AKI From Combined Vancomycin and Piperacillin/Tazobactam: How Real Is the Risk?

Linda L. Cheng, PharmD


December 30, 2014


Does concomitant use of piperacillin/tazobactam with vancomycin increase the risk for nephrotoxicity?

Response from Linda L. Cheng, PharmD
PGY-1 Pharmacy Practice Resident, Albany Medical Center, Albany, New York

Vancomycin is a glycopeptide antibiotic that is primarily active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The beta-lactam/beta-lactamase inhibitor combination piperacillin/tazobactam (PT) is a broad-spectrum antibiotic with antipseudomonal activity. Vancomycin and PT are commonly used together as broad empirical therapy for hospitalized patients.[1]

Whereas an association between vancomycin and nephrotoxicity is well documented, PT is not commonly associated with nephrotoxicity.[2,3] However, there have been several recent reports of increased nephrotoxicity associated with the concurrent use of vancomycin and PT. A proposed mechanism is penicillin-associated (including semisynthetic agents, such as PT) acute interstitial nephritis, which may augment vancomycin-associated nephrotoxicity from renal cellular necrosis.[1]

Earlier this year, four single-center retrospective cohort studies found an association between concurrent use of vancomycin and PT and increased risk for nephrotoxicity compared with vancomycin without PT or vancomycin and concurrent cefepime.[1,2,4,5] All four studies included adult patients who received antibiotic therapies for at least 48 or 72 hours. The definition of nephrotoxicity was similar among the studies (usually, increase in serum creatinine by 0.5 mg/dL or ≥ 1.5 times baseline). Exclusion criteria for each study included history of renal impairment, although the exact criteria differed with each study.

The findings from the studies are summarized below:

  • Concomitant use of PT with vancomycin was associated with increased nephrotoxicity, with an adjusted odds ratio (OR) of 5.36 (95% confidence interval [CI], 1.41-20.5).[4]

  • Rates of nephrotoxicity were significantly higher in patients receiving vancomycin/PT than in those receiving vancomycin without PT (16.3% vs 8.1%; P = .041). The adjusted OR for developing nephrotoxicity with vancomycin/PT was 2.48 (P = .032).[2]

  • Rates of nephrotoxicity were significantly higher in patients receiving vancomycin/PT than in those receiving vancomycin and cefepime (unmatched analysis: 34.8% vs 12.5%; P < .001 and matched analysis: 36.4% vs 10.9%; P = .003). Patients receiving vancomycin/PT were 5.67 times more likely to develop nephrotoxicity than were patients receiving vancomycin/cefepime (OR, 5.67; 95% CI, 1.66-19.33).[1]

  • Rates of nephrotoxicity were nonsignificantly higher in diabetic patients with osteomyelitis receiving vancomycin/PT compared with a similar population receiving vancomycin/cefepime (29.3% vs 13.3%; P = .099). Vancomycin/PT was associated with an OR of 3.45 for nephrotoxicity (95% CI, 0.96-12.40; P = .057).[5]

The results of these studies have some limitations. More research, ideally with larger sample sizes across multiple centers and a prospective design controlling for potential biases and confounding factors, is needed to better understand this trend.

Nevertheless, in light of these findings, healthcare professionals should continue to monitor their patients for early signs of impaired renal function and practice increased vigilance if concomitant therapy with vancomycin and PT is initiated. Factors that may increase risk for nephrotoxicity, such as existing renal impairment, older age, and initiation of concomitant nephrotoxic agents, should also be considered. For patients at increased risk, it may be necessary to obtain vancomycin trough levels earlier in therapy and to monitor for even small changes in renal function (ie, increased serum creatinine/blood urea nitrogen level and decreased urine output).


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