Vanco zosynThere 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 cefriaxone, 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!

Peyko V, et al.6 (1st prospective study)

This is the first prospective study to evaluate the observed incidence of AKI. The authors conducted a prospective, open label cohort study at a community academic medical center involving adult patients over a 3-month time period who received either the combination of pip-tazo + vancomycin or the combination of cefepime or meropenem + vancomycin for greater than 72 hours. AKI was defined using specific criteria introduced by Kidney Disease: Improving global outcomes (KDIGO) acute kidney injury work group in 2012. 85 patients were enrolled (59 in the pip-tazo + vancomycin group). The incidence of AKI was significantly higher in the pip-tazo + vancomycin group (37.3%) compared with the cefepime or meropenem + vancomycin group (7.7%; χ2 = 7.80, P = .005). There was no difference in mean of steady state vancomycin trough levels between groups. The study did not reach the projected sample size of 120 patients and there were disproportionately more patients in the pip-tazo group, both decreasing the power of the study’s findings. Development of AKI was strictly by KDIGO definition and patients were not followed for the clinical significance of the AKI.

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. [Navalkele 2016]

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.11–17 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.18

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. Two meta-analyses, one with 963 patients and the other with 3,528 patients, drew the same conclusion.19,20
  • 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

Image credit

1.
Abstracts of the Society of Critical Care Medicine 41st Critical Care Congress. February 4-8, 2012. Houston, Texas, USA. Crit Care Med. 2011;39(12 Suppl):1-264. [PubMed]
2.
Moenster R, Linneman T, Finnegan P, Hand S, Thomas Z, McDonald J. Acute renal failure associated with vancomycin and β-lactams for the treatment of osteomyelitis in diabetics: piperacillin-tazobactam as compared with cefepime. Clin Microbiol Infect. 2014;20(6):O384-9. [PubMed]
3.
Gomes D, Smotherman C, Birch A, et al. Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin-tazobactam or cefepime. Pharmacotherapy. 2014;34(7):662-669. [PubMed]
4.
Meaney C, Hynicka L, Tsoukleris M. Vancomycin-associated nephrotoxicity in adult medicine patients: incidence, outcomes, and risk factors. Pharmacotherapy. 2014;34(7):653-661. [PubMed]
5.
Burgess L, Drew R. Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with and without concomitant piperacillin-tazobactam. Pharmacotherapy. 2014;34(7):670-676. [PubMed]
6.
Peyko V, Smalley S, Cohen H. Prospective Comparison of Acute Kidney Injury During Treatment With the Combination of Piperacillin-Tazobactam and Vancomycin Versus the Combination of Cefepime or Meropenem and Vancomycin. J Pharm Pract. February 2016. [PubMed]
7.
Karino S, Kaye K, Navalkele B, et al. Epidemiology of Acute Kidney Injury among Patients Receiving Concomitant Vancomycin and Piperacillin-Tazobactam: Opportunities for Antimicrobial Stewardship. Antimicrob Agents Chemother. 2016;60(6):3743-3750. [PubMed]
8.
Hammond D, Smith M, Painter J, Meena N, Lusardi K. Comparative Incidence of Acute Kidney Injury in Critically Ill Patients Receiving Vancomycin with Concomitant Piperacillin-Tazobactam or Cefepime: A Retrospective Cohort Study. Pharmacotherapy. 2016;36(5):463-471. [PubMed]
9.
Lorenz M, Moenster R, Linneman T. Effect of piperacillin/tazobactam restriction on usage and rates of acute renal failure. J Med Microbiol. 2016;65(2):195-199. [PubMed]
10.
McQueen K, Clark D. Does Combination Therapy With Vancomycin and Piperacillin-Tazobactam Increase the Risk of Nephrotoxicity Versus Vancomycin Alone in Pediatric Patients? J Pediatr Pharmacol Ther. 2016;21(4):332-338. [PubMed]
11.
Pill M, O’Neill C, Chapman M, Singh A. Suspected acute interstitial nephritis induced by piperacillin-tazobactam. Pharmacotherapy. 1997;17(1):166-169. [PubMed]
12.
Sakarcan A, Marcille R, Stallworth J. Antibiotic-induced recurring interstitial nephritis. Pediatr Nephrol. 2002;17(1):50-51. [PubMed]
13.
Mannaerts L, Van der, Wolfhagen F. [Interstitial nephritis attributed to treatment with piperacillin-tazobactam and with ciprofloxacin]. Ned Tijdschr Geneeskd. 2006;150(14):804-807. [PubMed]
14.
Bajaj P, Prematta M, Ghaffari G. A sixty-five-year-old man with rash, fever, and generalized weakness. Allergy Asthma Proc. 2011;32(1):e1-3. [PubMed]
15.
Elyasi S, Khalili H, Dashti-Khavidaki S, Mohammadpour A. Vancomycin-induced nephrotoxicity: mechanism, incidence, risk factors and special populations. A literature review. Eur J Clin Pharmacol. 2012;68(9):1243-1255. [PubMed]
16.
Liu T, Lam J. Piperacillin-tazobactam-induced acute interstitial nephritis with possible meropenem cross-sensitivity in a patient with osteomyelitis. Am J Health Syst Pharm. 2012;69(13):1109. [PubMed]
17.
Pratt J, Stricherz M, Verghese P, Burke M. Suspected piperacillin-tazobactam induced nephrotoxicity in the pediatric oncology population. Pediatr Blood Cancer. 2014;61(2):366-368. [PubMed]
18.
Navalkele B, Karino S, Pogue J, et al. Acute Kidney Injury in Patients on Concomitant Vancomycin and Piperacillin/Tazobactam: Are Extended Infusions to Blame? Open Forum Infect Dis. 2015;2(Suppl 1):128. [PubMed]
19.
Rindone J, Mellen C, Ryba J. Does Piperacillin-Tazobactam Increase The Risk Of Nephrotoxicity When Used With Vancomycin: A Meta-Analysis Of Observational Trials. Curr Drug Saf. October 2016. [PubMed]
20.
Giuliano C, Patel C, Kale-Pradhan P. Is the Combination of Piperacillin-Tazobactam and Vancomycin Associated with Development of Acute Kidney Injury? A Meta-analysis. Pharmacotherapy. November 2016. [PubMed]
Bryan D. Hayes, PharmD, FAACT

Bryan D. Hayes, PharmD, FAACT

Associate Editor, ALiEM
Creator and Lead Editor, CAPSULES series, ALiEMU
Clinical Pharmacist, EM and Toxicology, MGH