There are a few reasons why piperacillin/tazobactam (Zosyn) is not usually my first choice for a broad-spectrum gram-negative agent in the ED. First, at my institution, the Pseudomonas aeruginosa susceptibilities to pip-tazo are lower than that for cefepime. Second, pip-tazo does not have great CNS penetration, especially compared to ceftriaxone, cefepime, or even meropenem. Third, do we really need the anaerobic coverage that pip-tazo provides for every sick patient? Pip-tazo is great for empiric treatment of intra-abdominal and severe diabetic foot infections, but may not be needed for a hospital-acquired pneumonia. Fourth, with its frequent dosing (every 6 hours), too often the second dose is missed if the patient is still boarding in the ED.

Don’t get me wrong, pip-tazo is a great drug. I just want to have it around in the future to treat difficult gram-negative and anaerobic infections.

Link to Acute Kidney Injury

2012 – SCCM Abstracts

Two abstracts presented at the 2012 Society of Critical Care Medicine meeting suggested that patients who received vancomycin PLUS pip-tazo OR pip-tazo alone had a higher risk of developing acute kidney injury (AKI) compared to patients who received vancomycin alone.

Hellwig T, et al.¹

Retrospective evaluation of all adult patients admitted to Sanford USD Medical Center over a 6 month period who received vancomycin +/- pip-tazo for more than 48 hours. AKI was defined as an increase of serum creatinine > 0.5 mg/dL or a 50% increase from baseline. Of the 735 patients evaluated, the incidence of AKI for vancomycin alone, pip-tazo alone, and combination of vancomycin + pip-tazo were 4.9%, 11.1%, and 18.6%, respectively (vancomycin vs. pip-tazo, p = 0.014; vancomycin vs. combination, p = 0.005). When looking at just the ICU patients, a similar result was seen. Incidence of AKI was 6.0%, 12.2%, and 21.2%, respectively (vancomycin vs. pip-tazo, p = 0.279; vancomycin vs. combination, p = 0.005).

Min E, et al.¹

Evaluation of 140 surgical ICU patients over the course of a year who received vancomycin +/- pip-tazo for at least 48 hours. AKI was defined as an increase in serum creatinine more than 1.5 times baseline during antibiotic therapy. The authors controlled for severity of illness and concomitant use of other nephrotoxic antibiotics. The incidence of AKI was higher in the vancomycin + pip-tazo group (40.5%) compared to the vancomycin alone group (9.0%, p < 0.001).

My thoughts: Two abstracts are certainly not enough to demonstrate causation, but it is an interesting association nonetheless.

2014 – Four Retrospective Studies

Is it really true? Could pip-tazo actually be increasing risk of AKI?

Moenster RP, et al.²

A retrospective cohort study was conducted of all diabetic patients with osteomyelitis treated with vancomycin plus either pip-tazo or cefepime for at least 72 hours at a VA Medical Center between January 2006 and December 2011. The primary outcome was development of AKI, defined as an increase in SCr of 0.5 mg/dL or 50% of baseline. 139 patients met inclusion criteria; 109 in the pip-tazo group and 30 in the cefepime group. In patients receiving vancomycin + pip-tazo, 29.3% (32/109) developed AKI compared to 13.3% (4/30) treated with vancomycin + cefepime (p=0.099). A multiple logistic regression analysis identified weight and average vancomycin trough as the only significant predictors of AKI. The authors were unable to detect a statistically significant difference in AKI between groups; however, power was not met.

Gomes DM, et al.³

A retrospective matched cohort of 224 patients receiving vancomycin + pip-tazo OR vancomycin + cefepime for more than 48 hours. Included patients had no preexisting kidney disease. AKI was defined according to the Acute Kidney Injury Network criteria. The incidence of AKI was higher in the pip-tazo + vancomycin group (34.8%) compared with the cefepime + vancomycin group (12.5%) in the unmatched analysis (p<0.0001). After adjusting for potential sources of bias through propensity score matched pairs and conditional logistic regression, pip-tazo + vancomycin combination therapy (p=0.003) was an independent predictor of AKI. There were no significant differences in time to AKI or hospital length of stay between groups.

Meaney CJ, et al.⁴

This group retrospectively evaluated 125 adult internal medicine patients receiving vancomycin treatment for at least 72 hours. Nephrotoxicity, defined as an increase in serum creatinine of 0.5 mg/dl or 50% above baseline (whichever was larger), occurred in 17 (13.6%) of 125 patients. On multivariable logistic regression analysis, after controlling for hypotensive episodes, Charlson Comorbidity Index, and baseline creatinine clearance, concomitant use of pip-tazo was associated with increased vancomycin-associated nephrotoxicity (adjusted odds ratio 5.36, 95% confidence interval 1.41-20.5). Thirteen of the 58 patients (22.4%) of patients receiving the combination developed nephrotoxicity. They concluded that vancomycin-associated nephrotoxicity is prevalent among internal medicine patients, with 5.36-fold higher odds if pip-tazo is concomitantly administered.

