Mortality of Patients With Sepsis Administered Piperacillin-Tazobactam vs Cefepime

Rishi Chanderraj; Andrew J. Admon; Ying He; Mark Nuppnau; Owen R. Albin; Hallie C. Prescott; Robert P. Dickson; Michael W. Sjoding

doi:10.1001/jamainternmed.2024.0581

Original Investigation

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May 13, 2024

Mortality of Patients With Sepsis Administered Piperacillin-Tazobactam vs Cefepime

Rishi Chanderraj, MD, MSc^1,2,3; Andrew J. Admon, MD, MSc, MPH^3,4,5; Ying He, PhD⁴; et al Mark Nuppnau, MSc⁴; Owen R. Albin, MD^1,3; Hallie C. Prescott, MD, MSc^3,4,5,6,7; Robert P. Dickson, MD^3,4,8; Michael W. Sjoding, MD, MSc^3,4,5,9

Author Affiliations Article Information

¹Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor
²Medicine Service, Infectious Diseases Section, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan
³Weil Institute for Critical Care Research & Innovation, Ann Arbor, Michigan
⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor
⁵Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor
⁶Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan
⁷Veterans Affairs Center for Clinical Management Research, Ann Arbor, Michigan
⁸Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor
⁹Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor

JAMA Intern Med. 2024;184(7):769-777. doi:10.1001/jamainternmed.2024.0581

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Key Points

Question In patients with sepsis without a specific indication for antianaerobic antibiotics, is use of a combination of vancomycin and piperacillin-tazobactam associated with increased mortality risk compared with a combination of vancomycin and cefepime?

Findings In this cohort study of 7569 patients with sepsis, an instrumental variable analysis using a 15-month piperacillin-tazobactam shortage as a natural experiment was conducted. The results found that treatment with vancomycin and piperacillin-tazobactam was associated with higher mortality than vancomycin combined with cefepime.

Meaning The findings of this study suggest that, for patients with sepsis not requiring antianaerobic antibiotics, a combination of vancomycin and piperacillin-tazobactam may pose a greater mortality risk than vancomycin and cefepime.

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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3 Comments for this article

EXPAND ALL

July 12, 2024

Estimates are likely biased due to collider bias

FERGUS HAMILTON, MRCP, PhD, FRCPath | University of Bristol

Dear Editor,

Instrumental variable (IV) analysis is a widely used technique in econometrics to estimate causal effects in the presence of confounding. A recent application of this technique was used in a high-profile analysis in this paper to estimate the effect of cefepime, a broad-spectrum antibiotic, on mortality in severe infection. There has been ongoing concern that piperacillin-tazobactam, another broad-spectrum antibiotic with greater anaerobic activity might be inferior to cefepime, however this has not been shown in randomized controlled trials. The authors used an international shortage of piperacillin-tazobactam as an instrument, as during this shortage period, cefepime was used as an alternative. The authors report a strong mortality effect (5% absolute increase) with piperacillin-tazobactam. In an attached paper (https://www.medrxiv.org/content/10.1101/2024.07.11.24310262v1), we closely examine this estimate and find it is likely conditional on inclusion of a control variable (metronidazole usage). Inclusion of this variable is highly likely to lead to collider bias, which we show via simulation. We then generate estimates unadjusted for metronidazole which are much closer to the null and may represent residual confounding or confounding by indication. We highlight the ongoing challenge of collider bias in empirical IV analyses and the potential for large biases to occur. We finally suggest the authors consider including these unadjusted estimates in their manuscript, as the large increase in mortality reported with piperacillin-tazobactam is unlikely to be true.

CONFLICT OF INTEREST: None Reported

July 19, 2024

Response to Hamilton et al. (2/2)

Rishi Chanderraj, MD | University of Michigan

3B) Drs. Hamilton and colleagues present as a potential explanation that anatomic sources of infection may differ between patients who received cefepime with and without metronidazole, driving differences in mortality, However, as reported in our manuscript, patients with suspected intraabdominal infections were excluded from our study because they may have a legitimate indication for anti-anaerobic antibiotics. We find no significant difference between sources of infection in aggregate (p = 0.2, Chi-square test) or by individual anatomic source (p >0.05 with t-test for all). Additionally, we accounted for differences in severity of illness by including the SOFA score in all our analyses, and the source of infection in our sensitivity analyses.

