Recently, a nephrologist I work with chased me down to ask my opinion of the new and interesting study that concludes concomitant vancomycin and piperacillin-tazobactam (hereforth to be called vancosyn) was more nephrotoxic than concomitant vancomycin and cefepime (vancopime). “Yes, indeed, I have heard the data but which study are you calling new?” I wondered. “Why aren’t we doing anything about it?” he asked. Hmmm, why indeed?
Background
Combinations of vancomycin and anti-pseudomonal beta-lactam antibiotics are often prescribed empirically in patients with a myriad of infectious illnesses with the intent to give “broad coverage”. The vancomycin and piperacillin-tazobactam (Zosyn) combination is particularly used often. It is a decerebrate regimen that is easy to give because most hospitals carry both and do not restrict their use up front. The combination covers gram positives, gram negatives, anaerobes and has good penetration into abdomen, lungs, urine, and skin. COVERED!
Elderly woman comes from the nursing home with fever and decreased responsiveness and is found to have “dirty urinalysis” and “basilar infiltrates” on chest x-ray. Vancosyn to the rescue! She is from a nursing home after all! Middle-aged man scraped his shin while fishing in a nearby river 2 days ago and now presents with a red, hot, swollen leg but otherwise is not toxic-looking. Vancosyn! It looks like MRSA and he was in a river. Young man with diabetes has a foot ulcer that looks infected. Vancosyn, do not fear! He’s diabetic so it could be pseudomonas also we can’t forget MRSA!
Yes, I do dislike the “just in case” widespread use of this classic vancosyn combination from an antimicrobial stewardship viewpoint. I particularly abhor when the combination is used as an antipyretic. Actually, no antibiotic should be used as an antipyretic. Whenever I consult on a patient who is not on the vancosyn combo, I wonder what the thought process was behind the choice of other antibiotics….and then I see the charted penicillin allergy! Of course! That said, I am guilty of sometimes leaving patients on the vancosyn combination while waiting for culture results to come back. I know.
But this is not an antimicrobial stewardship post. It is a nephrotoxicity post. So moving on.
The Vancosyn vs. Vancopime Study
I’m not exactly sure which study my friendly nephrologist was referring to. I assume the most recent. This was a meta-analysis of 14 observational studies that found a three-fold increased odds of acute kidney injury (nephrotoxicity) with the vancomycin + piperacillin-tazobactam combination as compared to vancomycin monotherapy or vancomycin + cefepime or meropenem combinations. This is in keeping with a prospective study published ahead of print last year that sparked a series of discussions in the FOAM world that has not yet stopped.
Acute kidney injury (AKI) occurs frequently in hospitalized patients and it’s not uncommon for medications to be the cause. Piperacillin-tazobactam however is rarely associated with nephrotoxicity. Like other beta-lactam antibiotics it can cause acute interstitial nephritis (AIN) but according to the package insert, incidence of AKI is less than 1%. It has however been linked to delayed renal recovery in critically ill patients.
Vancomycin on the other hand was once known as Mississippi mud and has long been associated with nephrotoxicity. Vancomycin is also known to potentiate the nephrotoxicity of aminoglycosides.
The mechanism by which concurrent use vancomycin and piperacillin-tazobactam causes AKI is not clear in these retrospective studies. The AKI generally occurred within the first 4-7 days of therapy and was usually reversible if the offending agents were stopped.
What Can We Do About Vancosyn Nephrotoxicity?
We can think hard to decide if our patients truly need combination vancomycin + beta-lactam (whether piperacillin-tazobactam, cefepime, or a carbapenem). ID physicians have harped about the indiscriminate use of antibiotics for years to no effect. Zosyn was FDA approved in 1996 and saw an 84% increase in its use between 2002 and 2006. Mind-boggling. If the risk of kidney failure and the wrath of a nephrologist are going to be what it takes for physicians to carefully consider our choice of antibiotics so be it. My cynical self sees a pendulum switch to vancomycin + cefepime +/- metronidazole for everyone if the rumbling surrounding vancomycin + Zosyn nephrotoxicity continues. In fact, vancomycin + cefepime +/- metronidazole was the decerebrate combination at my institution when I was a fellow. Then we were discouraged from using this regimen in patients with kidney failure because of the risk of neurotoxicity (seizures or encephalopathy). You just can’t win in medicine! Damned if you do. Damned if you don’t.
We should be aware of comorbidities that are already associated with the risk of developing AKI such as pre-existing kidney failure, diabetes, old age, use of other nephrotoxic agents, and the presence of sepsis.
We should closely monitor vancomycin trough levels and watch out for early signs of kidney injury such as oliguria and rising creatinine.
We can self-steward and narrow therapy before the 4-7 day window. That will of course mean investing in improved rapid diagnostic tests so we have answers sooner. In one hospital I have worked in it can take up to 4 days for the lab to report that the gram positive bacteria in the blood culture is a coagulase negative staphyloccocus, which often doesn’t need to be treated. That is 4 days of unnecessary vancomycin receipt. Luckily, if appropriate diagnostics are done early very few patients will still need to be on combination empiric therapy at day 4.
We can have our nephrologists scold other physicians about their antimicrobial choices. Who knows. They might be more efficient antimicrobial stewards than us.
Conclusion
The studies do suggest possible harm (worsened AKI) but no effect on mortality and morbidity so far. We probably should wait for multi-center prospective randomized studies with large numbers of patients before completely vilifying vancomycin + Zosyn regimens. In the meantime, I intend to get my friendly nephrologist onto Twitter because he’s a year late on the hot debate this topic generated last year in the FOAM world. And of course, lets be mindful of the antibiotics we are prescribing and why.
Appendix
Broad coverage: also known as “broad spectrum” and “big gun” – an oft-used term that intends to convey that any bacteria out there is being targeted; but in fact there’s no such thing as broad coverage. There will always be holes. In addition, ampicillin is technically a broad-spectrum antibiotic. Hmmm!
Decerebrate: requires no thought process
Dirty urinalysis: the urine was cloudy, or there was any amount of white cells or bacteria (and often skin cells!) in the microscopic analysis
FOAM/#FOAMed: acronym for Free Open Access Medical Education ie. medical education for anyone at anytime anywhere in the world using all forms of social media. It’s free and it’s fun.
MRSA: pronounced Merr-sa, stands for methicillin resistant Staphylococcus aureus, one of those superbugs everybody is worried about. 1-2% of the population are “colonized” (carry MRSA on/in their body without having illness).
Superbug: A favourite term of lay-people to describe a micro-organism that is resistant to at least one or more commonly used antibiotics. For example, gonorrhea is a superbug. Yes indeed, chew on that.
Toxic-looking: the patient looks very ill
References
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