Burgess L, et al.⁵

A retrospective, single-center cohort of 191 internal medicine and ICU patients receiving vancomycin or vancomycin + pip-tazo for at least 48 hours. AKI was defined as an increase in serum creatinine more than 1.5 times baseline during antibiotic therapy. Nephrotoxicity developed in 8 (8.1%) of 99 patients in the vancomycin group and in 15 (16.3%) of 92 patients in the combination group (1-sided χ2 test, p=0.041). A steady-state vancomycin trough concentration of 15 μg/ml or greater was also associated with an increased risk of the development of nephrotoxicity. This is yet another study where it is difficult to conclude that pip-tazo is the cause of increased AKI compared to vancomycin alone. If the groups are equally sick, then what is the rationale for using two antibiotics compared to one?

My thoughts: Four retrospective studies are also not enough to demonstrate absolute causation, but they certainly add some strength to the association.

2016 – It’s now getting popular to study this phenomenom!

Karino S, et al.⁷

A combination of retrospective cohort and case-control studies was performed with a primary objective to evaluate the incidence of AKI between intermittent versus extended infusions of pip-tazo in combination with vancomycin. Overall, AKI occurred in 105/320 (33%) of the cohort receiving combination therapy. There were similar rates in those receiving intermittent (53/160 (33.1%)) and extended infusions (52/160 (32.5%)) of pip-tazo. The authors identified independent risk factors for AKI of: having a documented Gram-positive infection, the presence of sepsis, receipt of a vancomycin loading dose, and receipt of any concomitant nephrotoxin.

Hammond DA, et al.⁸

This was a retrospective cohort study of 122 ICU patients (medical, surgical, and neuroscience) who received at least 48 hours of combination therapy with vancomycin and pip-tazo (49 patients) or vancomycin and cefepime (73 patients). The primary outcome was development of AKI as determined by the Acute Kidney Injury Network criteria. Overall, 37 patients (30.3%) developed AKI. The incidence of AKI was similar in the pip-tazo group compared with the cefepime group (32.7% vs 28.8%, p=0.647).

Lorenz M, et al.⁹

Lorenz et al described a pip-tazo restriction implemented at a single institution secondary to antimicrobial stewardship. They reported a mean reduction of 0.5 days of pip-tazo therapy in the post-implementation group (P = 0.224). Among patients who received both vancomycin + pip-tazo, there was no difference in AKI incidence between the groups in the pre- and post-implementation period group, 11.6% vs 12.1%, respectively (P>0.05). Overall, 11.8% (22/186) of patients who received therapy with pip-tazo + vancomycin developed AKI, compared with 1.7% (1/56) who received pip-tazo monotherapy (P < 0.0001).

McQueen KE, et al.¹⁰ (1st pediatric study)

The first pediatric study was published this year. A retrospective, single-center, cohort study of 79 patients treated with vancomycin and 106 patients treated with vancomycin and pip-tazo. AKI was defined as at least a 100% increase in serum creatinine or an increase of ≥0.5 mg/dL from the baseline value. Nephrotoxicity developed in 3 of 79 patients (3.8%) in the vancomycin group and in 25 of 106 patients (23.6%) on combination therapy (p = 0.0001). In the combination group, having higher serum vancomycin trough concentrations increased the risk of nephrotoxicity (RR 5.22, CI 2.407-11.306, p < 0.0001). Although the authors did attempt to control for some factors, including similar ICU admissions between the groups, it is not possible to exclude that sicker patients received the combination more often which may have influenced the incidence of AKI in that group.

Navalkele B, et al.¹¹

A retrospective matched cohort study was performed with patients who received combination therapy with either vanc + cefepime or vanc + pip-tazo for ≥ 48 hours. Patients were excluded if their baseline serum creatinine was >1.2mg/dl or they were receiving renal replacement therapy. Patients were matched based on severity of illness, ICU status, duration of combination therapy, vancomycin dose and number of concomitant nephrotoxins. The primary outcome was the incidence of RIFLE criteria-defined AKI. Patients in the VPT group had a higher incidence of septic shock and skin and soft tissue infections. AKI rates were significantly higher in the vanc + pip-tazo than the vanc + cefepime group (81/279 (29%) vs. 31/279 (11%), p<0.0001.) In multivariate analysis, therapy with vanc + pip-tazo was an independent predictor for AKI (HR=4.27, 95% CI 2.73-6.68). Among patients who developed AKI, the median onset was more rapid in the vanc + pip-tazo compared to the vanc + cefepime group (3 vs. 5 days, p=<0.0001).

