Mortality of Patients With Sepsis Administered Piperacillin-Tazobactam vs Cefepime

Abstract

ImportanceExperimental and observational studies have suggested that empirical treatment for bacterial sepsis with antianaerobic antibiotics (eg, piperacillin-tazobactam) is associated with adverse outcomes compared with anaerobe-sparing antibiotics (eg, cefepime). However, a recent pragmatic clinical trial of piperacillin-tazobactam and cefepime showed no difference in short-term outcomes at 14 days. Further studies are needed to help clarify the empirical use of these agents.ObjectiveTo examine the use of piperacillin-tazobactam compared with cefepime in 90-day mortality in patients treated empirically for sepsis, using instrumental variable analysis of a 15-month piperacillin-tazobactam shortage.Design, Setting, and ParticipantsIn a retrospective cohort study, hospital admissions at the University of Michigan from July 1, 2014, to December 31, 2018, including a piperacillin-tazobactam shortage period from June 12, 2015, to September 18, 2016, were examined. Adult patients with suspected sepsis treated with vancomycin and either piperacillin-tazobactam or cefepime for conditions with presumed equipoise between piperacillin-tazobactam and cefepime were included in the study. Data analysis was conducted from December 17, 2022, to April 11, 2023.Main Outcomes and MeasuresThe primary outcome was 90-day mortality. Secondary outcomes included organ failure–free, ventilator-free, and vasopressor-free days. The 15-month piperacillin-tazobactam shortage period was used as an instrumental variable for unmeasured confounding in antibiotic selection.ResultsAmong 7569 patients (4174 men [55%]; median age, 63 [IQR 52-73] years) with sepsis meeting study eligibility, 4523 were treated with vancomycin and piperacillin-tazobactam and 3046 were treated with vancomycin and cefepime. Of patients who received piperacillin-tazobactam, only 152 (3%) received it during the shortage. Treatment groups did not differ significantly in age, Charlson Comorbidity Index score, Sequential Organ Failure Assessment score, or time to antibiotic administration. In an instrumental variable analysis, piperacillin-tazobactam was associated with an absolute mortality increase of 5.0% at 90 days (95% CI, 1.9%-8.1%) and 2.1 (95% CI, 1.4-2.7) fewer organ failure–free days, 1.1 (95% CI, 0.57-1.62) fewer ventilator-free days, and 1.5 (95% CI, 1.01-2.01) fewer vasopressor-free days.Conclusions and RelevanceAmong patients with suspected sepsis and no clear indication for antianaerobic coverage, administration of piperacillin-tazobactam was associated with higher mortality and increased duration of organ dysfunction compared with cefepime. These findings suggest that the widespread use of empirical antianaerobic antibiotics in sepsis may be harmful.

Instrumental variable analysis: choice of control variables is critical and can lead to biased results

“…In our simulation study, we aimed to closely replicate the Chanderraj et al's analysis. 1 In the presented paper, they report that the IV strongly influences metronidazole (M) usage, alongside having a large eUect on the exposure (X). In our simulation, we have no causal eUect of the exposure on the outcome, so when analyses are run unadjusted for metronidazole, IV estimates are null (Figure 2).…”

“…We strongly suggest that consideration should be given to reporting the unadjusted results in the original manuscript. 1 Currently, readers of the manuscript might assume that cefepime is a far superior agent to piperacillin-tazobactam which is not likely to be the case.…”

“…UTI (no metronidazole, lower mortality) vs. intrabdominal or undiUerentiated sepsis (metronidazole, higher mortality)). We can strongly suspect this is the case, as metronidazole users had a strong marginal association with mortality in the reported logistic regression analysis (OR 1.54, 95% CI 1.32, 1.8, data from eTable 6 in the original publication 1 ). Simulated variables were generated in R for 5,000 participants, using the tidyverse package, and IV analysis was performed using the AER package to generate estimates.…”

“…In a recent issue of JAMA Internal Medicine, Chanderraj et al 1 provide an innovative analysis attempting to use a shortage of a widely used broad-spectrum antimicrobial, piperacillin-tazobactam (TZP), to conduct a comparative eUectiveness study versus cefepime (CPM), an agent used as a replacement during this period which has a similar spectrum of activity except less anaerobic activity. Their instrumental variable (IV) analysis 1 utilises the 'natural experiment' of substitution of TZP with CPM over this period in a manner which is, in principle, unrelated to other confounders. They hypothesize that the additional anti-anaerobic activity of TZP might lead to increased mortality via eUects on the microbiome or resistome.…”

Infection on Frail Patients in the Intensive Care Unit: Insights From the PalMuSIC Study

“…We also did not collect data on the adequacy of empirical antibiotic therapy, and this limits our conclusions. However, a large recently published study has enlightened that using large-spectrum antibiotics when there is no clear microbiological risk for the presence of difficult-to-treat bacteria may lead to a worse outcome [ 21 ].…”