4. IMPORTANCE
• Cefepime and piperacillin-tazobactam are commonly used empirical
antibiotics administered to hospitalized adults.
• Regarding to side effects of the two antibiotics, specifically acute kidney injury
and neurological dysfunction, which one is safer?
• There has not been a RCT conducted to answer this question.
• Why these 2 antibiotics?
• Because cefepime and piperacillin-tazobactam have similar activity against many gram-negative bacteria
(efficacy), selection between the 2 is likely to depend on differences within their adverse effect profiles
(safety).
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5. OBJECTIVE
PICO approach:
Population: Adults hospitalized with acute infection
Intervention: Cefepime (anti-pseudomonal cephalosporins)
Comparison: Piperacillin-Tazobactam (anti-pseudomonal penicillins)
Outcome: Incidence of acute kidney injury or neurological dysfunction.
Research Question: In adults hospitalized with acute infection, does the choice
between cefepime and piperacillin-tazobactam affect the risks of acute kidney injury
or neurological dysfunction?
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6. Primary Hypothesis:
Among acutely ill patients with sepsis, use of anti-pseudomonal
cephalosporins (cefepime) will decrease the incidence of acute kidney
injury (AKI), compared to anti-pseudomonal penicillins (piperacillin-
tazobactam).
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8. Inclusion Criteria:
1. Age ≥ 18 years old
2. Located in a emergency department or medical intensive care unit
3. Less than 12 hours from presentation to study hospital
4. Treating clinician initiating an order for an anti-pseudomonal cephalosporin
(cefepime) or anti-pseudomonal penicillin (Piperacillin-Tazobactam).
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9. Exclusion Criteria:
1. Known receipt of > 1 dose of cefepime or Piperacillin-Tazobactam during the
last 7 days.
2. Current documented allergy to cephalosporins or penicillin
3. Known to be a prisoner
4. Either regimens is not required or contraindicated for the optimal treatment of the
patient, including for more directed antibiotic therapy against known prior resistant
infections or suspected sepsis with an associated central nervous system infection.
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10. Trial Design
A pragmatic, open-label, parallel-group, randomized comparative safety trial of
cefepime vs piperacillin-tazobactam in adult patients with suspected infection in the
emergency department (ED) or medical intensive care unit (ICU).
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11. Trial Design
Pragmatic: designed to determine the effectiveness of an intervention in real-world clinical practice
rather than in ideal conditions
Open-label: both the participants and the researchers know which treatment is being administered.
Parallel-group: participants are randomly assigned to one of two or more groups. Each group
receives a different treatment, and there is no crossover between groups during the trial.
Randomized: Using software within the electronic health record, patients were assigned via simple
randomization without stratification in a 1:1 ratio → helps to minimize selection bias and increase
the validity of the study results.
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12. Study Interventions:
Cefepime: 2-g intravenous push over 5 minutes every 8 hours
Piperacillin-tazobactam: 3.375-g bolus over 30 minutes for the initial
administration, followed by an extended infusion of 3.375 g every 8
hours infused over 4 hours for subsequent doses.
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13. Data Collection
1. Demographics and ethnicity
2. Diagnoses; pre enrollment kidney function;
3. Medication administration;
4. Vital signs; laboratory values; microbiological cultures; organ support therapies;
5. Sequential Organ Failure Assessment score
6. Confusion Assessment Method for the ICU (CAM-ICU) score;
7. Richmond Agitation-Sedation Scale (RASS) score ;
8. Glasgow Coma Scale score;
9. Dates of admission, transfer, and discharge;
10. Vital status at hospital discharge.
11. Presence of sepsis, using Sepsis-3 criteria.
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14. Primary Outcome
Death or The highest stage of acute kidney injury (AKI) arising between randomization and
day 14, using Kidney Disease: Improving Global Outcomes (KDIGO) AKI creatinine criteria.
• 0 = No AKI
• 1 = Stage 1 AKI (Creatinine increase by 1.5-1.9 times baseline OR increase by >= 0.3 mg/dL)
• 2 = Stage 2 AKI (Creatinine increase by 2.0-2.9 times baseline)
• 3 = Stage 3 AKI (Creatinine increase by >= 3.0 times baseline OR increase to >= 4.0 mg/dL
OR New kidney replacement therapy (KRT) )
• 4 = Death
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15. Two Secondary outcomes
First secondary outcome: a major adverse kidney event at day 14, which was the
composite of death, receipt of new KRT, or persistent kidney dysfunction (final
inpatient creatinine level that was ≥2 times the baseline level).
Second secondary outcome: the number of days alive and free of delirium and
coma within 14 days, which was defined as alive and without a positive
assessment on the CAM-ICU or a RASS score of −4 or −5.
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20. Primary Outcome
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The distribution of values for the highest stage of
acute kidney injury (AKI) or death between
enrollment and day 14 did not differ significantly
between the cefepime and piperacillin-tazobactam
groups (odds ratio, 0.95; 95% confidence interval,
0.80 to 1.13; P = 0.56).
24. Strengths
1. A large randomized clinical trial embedded within real-world clinical care through the
electronic health record.
2. The trial design included randomization to balance baseline characteristics,
concealment of group assignment until enrollment to prevent selection bias.
3. Enrollment occurring at a median of 1 hour after hospital presentation to minimize
exposure to antibiotics prior to enrollment.
4. Large enough sample size (1939 patients)
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25. Limitations
1. Conducting a trial at a single academic center may limit generalizability.
2. Patients and clinicians were not blinded to group assignment, which could have
affected clinical assessments like RASS and CAM-ICU or the frequency of laboratory
measurements like creatinine.
3. Confounding factor: almost 1 in 5 patients in each group received a least 1 dose of
the unassigned antibiotic within the first 14 days, which decreases the separation
between groups and increases the risk of failing to detect a true between-group
difference in the outcomes (type II error).
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26. Limitations
4. Outcome assessment was censored at hospital discharge, which means the study could
not fully evaluate the longer-term effects of the two antibiotics on kidney injury,
neurological issues, or death beyond the hospitalization period.
5. The current trial collected data on delirium and coma, but not other types of
neurological dysfunction that might be attributed to cefepime, such as agitation,
myoclonus, and seizures.
6. Small mean difference of only 0.3 days (odds ratio [OR], 0.79 [95% CI, 0.65-0.95])
in neurologic dysfunction.
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27. Areas for further investigation
Omission of the crucial difference of antimicrobial activity against anaerobic bacteria
between the 2 medications. Cefepime has no activity against anaerobic pathogens,
whereas piperacillin-tazobactam has potent antianaerobic activity, which leads to 2
consequences:
a. Piperacillin-tazobactam is more disruptive than cefepime to the gut microbiome →
more adverse outcomes
b. Given cefepime’s lack of antianaerobic activity, it is often co-administered with
other antianaerobic antibiotics (most commonly metronidazole) → confounding
effect
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29. GENERALIZABILITY TO OUR PATIENT POPULATION
● Age is limited from 42-68
● Study conducted in United States at an academic medical center with patients are mostly
White.
● There may be differences compared to Vietnamese patients in terms of underlying
comorbidities, infectious disease epidemiology, resistant organism patterns.
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30. Value the study would bring to local population
● The study suggests piperacillin-tazobactam may reduce neurological adverse events compared
to cefepime, which could:
- Improve patient safety/outcomes.
- Reduce delirium/agitation and need for sedation/antipsychotics.
- Potentially decrease lengths of stay.
● However, given many limitations and the cost of cefepime is cheaper.
● We conclude that piperacillin-tazobactam is not superior than cefepime and the choice of
either medication is up to their availability and the decision of clinicians
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