulation impurities have been corrected and the Infectious Diseases Society of America (IDSA) says the vancomycin and nephrotoxicity data are subject to confounding. They also note that vancomycin toxicity is most likely after extended infusions targeting trough levels > 15-20 mg/L and is otherwise uncommon. Urban legend somewhat dispelled, vancomycin may still cause nephrotoxicity, but less so sans Mississippi mud or higher targets.

What about the vanc-PT combination? In 2017, my academic program reviewed a paper comparing acute kidney injury (AKI) with vanc-PT vs vanc-cefepime. AKI rates were three times higher with vanc-PT. Vanc trough levels were associated with AKI in the presence of cefepime but not PT, a finding the authors attributed to synergistic vanc-PT toxicity that’s unrelated to dosing. I never considered abandoning vanc-PT, but the nephrotoxicity concern remained buried in my subconscious beside maintenance of certification (MOC) exams, aspirational recycling, and other phenomena I don’t want to deal with but can’t seem to forget.

A review published in 2021 provided the deep dive I never had time to perform. Although I recommend reading it for yourself, I’ll try and summarize here. Just like the 2023 college football playoff rankings, the reality is complicated. To start, most studies (including the 2017 paper I cited earlier) are retrospective and observational. Vanc-PT is typically used for hospitalized patients who are pretty sick and often have sepsis. There’s usually suspicion for drug-resistant organisms, thus further selecting for the presence of comorbid disease — in short, confounding by indication and related to multiple patient factors that increase the risk for renal injury. Many meta-analyses have been done, but grouping flawed studies just amplifies the bias and instills false confidence. Finally, whereas serum creatinine changes are well described, the effects on long-term clinical outcomes are not. After reading this review, I thought vanc-PT nephrotoxicity should have stayed buried in my subconscious.

Sepsis and hospital/ventilator-associated pneumonia (HAP/VAP) guidelines don’t help much here. Surviving Sepsis makes no comment on specific antibiotics. The American Thoracic Society/IDSA HAP/VAP guidelines make a case against pairing vancomycin with carbapenems, aminoglycosides, and other drugs for various reasons but make no distinction between vanc-PT vs vanc plus a cephalosporin (cefepime or ceftazidime). Cost may be an issue within a given system, but PT, cefepime, and ceftazidime are all generic.

This past year we finally got what we needed: a prospective randomized study called ACORN. The authors randomly assigned 2511 patients to receive PT vs cefepime (77% of whom were also receiving vancomycin). Renal outcomes weren’t different in the PT group but, patients in the cefepime arm experienced fewer days alive and free of coma or delirium at day 14 (a secondary outcome). On balance, these results favor PT. These data are better than anything else we have. It’s not even close.

In summary, the vanc-PT association with nephrotoxicity was overblown. It is no more. In a high-acuity unit, you’d better be drowning in it. You can stop worrying about effects on the kidney. Now it’s time to go sign up for my MOC exam.