Proposed Mechanism

The exact mechanism behind AKI due to beta-lactams and vancomycin is unknown. The two most common proposed mechanisms for pip-tazo induced AKI include acute interstitial nephritis (AIN) or toxic effects on the renal tubule. It could be an additive effect of AIN and direct cellular necrosis.^12–18 Some have suggested a decreased clearance of vancomycin by pip-tazo resulting in vancomycin accumulation, however the one prospective study reported no difference in mean vancomycin levels between the two groups.⁶

Possible Risk Factors

Karino et al found 4 independent risk factors for AKI in the vanc + pip-tazo cohort:⁷

• Having a documented Gram-positive infection
• The presence of sepsis
• Receipt of a vancomycin loading dose (OR 2.22, 95% CI 1.05-4.71)
• Receipt of any concomitant nephrotoxin (OR 2.44, 95% CI 1.41-4.22)

Extended infusions of pip-tazo do not seem to reduce the risk of AKI compared to standard infusions.¹⁹

Final Thoughts

• It seems time to acknowledge there is an association between pip-tazo and risk of AKI (with vancomycin). There have been 12 different groups with internal medicine, pediatric, and ICU patients (including a prospective study) demonstrating this adverse effect. Three meta-analyses, with 963 patients, 3,528 patients, and 3,549 patients, drew the same conclusion.^20,21 ,²²
• The prospective study supports the association, even with vancomycin trough levels the same in each group.
• In ICU patients specifically, the results have been conflicting. All 3 ICU studies reported a high rate of AKI with vanc + pip-tazo (21.2-40.5%). Two of the ICU studies showed a significantly higher rate in the combo group compared with vancomycin alone; the other did not demonstrate a difference when pip-tazo was replaced with cefepime. A prospective study in ICU patients is needed.
• Proposed mechanisms for pip-tazo induced AKI include acute interstitial nephritis or toxic effects on the renal tubule.
• To me, this adds one more reason to at least think twice before reflexively ordering pip-tazo for every sick patient, especially when combined with vancomycin. The AKI association should be taken into account when creating sepsis order sets and treatment plans.

Dr. Josh Farkas (@PulmCrit) tackles the question ‘Is Piperacillin-Tazobactam Nephrotoxic?‘ on his blog at EMCrit.

Original: May 20, 2014; Updated: February 26, 2016, April 17, 2016, October 28, 2016

Additional publications since October 2016 update:

• Rutter WC, et al. Antimicrob Agents Chemother 2017.²³
• Rutter WC, et al. J Hosp Med 2017.²⁴
• Al Yami MS. J Infect Public Health 2017.²⁵
• LeCleir LK, et al. Pediatr Pulmonol 2017.²⁶ [pediatric cystic fibrosis]
• Jeon N, et al. Int J Antimicrob Agents 2017.²⁷
• Anderson CW, et al. Mil Med 2017.²⁸
• Holsen MR, et al. Pediatr Crit Care Med 2017.²⁹ [pediatric critically ill]
• Downes KJ, et al. JAMA Pediatr 2017.³⁰ [pediatrics]
• Luther MK, et al. Crit Care Med 2107.³¹ [systematic review and meta-analysis]
• Abouelkheir M, et al. Pediatr Int 2017.³² [pediatrics]
• Hundeshagen G, et al. Crit Care 2017.³³ [adult and pediatric burn patients]
• Clemmons AB, et al. Biol Blood Marrow Transplant 2018.³⁴ [Hematopoietic Cell Transplantation Patients]
• Mullins BP, et al. Ann Pharmacother 2018.³⁵ [Prospective, multicenter study]
• Cook KM, et al. J Pediatric Infect Dis Soc 2018.³⁶ [pediatric]
• Rutter WC, et al. Antimicrob Agents Chemother 2018.³⁷
• Chen XY, et al. Int Urol Nephrol 2018.³⁸ [systematic review and meta-analysis]
• Mellen CK, et al. Curr Drug Saf 2018.³⁹ [meta-analysis of observational trials]
• Carreno JJ, et al. Int J Antimicrob Agents 2018.⁴⁰
• Schreier DJ, et al. Clin Infect Dis 2018.⁴¹ [no increased risk if < 72 hours]
• Robertson AD, et al. Pharmacother 2018.⁴²
• Buckley AS, et al. J Crit Care 2018.⁴³ [ICU patients – no increased risk of AKI]
• Nuhait AL, et al. Acute Kidney Injury in Pediatric Treated with Vancomycin and Piperacillin-Tazobactam in Tertiary Care Hospital. Int J Pediatr 2018. [pediatric] [PubMed]
• Molina KC, et al. The Risk of Acute Kidney Injury in Critically Ill Patients Receiving Concomitant Vancomycin with Piperacillin-Tazobactam or Cefepime. J Intensive Car Med 2019. [PubMed]

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