Increased Nephrotoxicity With Piperacillin-Tazobactam and Vancomycin

Apryl L. Jacobs, PharmD


October 02, 2017


As evidence of an increased risk for nephrotoxicity with vancomycin and piperacillin-tazobactam grows, is it time to change practice?

Response from Apryl L. Jacobs, PharmD
PGY-1 Pharmacy Resident, Albany Medical Center, Albany, New York

The addition of an antipseudomonal beta-lactam to vancomycin is a common approach in hospitalized patients with risk factors for resistant pathogens.[1] Several publications have brought attention to the potential for synergistic nephrotoxicity with the combination of piperacillin-tazobactam and vancomycin (TZP-VAN) compared with vancomycin with or without alternative beta-lactam antibiotics.[1,2,3] The most recent evidence regarding the potential for TZP-VAN–associated nephrotoxicity and the approaches to minimize this risk in practice are reviewed herein.

Vancomycin-associated nephrotoxicity is well described. Its incidence is thought to be increased by several risk factors, including a daily dose above 4 g, patient weight above 101 kg, extended duration of treatment, preexisting renal dysfunction, increased severity of illness, hypotension, elevated trough concentrations, and receipt of concomitant nephrotoxic medications.[2,4]

In contrast, nephrotoxicity with piperacillin-tazobactam is much less common and has only been described in a few case reports of acute interstitial nephritis.[3]

Increased incidence of acute kidney injury (AKI) with TZP-VAN is speculated to be the result of the combined effects of vancomycin-associated cellular necrosis and piperacillin-tazobactam–associated acute interstitial nephritis or decreased vancomycin clearance caused by piperacillin-tazobactam via an unknown mechanism.[2,3]

Hammond and colleagues[2] conducted a meta-analysis of 14 observational cohort studies, including 3549 adult and pediatric patients, to evaluate the risk for AKI with TZP-VAN compared with vancomycin monotherapy or vancomycin in combination with another beta-lactam using variable definitions of AKI. Per the overall analysis, the incidence of AKI was significantly increased in patients treated with TZP-VAN compared with those receiving vancomycin with or without an alternative beta-lactam. In the adjusted analysis, the odds of AKI were 3.11-fold higher in TZP-VAN–treated patients versus those receiving either vancomycin alone or vancomycin plus another beta-lactam. The difference was also statistically significant when comparing TZP-VAN with cefepime plus vancomycin (CEF-VAN); CEF-VAN or meropenem plus vancomycin (MER-VAN); and vancomycin plus another beta-lactam. Similar trends were seen in children, adults, the critically ill, and the non–critically ill. Of note, there was no difference in AKI rates with TZP-VAN versus vancomycin alone, which may be due to inherent differences in the patient groups.

Giuliano and colleagues[3] conducted a similar meta-analysis of 15 observational cohort studies, including 3258 adult patients, to evaluate the risk for AKI using variable definitions of AKI in patients who received TZP-VAN compared with those who received vancomycin alone; vancomycin plus cefepime or meropenem; or vancomycin with or without another beta-lactam. These researchers found a statistically significant difference in AKI risk with TZP-VAN versus vancomycin with or without another beta-lactam. In this analysis, the odds of AKI were 3.65-fold higher in patients receiving TZP-VAN versus vancomycin with or without beta-lactam therapy. In contrast to the findings by Hammond and colleagues, the difference remained significant for TZP-VAN versus vancomycin alone; however, the relationship lacked significance when evaluating TZP-VAN versus vancomycin plus another beta-lactam.

While both of these analyses provide an overall estimate of the risk for AKI with TZP-VAN, the lack of randomized controlled trials, nonstandardized definitions of AKI, and significant heterogeneity limit the results.

Since the meta-analyses above were conducted, a large retrospective cohort study by Rutter and colleagues[1] assessing the risk for AKI with TZP-VAN was published. This study is the largest to date, evaluating the incidence of AKI in nearly 4200 adult patients, without a history of renal disease, receiving TZP-VAN or CEF-VAN. The risk, injury, failure, loss of kidney function, and end-stage kidney disease (RIFLE) criteria were used to assess the development of AKI, and patients were matched on the basis of demographics, renal function, and nephrotoxicity risk factors. The TZP-VAN group maintained a significantly higher incidence of AKI versus the CEF-VAN group (21.4% versus 12.5%, P < .0001) in the final matched analysis, a trend consistent for all RIFLE criteria classifications. In the final analysis, TZP-VAN was associated with 2.18-fold greater odds of AKI versus the CEF-VAN group, which was statistically significant. When combining data from both groups, vancomycin doses between 3000 mg and 3999 mg were correlated with an increased risk for AKI compared with vancomycin dosing between 1500 mg and 1999 mg, but significant differences for other dose ranges were not found. Vancomycin trough was not associated with increased AKI risk; however, duration of vancomycin for greater than 7 days was. The risk for AKI was significantly lower with piperacillin-tazobactam at 3.375 g intravenously every 6 hours compared with 4.5 g intravenously every 6 hours, suggesting potential dose-dependent toxicity.

Overall, the literature to date is suggestive of an increased risk for nephrotoxicity in patients receiving TZP-VAN versus vancomycin with or without alternative beta-lactams. In one meta-analysis, there was nearly a fourfold greater odds of developing AKI with TZP-VAN versus vancomycin alone.[3] The odds of developing AKI with TZP-VAN versus vancomycin plus an alternative beta-lactam ranged from 2.18- to 7.14-fold in three recent studies.[1,2,3]

Although the evidence is compelling, rigorous prospective studies are necessary. At this time, though, there appears to be enough data to support the avoidance of the combination of TZP-VAN whenever possible. This could involve stopping both agents or switching one (or both) agents to alternative therapy. Carreno and colleagues[5] conducted a prospective, randomized controlled trial that evaluated switching from vancomycin to a nonnephrotoxic alternative antimicrobial, such as ceftaroline, daptomycin, or linezolid, in 103 patients who had at least two risk factors for AKI. No significant difference in AKI incidence was found using the 2009 vancomycin therapeutic guideline definition of nephrotoxicity and the Acute Kidney Injury Network (AKIN) definition of AKI; however, this trial was limited by a small sample size.

Avoidance of broad-spectrum empiric coverage also may be reasonable in some types of infections to reduce AKI risk. Jenkins and colleagues[6] evaluated a cohort of 322 patients hospitalized with skin and soft tissue infection and found that Staphylococcus aureus, particularly methicillin-resistant S aureus (MRSA), and streptococci were isolated from >95% of positive cultures. This finding supports the idea that narrow empiric therapy may be sufficient for infections in which likely pathogens are suspected. As always, antimicrobial stewardship and education can aid in the appropriateness of therapy. For gram-positive coverage (ie, MRSA or enterococcus), alternative options could include linezolid, daptomycin, or ceftaroline. For gram-negative coverage, meropenem, cefepime, or a fluoroquinolone could be substituted.[5] However, substitution may result in more expensive alternatives and necessitates evaluation on a case-by-case basis.

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