Journal Club: Comparison of Clinical Outcomes among Intensive Care Unit Patients Receiving One or Two Grams of

Ceftriaxone Daily
Morgan Smith, Pharm.D.
August 24th, 2020

BACKGROUND- THE STUDY QUESTION

Background  Ceftriaxone is a commonly prescribed beta-lactam antibiotic with bactericidal activity and extensive protein binding
o Pharmacokinetic properties and data suggest that patients within the ICU, including those with hypoalbuminemia,
may experience ceftriaxone underexposure
 Ceftriaxone is ~ 95% bound to albumin
 Ceftriaxone is a commonly used appropriate antibiotic choice for many ICU patients, specifically those with high suspicion
of pneumonia and/or urinary tract infections
o Antibiotic Prescription in Intensive Care Unit guidelines recommendations:
 Preferred regimen for empiric CAP treatment in patients requiring ICU admission (plus macrolide), if no
risk of P. aeruginosa infection
 Preferred regimen for empirical therapy in combination with doxycycline or macrolide for community
-acquired sepsis of unknown origin in ICU
Previous trials  Believe this study is the first to examine ceftriaxone clinical outcomes between 1g and 2g dosing in ICU patients.
Why this study?  Pharmacokinetic data suggest ICU patients may experience ceftriaxone underexposure, however clinical outcomes data are
lacking.
GENERAL STUDY OVERVIEW
Title/Citation Ackerman A, Zook NR, Siegrist JF, Brummitt CF, Cook MM, Dilworth TJ. 2020. Comparison of clinical outcomes among intensive
care unit patients receiving one or two grams of ceftriaxone daily. Antimicrob Agents Chemother 64:e00066-20.
Null hypothesis 2g of ceftriaxone daily would be associated with better clinical outcomes than 1g of ceftriaxone daily among ICU patients
Trial design Retrospective propensity matched cohort
Objectives To determine the impact of ceftriaxone dosing on clinical outcomes among ICU patients without central nervous system (CNS)
infection.
Enrollment Patients admitted to the ICU were enrolled between January 1, 2016 and January 1, 2018.

Inclusion criteria  Patients ≥ 18 years old

 IV empirical ceftriaxone
 Admitted to one of 7 ICUs within 5 different hospitals
o Medical ICU
o Surgical ICU
o Cardiac ICU
 Received ≤ 2g of empirical ceftriaxone IV daily for ≥ 72 hours during ICU admission
 At least one serum albumin concentration obtained within 24 hours of ceftriaxone initiation
Exclusion Excluded electronically:
criteria  Ceftriaxone duration <72 hours
 Ceftriaxone dose >2g daily
 No albumin level obtained within 24 hours of ceftriaxone initiation
 Diagnosis of meningitis
 Pregnancy
Excluded during chart review:
 Empiric coverage with alternative antibiotic for >24 hours
 Ceftriaxone prescribed for antibacterial prophylaxis
 Received both ceftriaxone 1g daily and ceftriaxone 2g daily
 Ceftriaxone-resistant pathogen
 Ceftriaxone dose 1g twice daily
Interventions Diagnoses were classified as either bacteremia, pneumonia, urinary tract infection (UTI), and other
 Patients with more than one diagnosis were placed in the most severe category
Bacterial culture data was collected and classified as gram-positive, gram-negative, mixed or culture negative
Monitoring  Clinical worsening vs. clinical improvement
 Culture data/results
Endpoints Primary endpoint:
 Composite outcome of treatment failure
o Inpatient mortality
o Antibiotic escalation
 Switching to an alternative antibiotic due to clinical worsening at any time during ceftriaxone
therapy
Secondary endpoints:
 ICU and hospital length of stay
 Adverse effects attributed to ceftriaxone
 Treatment success in those with hypoalbuminemia
  COFA scores >10
Statistical  A propensity score was developed using a multivariable logistic regression model (n=212)
analysis o Propensity score matching was done using a 1:1 nearest neighbor approach
o Treatment failure was assessed in the propensity-matched population
 Categorical variables:
o Person’s chi-square test
o Fisher’s exact test
 Continuous variables:
o Two-sample t test
o Mann-Whitney U test
 Multivariable analyses of factors associated with treatment failure were performed using logistic regression.
All tests were 2-tailed and a P value of ≤ 0.05 was considered statistically significant.

Baseline Patient data collected:

characteristics  Age
 Gender
 Height
 Weight
 Comorbidities
o As documented by the treating physician
Laboratory data:
 Albumin: concentration obtained closest to ceftriaxone initiation
 Creatine clearance: calculated using Cockcroft-Gault
o Upon ceftriaxone initiation
o 72 hours after initiation
Patient characteristics, stratified by ceftriaxone exposure, are presented in Table 1
Primary Composite outcome of treatment failure
outcome  Inpatient mortality
 Antibiotic escalation
Predictor variables associated with treatment failure may be found in Table 2
Secondary ICU and hospital length of stay
outcome Adverse effects attributed to ceftriaxone:
 Only 3 adverse effects were noted in the entire sample and there was no appreciable difference among the two
treatment arms.
Treatment success in patients with:
o Hypoalbuminemia (≤ 2.5 g/dl)
o SOFA scores of >10
AUTHORS’ CONCLUSIONS
ICU patients receiving empirical ceftriaxone were found to have a higher rate of treatment failure when receiving 1g daily when compared
to 2g daily, primarily due to antibiotic escalation. ICU patients prescribed empirical ceftriaxone for a non-CNS indication may benefit from
2g daily regardless of diagnosis and culture type.
STUDY CRITIQUE & DISCUSSIONS
Patient  Equal baseline patient characteristics
population/  Patients were identified from the electronic medical record
Design  Those with CNS infection were excluded from the study
 Retrospective review of adults admitted to ICU
o Reviewed and approved by the Aurora Health Care Research Subject Protection Program
o Performed in accordance with the Declaration of Helsinski
o Conforms to STROBE recommendations for reporting observational studies.
Intervention  Equal patients assigned to different treatment arms based on diagnosis
o Exception: higher number of patients with bacteremia were given 1g ceftriaxone vs. 2g daily
 72 hours vs 48 hours for determining antibiotic escalation- preliminary culture results
Endpoints  Primary and secondary endpoints were evaluated appropriately
Statistics  Treatment failure was more common among patients receiving 1g of ceftriaxone (19.8%) than those receiving 2g (6.6%)
daily. (p= 0.0156)
LEADER’S CONCLUSIONS
 Lack of generalizability: under evaluation of application to ICUC patients due to the lower SOFA scores reported. Additionally, admission to
the ICU was not defined.
 Selection bias: fair attempt to eliminate selection bias by utilization of propensity-score matching.