By Vibhu Sharma, MD

Attending Physician, Division of Pulmonary and Critical Care Medicine, John H. Stroger Hospital of Cook County, Assistant Professor of Medicine, Rush University Medical Center, Chicago

Dr. Sharma reports no financial relationships relevant to this field of study.

SYNOPSIS: In this retrospective study, a short course (24 to < 72 hours) of combination antibiotic therapy with piperacillin-tazobactam and vancomycin was not associated with an increased risk of acute kidney injury among critically ill patients when compared with other β-lactam and vancomycin combinations.

SOURCE: Schreier DJ, Kashani KB, Sakhuja A, et al. Incidence of acute kidney injury among critically ill patients with brief empiric use of antipseudomonal β-lactams with vancomycin. Clin Infect Dis 2019;68:1456-1462.

In this retrospective study, the authors attempted to define the incidence of acute kidney injury (AKI) with a short course (at least 24 but less than 72 hours of therapy) of β-lactam and vancomycin combination therapy in the critically ill. AKI was defined by the Acute Kidney Injury Network (AKIN) criteria based on both urine output and serum creatinine (SCr). The three antibiotic combinations assessed for outcomes were piperacillin-tazobactam/vancomycin (PTZ/VAN), cefepime/vancomycin (CEF/VAN), and meropenem/vancomycin (MER/VAN).

The authors created an electronic alert that continuously “sniffed” the medical record for changes in either urine output or baseline serum creatinine. Baseline SCr was defined as the median of all creatinine values in the preceding six months prior to the index admission during which exposure to the β-lactam/vancomycin combination occurred. The authors manually confirmed AKI when a “sniff” (i.e., electronic alert) popped up. The primary endpoint for the purpose of analysis was the incidence of AKI (stage 2 or 3). Secondary endpoints included maximal stage AKI and a composite of major kidney events 60 days after the start of therapy (MAKE60), consisting of a new need for renal replacement therapy (RRT), persistent doubling of serum creatinine at 60 days, or death. Researchers reviewed 5,791 patient records (regardless of ICU type) and they used 3,299 patient data sets for analysis. Exclusion criteria included use of more than one antipseudomonal drug, recent use of combination antibiotic therapy, presence of stage 2 or 3 AKI at baseline, or death within 48 hours of the start of therapy. Patients with end-stage renal disease also were excluded.

AKI incidence was assessed beginning 24 hours after the start of continuous concurrent therapy with one of the three antibiotic combination groups (PTZ/VAN, CEF/VAN, or MER/VAN). Logistic regression models were fit using AKI as the outcome variable and the three combination therapies as independent variables. One model was fit using a validated AKI risk score as a predictor variable that assigns points for chronic conditions, acute conditions, and nephrotoxin exposure in the intensive care unit. The second model used all patient and treatment variables as predictors thought to affect AKI risk.

All three combination antibiotic groups had similar characteristics at baseline, although the MER/VAN group had a slightly greater frequency of acidosis, anemia, sepsis, and need for mechanical ventilation. The overall incidence of any stage AKI was 34%, with most developing stage 1 AKI (26%). With unadjusted analysis, no increased risk of AKI stage 2 or 3 was found with short courses of PTZ/VAN when compared to short courses of CEF/VAN or MER/VAN. Similarly, the antibiotic group was not associated with an increased risk of stage 2 or 3 AKI in the multivariable models adjusting for baseline AKI risk.

The authors performed stratified analyses according to the presence or absence of stage 1 AKI at initiation of antibiotic therapy and similarly found no increased risk of stage 2 or 3 AKI development with any of the three combination antibiotic regimens. A numerically higher incidence of AKI stage 1 was noted in patients treated with PTZ/VAN relative to other groups, but was attributed to competitive inhibition of secretion of creatinine by piperacillin. With respect to the MAKE60 composite endpoint, there were no differences between groups. When stratified by MAKE60 subsets, there was an increased risk of death in the MER/VAN group, reflecting higher baseline disease severity.

COMMENTARY

Previous studies have raised concerns about combination antibiotic therapy and AKI risk, but they did not exclusively study critically ill patients and/or were meta-analyses of small, heterogeneous studies.1,2 A single-center, retrospective study that compared rates of AKI among critically ill patients receiving combination therapy (PTZ/VAN, CEF/VAN, or MER/VAN) showed increased odds of AKI using PTZ/VAN compared to the other groups.3 The groups were well-matched except most patients were in surgical intensive care units and more patients in the surgical/burn/trauma ICUs received PTZ/VAN. However, this study assessed AKI with three to five days of combination antibiotic therapy. The incidence of AKI in this study also increased as the vancomycin trough increased.

The study by Schreier et al reviewed here included a large cohort of critically ill patients from mixed ICU settings, used validated risk scores, and applied a rigorous multivariable model to determine risk. More than one-third of patients exposed to β-lactam/vancomycin developed AKI with a short course of therapy, with most of those developing stage 1 AKI. Additionally, when therapy was de-escalated rapidly, the risk of AKI was identical regardless of type of β-lactam/vancomycin combination chosen. It appears that if therapy lasts for less than three days, the risk of AKI is not different for the most commonly used β-lactam/vancomycin combinations regardless of the duration used inside the 72-hour “safe window.” This finding points to the importance of obtaining relevant cultures early to facilitate early antibiotic de-escalation, within 72 hours or sooner. However, practitioners still need to be aware of the higher risk of AKI with PTZ/VAN combinations in the critically ill when used for more than three days, especially in surgical ICU patients. In scenarios necessitating prolonged empiric therapy for MDR organisms, combination therapy other than PTZ/VAN may be appropriate.

REFERENCES

  1. Hammond DA, Smith MN, Li C, et al. Systematic review and meta-analysis of acute kidney injury associated with concomitant vancomycin and piperacillin/tazobactam. Clin Infect Dis 2017;64:666-674.
  2. Luther MK, Timbrook TT, Caffrey AR, et al. Vancomycin plus piperacillin-tazobactam and acute kidney injury in adults: A systematic review and meta-analysis. Crit Care Med 2018;46:12-20.
  3. Blevins AM, Lashinsky JN, McCammon C, et al. Incidence of acute kidney injury in critically ill patients receiving vancomycin with concomitant piperacillin-tazobactam, cefepime, or meropenem. Antimicrob Agents Chemother 2019;63. doi: 10.1128/AAC.02658-18.