While some other unmeasured variable explaining some of the relationship between metronidazole use and mortality cannot be definitively excluded, we do not believe that the sources of bias considered in Dr. Hamilton’s post (severity of illness and confounding by indication due to source of infection) can fully account for the observed differences in mortality.

4) Finally, our analysis unadjusted for metronidazole use revealed an absolute mortality increase with piperacillin-tazobactam of 0.5% (95% CI 0.2% to 0.8%). If some of the observed relationship in our primary analysis is due to an unmeasured variable related to both metronidazole use and mortality (after adjusting for severity of illness and after excluding intrabdominal infections), the unbiased treatment effect is likely to be somewhere in between 0.5% and 5.0%. In a condition as common as sepsis with such high baseline mortality, even a modest increase in mortality (between 0.5% and 5.0%) could translate into thousands of lives lost or saved per year. Despite this conclusion, we would welcome prospective, randomized controlled trials to more conclusively determine the impact of gut anaerobe depletion on outcomes in sepsis.

CONFLICT OF INTEREST: None Reported

July 19, 2024

Response to Hamilton et al. (1/2)

Rishi Chanderraj, MD | University of Michigan

We thank Drs. Hamilton and colleagues for their comments and thoughtful consideration of our findings. While we disagree with their interpretation, we appreciate their good-faith effort to ensure instrumental variable analyses are performed rigorously. We here outline our primary points of divergence with their analysis.

1) Though unmentioned by Drs. Hamilton et al., our study’s secondary analysis used the drug shortage as an instrumental variable to test the effect of _any_ antibiotics with anti-anaerobic coverage, including metronidazole, on clinical outcomes. This analysis does not adjust for post-treatment variables and is not vulnerable to the type of collider bias highlighted by Drs. Hamilton and colleagues. As reported in our manuscript, results of this analysis were consistent with our primary findings.

2) In Dr. Hamilton and colleague’s analysis unadjusted for metronidazole, administration of piperacillin-tazobactam is associated with a point estimate of a 2.2% increase in mortality. While not statistically significant, this point estimate is 1) within our own reported confidence interval for mortality risk associated with piperacillin-tazobactam (1.9%-8.1%) and 2) comparable to the difference associated with anti-anaerobic antibiotics in two observational cohort studies (PMIDs: 36229047 and 37169379).

3) Our primary disagreement with Drs. Hamilton et al. is in our interpretation of the likely cause of the relationship between metronidazole exposure and mortality. Whereas we believe this relationship likely reflects a causal relationship (A, below), Drs. Hamilton et al. believe it represents collider bias and confounding by indication (B, below).

3A) We believe there is considerable face validity for a causal relationship between metronidazole and mortality, mediated via depletion of gut anaerobes. This is the core hypothesis that motivated our study. Considerable observational human data (PMIDs: 36229047 and 37169379) and multiple animal models (PMID: 26511795, 36229047,36229047 and 32801143) support this interpretation. While the results of human cohorts could be ascribed to confounding by indication, controlled animal models are immune from this criticism. Therefore, we do not believe the strong marginal association between metronidazole and mortality is entirely due to confounding by an unmeasured variable.

Given that metronidazole treatment represents a potential distinct causal pathway in our hypothesized mechanism (depletion of gut anaerobes mediating adverse clinical outcomes), we believe that _not_ accounting for concurrent anaerobe depletion would introduce contamination of our primary comparison. We hypothesize that this may explain the findings of the recent ACORN trial (PMID: 37837651). In ACORN, 47% of the cefepime arm received concurrent metronidazole, and 19% also received piperacillin-tazobactam, precluding any comparison of the effects of anti-anaerobic antibiotics. By not controlling for metronidazole usage, our study design would be more like ACORN, with a predictable impact on results.

CONFLICT OF INTEREST: None Reported

Mortality of Patients With Sepsis Administered Piperacillin-Tazobactam vs Cefepime

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