By Richard R. Watkins, MD, MS, FACP, FIDSA
Professor of Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: A retrospective cohort study that included more than 7,000 patients with sepsis and no clear indication for anti-anaerobic coverage found receipt of piperacillin-tazobactam was associated with higher mortality and increased duration of organ dysfunction compared to cefepime.
SOURCE: Chanderraj R, Admon AJ, He Y, et al. Mortality of patients with sepsis administered piperacillin-tazobactam vs cefepime. JAMA Intern Med 2024;184:769-777.
When treating patients with sepsis, clinicians must balance choosing empirical antibiotic therapy that is broad enough to cover the likely causative pathogen(s), yet not create unnecessary risk from drug-related toxicity. Prior experimental models of bacterial sepsis have shown that treating with anti-anaerobic antibiotics leads to more adverse outcomes compared to anaerobic-sparing agents. Anti-anaerobic antibiotics are known to disrupt the gut microbiome, which can lead to detrimental downstream effects, such as immune system dysregulation and Clostridioides difficile infection (CDI). Therefore, Chanderraj and colleagues sought to determine whether there are differences in clinical outcomes for critically ill patients with sepsis treated with either cefepime or piperacillin-tazobactam who did not have an indication for anti-anaerobic coverage.
The study was a retrospective cohort study that used electronic medical records from a single healthcare system. Patients were included who were 18 years of age or older, presented to the emergency department (ED) with sepsis, met the modified Centers for Disease Control and Prevention (CDC) sepsis surveillance criteria, and received empiric therapy with vancomycin and either piperacillin-tazobactam or cefepime within the first 24 hours. Patients were excluded who were transferred from outside hospitals, for whom the infection source and antibiotic data were not available, and those with indications for anti-anaerobic therapy. The primary outcome measure was all-cause mortality within 90 days of ED presentation.
There were 7,569 patients included in the analysis, of whom 4,523 were treated with vancomycin and piperacillin-tazobactam, and 3,046 received vancomycin and cefepime. The median age of the patients was 63 years and 55% were male. The two groups were well balanced in terms of patient characteristics, such as age, comorbidities, Charlson Comorbidity Index, and sequential organ failure assessment (SOFA) score. Piperacillin-tazobactam was associated with a higher 90-day mortality (22.5%) compared to cefepime (17.5%; P = 0.002). Furthermore, piperacillin-tazobactam treatment resulted in 2.1 fewer organ failure-free days (95% confidence interval [CI], 1.4-2.7), 1.1 fewer ventilator-free days (95% CI, 0.57-1.62), and 1.5 fewer vasopressor-free days (95% CI, 1.01-2.01) compared to cefepime. A post-hoc analysis found no significant difference between piperacillin-tazobactam and cefepime in outcomes at 14 days.
The investigators performed a secondary sensitivity analysis for anti-anaerobic therapy (e.g., vancomycin plus cefepime and metronidazole or vancomycin plus piperacillin-tazobactam). Anti-anaerobic treatment was associated with a 12% or 14% increase in 90-day mortality, depending on the statistical model employed.
COMMENTARY
Sepsis is a serious illness with little margin for therapeutic error. Clinicians are understandably concerned about choosing appropriate antibiotic therapy, as there is clear evidence that this decision is crucial for optimal outcomes, including mortality. This makes it very tempting to prescribe broad-spectrum antibiotics when sepsis is first diagnosed, especially if the source is not readily apparent. Anaerobic pathogens typically cause infections in a limited number of anatomic sites, such as the abdomen (e.g., diverticulitis and cholecystitis), the skin (e.g., Fournier’s gangrene), the foot (e.g., diabetic foot infections), the head and neck (e.g., dental abscess), and CDI. Anaerobes sometimes show up in unexpected places (e.g., brain abscesses and endocarditis), but these infections often are more indolent than sepsis. Thus, it seems reasonable to assume that anti-anaerobic coverage often is not needed for many cases of sepsis. This brings to mind the ancient dictum of medicine to “first do no harm.”
Therefore, the study by Chanderraj and colleagues is important because it provides evidence that cefepime is a better choice for empirical treatment of sepsis compared to piperacillin-tazobactam when there is no clear indication for anaerobic coverage. This means most cases of urosepsis and pneumonia, the two most common etiologies of sepsis in hospitalized patients, should be treated with anaerobic-sparing antibiotics. Notably, the investigators found piperacillin-tazobactam was associated with an absolute mortality increase of 5.0% at 90 days. Thus, the combination of vancomycin and piperacillin-tazobactam may contribute to one additional death per every 20 patients treated for sepsis. This potentially translates into thousands of additional fatalities every year.
The study had some limitations. First, it was conducted at a single institution, so the results might not be generalizable to other geographic areas or patient populations. Second, the study relied on electronic medical records, making it susceptible to unobserved confounding variables. Third, it is not clear whether the observed effects are specific to piperacillin-tazobactam or if they also would have occurred with other anti-anaerobic agents (e.g., metronidazole and clindamycin).
The choice of empiric antibiotics in sepsis requires careful consideration, especially anti-anaerobic coverage. As the current study demonstrates, a nuanced approach that takes into account the potential off-target effects of antibiotics is necessary to ensure optimal outcomes. Further studies on anti-anaerobic therapy in sepsis are warranted.
