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Comparative Study
. 2024 Jul 1;184(7):769-777.
doi: 10.1001/jamainternmed.2024.0581.

Mortality of Patients With Sepsis Administered Piperacillin-Tazobactam vs Cefepime

Rishi Chanderraj  1   2   3 , Andrew J Admon  3   4   5 , Ying He  4 , Mark Nuppnau  4 , Owen R Albin  1   3 , Hallie C Prescott  3   4   5   6   7 , Robert P Dickson  3   4   8 , Michael W Sjoding  3   4   5   9
Affiliations
Comparative Study

Mortality of Patients With Sepsis Administered Piperacillin-Tazobactam vs Cefepime

Rishi Chanderraj et al. JAMA Intern Med. .

Abstract

Importance: Experimental 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.

Objective: To 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 participants: In 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 measures: The 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.

Results: Among 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 relevance: Among 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Admon reported receiving grants from the National Institutes of Health National Heart, Lung, and Blood Institute (NHLBI) during the study. Dr Albin reported receiving personal fees from Charles River Laboratories, Shiongi Pharmaceuticals, and the American College of Physicians, and grant funding from the Michigan Institute of Clinical & Health Research outside the submitted work. Dr Prescott reported receiving grants from the Agency for Healthcare Research and Quality, Veterans Affairs Health Services Research and Development, and the NHLBI; salary support from the Centers for Disease Control and Prevention and Blue Cross Blue Shield of Michigan outside the submitted work; and service on the Surviving Sepsis Campaign Guidelines. Dr Dickson reported receiving grants from the NHLBI. Dr Sjoding reported receiving grants from the NLHBI during the conduct of the study.

Figures

Figure 1.
Figure 1.. Cohort Creation Diagram for the Study of Piperacillin-Tazobactam Shortage and Sepsis
Claims data, medical records abstraction, microbiology test results, and radiology findings were used to identify a cohort with presumed equipoise between treatment groups.
Figure 2.
Figure 2.. Change in Antibiotic Use During Piperacillin-Tazobactam Shortage
Percentage of daily antibiotic use among hospitalized patients at University of Michigan during piperacillin-tazobactam shortage (June 12, 2015, to September 18, 2016) (calculated as number of doses of piperacillin-tazobactam administered in the hospital on a particular day divided by number of doses of all antibiotics administered in the hospital on a particular day.)
Figure 3.
Figure 3.. Ninety-Day Survival for Primary Cohort
Unadjusted analysis reveals a significant difference in 90-day survival among treatment groups. The inset shows the same data on an enlarged y-axis.
Figure 4.
Figure 4.. Primary Instrumental Variable and Sensitivity Analyses for 90-Day Mortality Among Adults Hospitalized With Suspected Sepsis Treated With Either Piperacillin-Tazobactam or Cefepime
Primary analysis and sensitivity analyses reveal a uniform effect of piperacillin-tazobactam. Whiskers indicate 95% CIs.
See this image and copyright information in PMC

References

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